Five-membered and six-membered compound, preparation method, pharmaceutical composition and application

Abstract

The invention discloses a five-membered to six-membered compound, a preparation method, a pharmaceutical composition and application. The invention provides a compound as shown in a formula I, and pharmaceutically acceptable salt or isotope compounds thereof. The compound provided by the invention has an inhibiting or / and degrading effect on IRAK4. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application date of June 15, 2023, application number 202380013793.8, and invention name "A five-membered and six-membered compound, preparation method, pharmaceutical composition and application".

[0002] This application claims priority to Chinese Patent Application No. 2022106755993 filed on June 15, 2022, Chinese Patent Application No. 2022116279194 filed on December 16, 2022, and Chinese Patent Application No. 202310658843X filed on June 5, 2023. This application cites the entire text of the above Chinese patent applications. Technical Field

[0003] The invention relates to a pentahedral and hexaahedral compound, a preparation method, a pharmaceutical composition and application. Background Art

[0004] Kinases have always been an important therapeutic target for the development of anti-inflammatory drugs (Current Opinion in Cell Biology 2009 21, 1-8). Interleukin-1 receptor-associated kinases (IRAKs) are serine / threonine protein kinases belonging to the tyrosine-like kinase (TLK) family. IRAKs are located downstream of the toll like receptor and IL-1R pathways, of which IRAK1 and IRAK4 have kinase activity. IRAK4 acts upstream of the IRAKs family kinase activation pathway and plays an important role in innate immune signal transduction (Science 1996, 271(5252): 1128-31). TLR stimulation can recruit myeloid differentiation primary response 88 (MYD88) and activate the receptor to form the Myddosome complex, which then forms a complex with IRAK4 to activate IRAK1. Subsequently, TRAF6 is activated by IRAK1, leading to the activation of NF-κB and AMPK signaling pathways, and ultimately leading to the expression of inflammatory cytokines (Molecules 2016, 21, 1529, J Biol Chem. 2018 Sep 28; 293(39): 15195-15207, Eur J. Immunol. 2008. 38: 614-618).

[0005] A very important feature of IRAK4 is that it has two functions: scaffolding and kinase phosphorylation in the TLR and IL-1R signaling pathways. The kinase domain (KD) provides kinase function, and the death domain (DD) provides scaffolding function for Myddosome (Molecules 2016, 21 (11), 1529). Myddosome is associated with a variety of diseases, not only autoimmune diseases and inflammatory diseases, but also cancer. For example, MYD88 mutations account for 39% of patients with active B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) and 86%-100% in several other types of B-cell malignancies and primary central nervous system lymphomas (Cell Chemical Biology 27, 1-10, December 17, 2020).

[0006] IRAK4 knockout mice and clinical pathological studies have shown that IRAK4 deficiency itself is not lethal, and individuals with IRAK4 mutations also have a protective effect on chronic lung disease and inflammatory bowel disease (Eur. J. Immunol. 2008. 38: 614–618). IRAK4 inhibitors have long been considered as targets for the treatment of immune diseases such as autoimmune diseases rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis (Expert Opinion on Therapeutic Patents Volume 29, 2019-Issue 4). At the same time, IRAK4 is also a popular target for the treatment of tumors, and there are currently a few IRAK4 kinase inhibitors that have entered the clinical stage. However, these clinical-stage drugs under development are inhibitors of IRAK4 kinase function (KD) and have no direct inhibitory effect on the scaffold function of IRAK4. Protein degraders (PROTACs) targeting IRAK4 are expected to simultaneously eliminate its kinase activity and scaffold function, thereby producing better and broader efficacy (Nature Biotechnology 2020, volume 38, pages 1221-1223, ACS Med Chem Lett. 2019 Jul 11; 10(7): 1081-1085). Summary of the invention

[0007] The present invention provides a pentad and hexaad compound, a preparation method, a pharmaceutical composition and an application thereof. The compound of the present invention has an inhibitory or / and degradation effect on IRAK4, has potential clinical application value, and is expected to improve the prognosis of patients and reduce the possibility of drug resistance.

[0008] The present invention provides a compound as shown in Formula I, and a pharmaceutically acceptable salt or isotope compound thereof;

[0009]

[0010] Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring; the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0011] for or

[0012] Q is C or N;

[0013] E is CH or N;

[0014] Y is C or N;

[0015] R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl, or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0016] Each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , cyano, nitro, unsubstituted or replaced by one or more R 1 -1-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-1-3 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R 1-1-8 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0017] Each R 1-1-1 , R 1-1-3 , R1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 are independently deuterium, halogen, oxo, hydroxyl, -SO2-R a 、-SO-R a , C1-C6 alkoxy, cyano, nitro, unsubstituted or substituted with one or more halogens, 1 -1-1-1 substituted 3- to 11-membered heterocycloalkyl, unsubstituted or substituted by one or more halogen or deuterium C1-C6 alkyl, 3- to 10-membered cycloalkyl, unsubstituted or substituted by one or more R 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R 1 -1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0018] Each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen, oxo, hydroxy, C1-C6 alkoxy or C1-C6 alkyl;

[0019] R 2 is hydrogen, hydroxy, cyano, halogen, unsubstituted or replaced by one or more R 2-3 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-2 Substituted C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-1 substituted 5- to 10-membered heteroaryl or unsubstituted or replaced by one or more R 2-4 substituted 4- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0020] Each R 2-1 , R 2-2 , R 2-3 and R 2-4 are independently halogen, hydroxy, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted with one or more halogens, or C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens;

[0021] R 3 is hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, -SO2-R a 、-SO-R a , unsubstituted or substituted with one or more R 3-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 substituted 3- to 10-membered cycloalkyl, unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-5 substituted 6 to 10 membered aryl, unsubstituted or substituted with one or more R 3-6 substituted 5- to 10-membered heteroaryl, 3-8 Substituted hydroxyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or -O-COR a The heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0022] Each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently deuterium, halogen, oxo, hydroxy, unsubstituted or substituted with one or more R 3-1-1 substituted 3- to 11-membered heterocycloalkyl, Cyano, unsubstituted or substituted with one or more R 3-1-3 Substituted alkoxy, unsubstituted or substituted with one or more R 3-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-1-5 Substituted 3- to 10-membered cycloalkyl, -SO2-R a 、-SO-R a , 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0023] R 3-8is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0024] Each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 are independently C1-C6 alkyl, halogen, oxo or hydroxy which are unsubstituted or substituted with one or more halogens;

[0025] Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl;

[0026] or R a and R b Together with the atoms connected thereto, a 3- to 11-membered heterocyclic ring is formed; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0027] Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0028] L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3substituted 5- to 12-membered heterocycloalkylene; the 5- to 12-membered cycloalkylene is bicyclic or polycyclic; the 5- to 12-membered heterocycloalkylene is a monocyclic, bicyclic or polycyclic compound; the heteroatoms of the 5- to 12-membered cycloalkylene are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently deuterium, hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted with one or more halogen or deuterium, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens or deuterium; each L0 -3 are independently deuterium, hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted with one or more halogen or deuterium, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens or deuterium;

[0029] L2 is the connecting subunit (connecting LLM to L0);

[0030] When L0 is When L2 contains at least one or more of the following fragments: Not substituted or replaced by one or more L2 1-1 Replaced a and b are independently 1 or 2, m is an integer of 1-4, q is an integer of 1-6, and X is O; L2 1-1 is halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or

[0031] Each R c are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl;

[0032] Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0033] LLM

[0034] Cyclo 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 3-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo;

[0035] Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 12-membered heterocycloalkyl, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 4-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo;

[0036] Cyclo 5 is unsubstituted or replaced by one or more Cy 5-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 5-1 are independently C1-C6 alkyl, hydroxy or oxo;

[0037] Cyclo 6 is unsubstituted or replaced by one or more Cy 6-1 Substituted 6- to 10-membered aromatic ring; Cy 6-1 are independently C1-C6 alkyl, hydroxyl or halogen;

[0038] Cyclo 7 is unsubstituted or replaced by one or more Cy 7-1 A substituted 5- to 9-membered heteroaromatic ring; the heteroatoms of the 5- to 9-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 7-1 are independently C1-C6 alkyl, hydroxyl or halogen;

[0039] R 4are independently hydrogen, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens;

[0040] p is 0, 1, 2 or 3;

[0041] Each R 5 are independently halogen;

[0042] L3 is unsubstituted or replaced by one or more L3 -1 Replaced Wherein, m is an integer of 1-4, q is an integer of 1-6, and X is absent or 0; L3 -1 and C1-C6 alkyl which is independently halogen or unsubstituted or substituted by one or more halogens.

[0043] The present invention provides a compound as shown in Formula I, and a pharmaceutically acceptable salt or isotope compound thereof;

[0044]

[0045] Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring; the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0046] for or

[0047] Q is C or N;

[0048] E is CH or N;

[0049] Y is C or N;

[0050] R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl, or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0051] Each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , cyano, nitro, unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-1-3Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R 1-1-8 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0052] Each R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 are independently halogen, oxo, hydroxyl, -SO2-R a 、-SO-R a , C1-C6 alkoxy, cyano, nitro, unsubstituted or substituted with one or more halogens, 1 -1-1-1 substituted 3- to 11-membered heterocycloalkyl, unsubstituted or substituted by one or more halogen C1-C6 alkyl, 3- to 10-membered cycloalkyl, unsubstituted or substituted by one or more R 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R 1-1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0053] Each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen, oxo, hydroxy, C1-C6 alkoxy or C1-C6 alkyl;

[0054] R 2 is hydrogen, hydroxy, cyano, halogen, unsubstituted or replaced by one or more R 2-3 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-2 Substituted C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-1substituted 5- to 10-membered heteroaryl or unsubstituted or replaced by one or more R 2-4 substituted 4- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0055] Each R 2-1 , R 2-2 , R 2-3 and R 2-4 are independently halogen, hydroxy, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted with one or more halogens, or C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens;

[0056] R 3 is hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, -SO2-R a 、-SO-R a , unsubstituted or substituted with one or more R 3-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 substituted 3- to 10-membered cycloalkyl, unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-5 substituted 6 to 10 membered aryl, unsubstituted or substituted with one or more R 3-6 substituted 5- to 10-membered heteroaryl, 3-8 Substituted hydroxyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or -O-COR a The heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0057] Each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently deuterium, halogen, oxo, hydroxy, unsubstituted or substituted with one or more R 3-1-1 substituted 3- to 11-membered heterocycloalkyl, Cyano, unsubstituted or substituted with one or more R 3-1-3 Substituted alkoxy, unsubstituted or substituted with one or more R 3-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-1-5 Substituted 3- to 10-membered cycloalkyl, -SO2-R a 、-SO-R a , 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0058] R 3-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0059] Each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 are independently C1-C6 alkyl, halogen, oxo or hydroxy which are unsubstituted or substituted with one or more halogens;

[0060] Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl;

[0061] or R a and R b Together with the atoms connected thereto, a 3- to 11-membered heterocyclic ring is formed; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0062] Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0063] L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene; the 5- to 12-membered cycloalkylene is bicyclic or polycyclic; the 5- to 12-membered heterocycloalkylene is a monocyclic, bicyclic or polycyclic compound; the heteroatoms of the 5- to 12-membered cycloalkylene are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; each L0 -3 are independently hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens;

[0064] L2 is the connecting subunit (connecting LLM to L0);

[0065] When L0 is When L2 contains at least one or more of the following fragments: Not substituted or replaced by one or more L2 1-1 Replaced a and b are independently 1 or 2, m is an integer of 1-4, q is an integer of 1-6, and X is O; L2 1-1 is halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or

[0066] Each R c are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl;

[0067] Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0068] LLM

[0069] Cyclo 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 3-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo;

[0070] Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 12-membered heterocycloalkyl, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 4-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo;

[0071] Cyclo 5 is unsubstituted or replaced by one or more Cy 5-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 5-1 are independently C1-C6 alkyl, hydroxy or oxo;

[0072] Cyclo 6 is unsubstituted or replaced by one or more Cy 6-1 Substituted 6- to 10-membered aromatic ring; Cy 6-1 are independently C1-C6 alkyl, hydroxyl or halogen;

[0073] Cyclo 7 is unsubstituted or replaced by one or more Cy 7-1 A substituted 5- to 9-membered heteroaromatic ring; the heteroatoms of the 5- to 9-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 7-1 are independently C1-C6 alkyl, hydroxyl or halogen;

[0074] R 4 are independently hydrogen, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens;

[0075] p is 0, 1, 2 or 3;

[0076] Each R 5 are independently halogen;

[0077] L3 is unsubstituted or replaced by one or more L3 -1 Replaced Wherein, m is an integer of 1-4, q is an integer of 1-6, and X is absent or 0; L3 -1 and C1-C6 alkyl which is independently halogen or unsubstituted or substituted by one or more halogens.

[0078] In a preferred embodiment, the five-membered and six-membered compound as shown in formula I, its pharmaceutically acceptable salt or isotope compound; the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any of the above embodiments (hereinafter referred to as "in a certain embodiment"): LLM is a group binding to a ligase; the ligase may be an E3 ligase, preferably VHL, CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, APC, UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3 B. UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-Tr CP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RN F128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb1 / MIB1, Mind Bomb 2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, more preferably VHL, CRBN, MDM2 or cIAP.

[0079] In a preferred embodiment, the linker unit may be a conventional linker unit in the art. Preferably, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 、L2-2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not substituted or replaced by one or more L2 1-3 Replaced m is an integer of 1-4, q is an integer of 1-6, X is absent or O; Cy 1 is a 4- to 12-membered heterocyclic ring or a 3- to 12-membered cycloalkane; 2 is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring; the heteroatoms of the 4- to 12-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0080] L2 1-1 and L2 1-2 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or

[0081] L2 1-3 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, cyano, Not substituted or replaced by one or more L2 1-3-1 Substituted 3 to 10 membered cycloalkyl, unsubstituted or substituted with one or more L2 1-3-2 substituted 3- to 11-membered heterocycloalkyl, -SO2-R a 、-SO-R a , or hydroxyl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0082] Each L2 1-3-1 and L2 1-3-2 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, hydroxy, oxo or

[0083] Each Rc are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl;

[0084] Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;

[0085] Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl;

[0086] Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0087] In a preferred embodiment, when the ring Cy is a 5-membered heterocyclic ring, the number of heteroatoms in the 5-membered heterocyclic ring is 0 and 1, and the 5-membered heterocyclic ring is preferably a tetrahydrofuran ring.

[0088] In a preferred embodiment, when ring Cy is a 5-membered heteroaromatic ring, the heteroatoms of the 5-membered heteroaromatic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the 5-membered heteroaromatic ring is preferably a pyrrole ring, a pyrazole ring, a thiazole ring, an oxazole ring or an imidazole ring.

[0089] In a preferred embodiment, when R 1 is unsubstituted or substituted with one or more R 1-1 When the 5- to 10-membered heteroaryl is substituted, the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5- to 10-membered heteroaryl may be oxazolyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl or pyrazolopyrimidinyl, for example, pyridyl, oxazolyl, pyrazolyl or

[0090] In a preferred embodiment, when R 1 is unsubstituted or substituted with one or more R 1-2 In the case of a substituted 6- to 10-membered aryl group, the 6- to 10-membered aryl group is preferably a phenyl group or a naphthyl group.

[0091] In a preferred embodiment, when each R 1-1 and R 1-2 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine; for example fluorine.

[0092] In a preferred embodiment, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-1 In the case of a substituted 3- to 11-membered heterocycloalkyl, the 3- to 11-membered heterocycloalkyl may be a 4- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; each R 1-1-1 Preferably, the 3- to 11-membered heterocycloalkyl radical is independently halogen, hydroxy, oxo, C1-C6 alkoxy radical which is unsubstituted or substituted by one or more halogen radicals, or C1-C6 alkyl radical which is unsubstituted or substituted by one or more halogen radicals; the 3- to 11-membered heterocycloalkyl radical is preferably piperazinyl, piperazinylene, piperidinyl, tetrahydropyrrolyl, oxetanyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example

[0093] In a preferred embodiment, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-3 When the C1-C6 alkoxy is substituted, the C1-C6 alkoxy may be a C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; each R 1-1-3 Independently preferred are halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0094] In a preferred embodiment, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-4 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; each R 1-1-4 Independently preferred are halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0095] In a preferred embodiment, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-5 When the 3- to 10-membered cycloalkyl group is substituted, the 3- to 10-membered cycloalkyl group may be a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each R 1-1-5 Independently preferred are halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0096] In a preferred embodiment, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-7 When the 5- to 10-membered heteroaryl is substituted, the heteroatom of the 5- to 10-membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; each R 1 -1-7 Independently preferably, halogen, hydroxyl, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; the 5 to 10 membered heteroaryl may be pyridyl, pyridylene, pyridazinyl, pyrazinyl, pyrimidinyl or triazinyl, for example pyridyl or pyridylene.

[0097] In a preferred embodiment, when each R1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-8 When the 6- to 10-membered aryl group is substituted, the 6- to 10-membered aryl group is preferably phenyl or naphthyl; each R 1-1-8 Independently preferred are halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0098] In a preferred embodiment, when each R 1-1-1 and R 1-1-7 When independently unsubstituted or substituted by one or more halogen-substituted C1-C6 alkyl groups, the C1-C6 alkyl groups may be C1-C4 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups.

[0099] In a preferred embodiment, when each R 1-1-4 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0100] In a preferred embodiment, when R 2 When halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0101] In a preferred embodiment, when R 2 is unsubstituted or substituted with one or more R 2-1 When the substituted 5- to 10-membered heteroaryl group is a substituted 5- to 10-membered heteroaryl group, the heteroatom of the 5- to 10-membered heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3; the 5- to 10-membered heteroaryl group is preferably a pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl or triazinyl group, for example pyridyl.

[0102] In a preferred embodiment, when R 2 is unsubstituted or substituted with one or more R 2-2 In the case of a substituted C1-C6 alkoxy group, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0103] In a preferred embodiment, when R 2 is unsubstituted or substituted with one or more R 2-3 In the case of a substituted C1-C6 alkyl group, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0104] In a preferred embodiment, when R 2 is unsubstituted or substituted with one or more R 2-4When the 4- to 10-membered heterocycloalkyl is substituted, the 4- to 10-membered heterocycloalkyl may be a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 4- to 10-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocycloalkyl is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example

[0105] In a preferred embodiment, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine; for example fluorine.

[0106] In a preferred embodiment, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently a C1-C6 alkyl group is unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halogen may be fluorine, chlorine, bromine or iodine; for example, fluorine.

[0107] In a preferred embodiment, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, and also such as a methoxy group; the halogen group may be fluorine, chlorine, bromine or iodine, such as fluorine.

[0108] In a preferred embodiment, when R 3 When halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0109] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-1When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl may be a 3- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are preferably N and / or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl is preferably piperidinyl, tetrahydropyrrolyl, tetrahydropyrrolylene, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, morpholinyl, tetrahydropyranyl, oxetanyl, azabicyclo[2.2.1]heptyl or diazabicyclo[2.2.1]heptyl; each R 3-1 is independently preferably halogen, oxo or hydroxy, such as hydroxy; the unsubstituted or substituted with one or more R 3-1 The substituted 3 to 8 membered heterocycloalkyl group is preferably

[0110] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-2 When the 3- to 10-membered cycloalkyl is substituted, the 3- to 10-membered cycloalkyl may be a C3-C6 cycloalkyl, or a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, a cyclopropyl, cyclobutyl or cyclohexyl; each R 3-2 is independently preferably halogen or hydroxy; unsubstituted or substituted by one or more R 3-2 The substituted 3- to 10-membered cycloalkyl group is preferably

[0111] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-4 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, tert-butyl, n-pentyl, isopentyl, primary pentyl, secondary pentyl, tert-pentyl or neopentyl, and may also be methyl, ethyl, propyl, isopropyl or isopentyl; each R 3-4 are independently preferably halogen, hydroxyl, -SO2-R a or R a is C1-C6 alkyl, R b is hydrogen; said unsubstituted or replaced by one or more R 3-4 The substituted C1-C6 alkyl group may be

[0112] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-4When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, tert-butyl, n-pentyl, isopentyl, primary pentyl, secondary pentyl, tert-pentyl or neopentyl, and may also be methyl, ethyl, propyl, isopropyl or isopentyl; each R 3-4 Preferably, deuterium, halogen, hydroxyl, -SO2-R a or R a is C1-C6 alkyl, R b is hydrogen; said unsubstituted or replaced by one or more R 3-4 The substituted C1-C6 alkyl group may be

[0113] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-7 When the C1-C6 alkoxy is substituted, the C1-C6 alkoxy may be a C1-C4 alkoxy, or may be a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, or may be a methoxy, ethoxy or isopropoxy; each R 3-7 is independently preferably halogen; the unsubstituted or substituted with one or more R 3-7 The substituted C1-C6 alkoxy group is preferably a methoxy group, isopropoxy or trifluoromethoxy.

[0114] In a preferred embodiment, when R 3 is unsubstituted or substituted with one or more R 3-7 When the C1-C6 alkoxy is substituted, the C1-C6 alkoxy may be a C1-C4 alkoxy, or may be a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, or may be a methoxy, ethoxy or isopropoxy; each R 3-7 is independently preferably deuterium or halogen; the unsubstituted or substituted with one or more R 3-7 The substituted C1-C6 alkoxy group is preferably a methoxy group, isopropoxy or trifluoromethoxy.

[0115] In a preferred embodiment, when R 3 For R 3-8 When the hydroxyl group is substituted, R 3-8 It can be a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, wherein the heteroatom of the 3- to 6-membered heterocycloalkyl is oxygen and the number of heteroatoms is 1; 3-8 The substituted hydroxyl group is preferably

[0116] In a preferred embodiment, when R 3 for When R a Can be H.

[0117] In a preferred embodiment, when each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0118] In a preferred embodiment, when each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently unsubstituted or substituted with one or more R 3-1-1 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl may be a 5- to 8-membered heterocycloalkyl, wherein the heteroatoms of the 3- to 11-membered heterocycloalkyl are preferably N and / or O, and the number of heteroatoms is 1 or 2; the unsubstituted or substituted with one or more R 3-1-1 The substituted 3- to 11-membered heterocycloalkyl is preferably tetrahydropyrrolyl, oxetanyl or contains one oxygen and / or one azoheptanyl, for example

[0119] In a preferred embodiment, when each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 When the C1-C6 alkyl group is independently unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group or an ethyl group.

[0120] In a preferred embodiment, when each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0121] In a preferred embodiment, when L0 is unsubstituted or replaced by one or more L0 -2 When the 5- to 12-membered cycloalkylene is substituted, the 5- to 12-membered cycloalkylene may be a spirocyclic, a bridged or a fused cyclic, or may be a, b, c and d are independently 0, 1 or 2; for example

[0122] In a preferred embodiment, when L0 is unsubstituted or replaced by one or more L0 -2 When the 5- to 12-membered cycloalkylene is substituted, the 5- to 12-membered cycloalkylene may be a spirocyclic, a bridged or a fused cyclic, or may be a, b, c and d are independently 0, 1 or 2; for example The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0123] In a preferred embodiment, when L0 is unsubstituted or replaced by one or more L0 -3 When the 5- to 12-membered heterocycloalkylene is substituted, the 5- to 12-membered heterocycloalkylene may be a monocyclic, spirocyclic, bridged or fused ring, or may be U and V are independently CH or N, and at least one is N, and a, b, c and d are independently 0, 1 or 2; for example

[0124] In a preferred embodiment, when L0 is unsubstituted or replaced by one or more L0 -3 When the 5- to 12-membered heterocycloalkylene is substituted, the 5- to 12-membered heterocycloalkylene may be a monocyclic, spirocyclic, bridged or fused ring, or may be U and V are independently CH or N, and at least one is N, and a, b, c and d are independently 0, 1 or 2; for example The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0125] In a preferred embodiment, when each L0 -2 When independently a C1-C6 alkyl group is unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-butyl, sec-butyl or tert-butyl, or may be methyl, ethyl or isopropyl; the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0126] In a preferred embodiment, when each L0 -2 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0127] In a preferred embodiment, when each L0 -2 When independently C1-C6 alkoxy is unsubstituted or substituted by one or more halogens, the halogens may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0128] In a preferred embodiment, when each L0 -2 When the C1-C6 alkoxy group is independently unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, or a methoxy group, an ethoxy group or an isopropoxy group.

[0129] In a preferred embodiment, when each L0 -3 When independently a C1-C6 alkyl group is unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-butyl, sec-butyl or tert-butyl, or may be methyl, ethyl or isopropyl; the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0130] In a preferred embodiment, when each L0 -3 When independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0131] In a preferred embodiment, when each L0 -3 When independently C1-C6 alkoxy is unsubstituted or substituted by one or more halogens, the halogens may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0132] In a preferred embodiment, when each L0 -3 When the C1-C6 alkoxy group is independently unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, or a methoxy group, an ethoxy group or an isopropoxy group.

[0133] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0134] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-2 When the 3 to 10 membered cycloalkyl group is substituted, the 3 to 10 membered cycloalkyl group may be a 3 to 6 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0135] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-3 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl may be a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example

[0136] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-3 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl may be a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl.

[0137] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-4 In the case of the substituted 6- to 10-membered aryl group, the 6- to 10-membered aryl group may be a benzene ring or a naphthalene ring.

[0138] In a preferred embodiment, when each R a and each R b are independently unsubstituted or substituted with one or more R a-5 When the 5- to 10-membered heteroaryl is substituted, the 5- to 10-membered heteroaryl may be a 5-membered heteroaryl or a 6-membered heteroaryl; the 6-membered heteroaryl is preferably a pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl or triazinyl; the 5-membered heteroaryl is preferably a pyrazolyl, thiazolyl or imidazolyl.

[0139] In a preferred embodiment, in the ring Cy 3In the above, the 5- to 12-membered heterocyclic ring may be a 5- to 6-membered heterocyclic ring, the heteroatom of the 5- to 12-membered heterocyclic ring is preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring.

[0140] In a preferred embodiment, in Cy 3-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0141] In a preferred embodiment, in the ring Cy 4 In the above, the 5- to 12-membered heterocyclic ring may be a 5- to 6-membered heterocyclic ring, the heteroatoms of the 5- to 6-membered heterocyclic ring are preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example a piperidine ring.

[0142] In a preferred embodiment, in Cy 4-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0143] In a preferred embodiment, in the ring Cy 5 In the above, the 5- to 12-membered heterocyclic ring may be a 5- to 6-membered heterocyclic ring, the heteroatom of the 5- to 12-membered heterocyclic ring is preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring.

[0144] In a preferred embodiment, in Cy 5-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0145] In a preferred embodiment, in Cy 6 In the above, the 6- to 10-membered aromatic ring may be a benzene ring or a naphthalene ring.

[0146] In a preferred embodiment, in Cy 6-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0147] In a preferred embodiment, in Cy 6-1In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0148] In a preferred embodiment, in the ring Cy 7 In the embodiment, the 5- to 9-membered heteroaromatic ring may be a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring is preferably a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring; the 5-membered heteroaromatic ring is preferably a pyrazole ring, an oxazole ring, a thiazole ring or an imidazole ring, for example

[0149] In a preferred embodiment, in Cy 7-1 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0150] In a preferred embodiment, in Cy 7-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group.

[0151] In a preferred embodiment, in R 4 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, or may be a tert-butyl group.

[0152] In a preferred embodiment, in R 4 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0153] In a preferred embodiment, in R 5 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0154] In a preferred embodiment, in L3 -1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group.

[0155] In a preferred embodiment, when the ring Cy 1 When it is a 5- to 12-membered heterocyclic ring; the heteroatom of the 5- to 12-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be an oxetane ring, a diazaspiro[3.3]heptane, a tetrahydrofuran ring, a piperidine ring, a piperazine ring, a diazaspiro[3.5]nonane, an azaspiro[3.3]heptane, a diazaspiro[5.5]undecane, an azaspiro[3.5]nonane or an azaspiro[5.5]undecane.

[0156] In a preferred embodiment, when the ring Cy 1 When it is a 3- to 12-membered cycloalkane, the 3- to 12-membered cycloalkane may be a 3- to 6-membered cycloalkane, such as cyclohexane.

[0157] In a preferred embodiment, when the ring Cy 2 When it is a 5- to 10-membered heteroaromatic ring; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the 5- to 10-membered heteroaromatic ring is preferably a 5- or 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring is preferably a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring; the 5-membered heteroaromatic ring is preferably a pyrazole ring, a thiazole ring or an imidazole ring.

[0158] In a preferred embodiment, in L2 1-1 and L2 1-2 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0159] In a preferred embodiment, in L2 1-1 and L2 1-2 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, or may be a methoxy group, an ethoxy group or an isopropoxy group.

[0160] In a preferred embodiment, in L2 1-1 and L2 1-2 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0161] In a preferred embodiment, in L2 1-3 In the above, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0162] In a preferred embodiment, in L2 1-3 In the C1-C6 alkyl group which is unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group; and the halogen group is preferably fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0163] In a preferred embodiment, in L2 1-3In the C1-C6 alkoxy group which is unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, or a methoxy group, an ethoxy group or an isopropoxy group; and the halogen group is preferably fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0164] In a preferred embodiment, when L2 1-3 wherein said unsubstituted or replaced by one or more L2 1-3-1 In the substituted 3- to 10-membered cycloalkyl, the 3- to 10-membered cycloalkyl may be a C3-C6 cycloalkyl, or a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, a cyclopropyl, cyclobutyl or cyclohexyl; each L2 1-3-1 Independently preferred are halogen or hydroxy.

[0165] In a preferred embodiment, in L2 1-3 wherein said unsubstituted or replaced by one or more L2 1-3-2 In the substituted 3- to 11-membered heterocycloalkyl, the 3- to 11-membered heterocyclic ring may be a 4- to 9-membered heterocyclic ring, and the heteroatoms of the 4- to 9-membered heterocyclic ring are preferably one or more of N, S and O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, such as a piperidine ring.

[0166] In a preferred embodiment, in L2 1-3-1 and L2 1-3-2 In the above, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, or may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, or may be a methoxy group, an ethoxy group or an isopropoxy group.

[0167] In a preferred embodiment, when R c is unsubstituted or substituted with one or more R c-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0168] In a preferred embodiment, in LLM, p is 0 or 1.

[0169] In a preferred embodiment, in L2, m is 1 or 2.

[0170] In a preferred embodiment, in L2, q is 1 or 2.

[0171] In a preferred embodiment, in L3, m is 1 or 2.

[0172] In a preferred embodiment, in L3, q is 1 or 2.

[0173] In the present invention, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1 -1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the 6- to 10-membered aryl groups may independently be phenyl or naphthyl.

[0174] In the present invention, in R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the C1-C6 alkoxy group may independently be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, and also a methoxy group.

[0175] In the present invention, in R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , Ra-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the halogen may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0176] In the present invention, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1 -1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the C1-C6 alkyl group may independently be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a prim-butyl group, a sec-butyl group or a tert-butyl group, or may be a methyl group, an ethyl group or an isopropyl group.

[0177] In the present invention, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1 -1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5In the above, the 3- to 11-membered heterocycloalkyl group may be independently a 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, an 8-membered heterocycloalkyl group or a 7-membered heterocycloalkyl group, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the 6-membered heterocycloalkyl group is preferably a piperazinyl group, a morpholinyl group or a piperidinyl group, for example The 5-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, for example The 8-membered heterocycloalkyl group is preferably azabicyclo[2.2.2]octyl or -azabicyclo[3.2.1]octyl, for example The 7-membered heterocycloalkyl group is preferably an azaspiro[3.3]heptyl group or an azabicyclo[2.2.1]heptyl group, for example

[0178] In the present invention, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1 -1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the 3- to 10-membered cycloalkyl group may independently be a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0179] In the present invention, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1 -1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , Rc-4 and R c-5 In the above, the 5- to 10-membered heteroaryl group may be independently a 5-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered and 5-membered heteroaryl group; the 6-membered heteroaryl group is preferably a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group, or a triazinyl group; the 5-membered heteroaryl ring is preferably a pyrazolyl group, an oxazolyl group, a thiazolyl group, or an imidazolyl group, for example The 5- to 9-membered heteroaryl group is preferably pyrazolyl, thiazolyl, imidazolyl, tetrahydropyrrolothiazolyl or tetrahydropyrrolopyrazolyl, for example

[0180] In a preferred embodiment, R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl or unsubstituted or substituted by one or more R 1-2 Substituted 6- to 10-membered aryl; the heteroatom of the 5- to 10-membered heteroaryl is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2. 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 substituted 5- to 6-membered heteroaryl or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatoms of the 5- to 6-membered heteroaryl group are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2.

[0181] In a preferred embodiment, R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl or unsubstituted or substituted by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatom of the 5- to 10-membered heteroaryl group is selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3. 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 substituted 5 to 9 membered heteroaryl or unsubstituted or substituted by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatom of the 5- to 9-membered heteroaryl group is selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3. 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 A substituted 5- to 9-membered heteroaryl group, wherein the heteroatom of the 5- to 9-membered heteroaryl group is one or both of N and O, and the number of heteroatoms is 1, 2 or 3. 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 substituted 5 to 9 membered heteroaryl, wherein the 5 to 9 membered heteroaryl is pyridyl, oxazolyl, pyrazolyl or R 1 Preferably, one or more R1-1 substituted pyridyl, or substituted by one or more R 1-1 Replaced

[0182] In a preferred embodiment, each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, or unsubstituted or replaced by one or more R 1-1-7 A substituted 5- to 10-membered heteroaryl group; wherein the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2. Each R 1-1 and R 1-2 are independently preferably halogen, unsubstituted or substituted with one or more R 1-1-7 substituted 5- to 6-membered heteroaryl or unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl; the heteroatom of the 5- to 6-membered heteroaryl is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2.

[0183] In a preferred embodiment, each R 1-1 is unsubstituted or substituted with one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11 membered heterocycloalkyl or unsubstituted or substituted by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0184] In a preferred embodiment, each R 1-1-4 are independently halogen.

[0185] In a preferred embodiment, each R 1-1-4 and C1-C6 alkyl which is independently halogen or unsubstituted or substituted by one or more halogens.

[0186] In a preferred embodiment, each R 1-1-7 are independently halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R1-1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3. Each R 1-1-7 Independently preferably it is C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0187] In a preferred embodiment, each R 1-1-7 Independently preferably, it is halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0188] In a preferred embodiment, each R 1-1-1 R is independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens. 1-1-1 Independently preferably, it is C1-C6 alkyl which is unsubstituted or substituted by one or more halogens.

[0189] In a preferred embodiment, each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen or C1-C6 alkyl.

[0190] In a preferred embodiment, R 2 For hydrogen.

[0191] In a preferred embodiment, R 3 is hydrogen, hydroxy, halogen, cyano, unsubstituted or replaced by one or more R 3-1 substituted 3 to 10 membered heterocycloalkyl, unsubstituted or substituted with one or more R 3-2 Substituted 3 to 8 membered cycloalkyl, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or R 3-8 substituted hydroxyl; the heteroatom of the 3- to 10-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3. 3 Preferably, it is unsubstituted or substituted with one or more R 3-1 substituted 3 to 6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, or R 3-8 Substituted hydroxyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1 or 2.

[0192] In a preferred embodiment, R 3 is hydrogen, hydroxyl, halogen, cyano, unsubstituted or substituted with one or more R 3-1 substituted 3 to 10 membered heterocycloalkyl, unsubstituted or substituted with one or more R 3-2 Substituted 3 to 8 membered cycloalkyl, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or R 3-8 substituted hydroxyl; the heteroatom of the 3- to 10-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3. 3 Preferably, halogen, unsubstituted or substituted with one or more R 3-1 substituted 3 to 6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, or R 3-8 substituted hydroxyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1 or 2. 3 Preferably, it is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy.

[0193] R 3 Preferably, it is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or unsubstituted or with one or more R 3-1 Substituted tetrahydropyrrolyl.

[0194] In a preferred embodiment, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently oxo, hydroxyl, halogen, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2. 3-1 Each R is independently preferably hydroxy or halogen. 3-2 Each R is independently preferably hydroxyl.3-4 is independently preferably hydroxyl; each R 3-7 Independently preferably, they are halogen.

[0195] In a preferred embodiment, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently deuterium, oxo, hydroxyl, halogen, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2. 3-1 Each R is independently preferably hydroxy or halogen. 3-2 Each R is independently preferably hydroxyl. 3-4 are independently preferably deuterium, halogen or hydroxyl; each R 3-7 Independently preferred are deuterium or halogen.

[0196] In a preferred embodiment, each R 3-1 are independently deuterium, hydroxyl or halogen.

[0197] In a preferred embodiment, each R 3-4 are independently deuterium, halogen or hydroxy.

[0198] In a preferred embodiment, each R 3-7 and R is independently deuterium or hydroxyl.

[0199] In a preferred embodiment, when R 3 For multiple R 3-4 When the C1-C6 alkyl group is substituted, at least one R 3-4 It is hydroxy, deuterium and hydroxy, or halogen and hydroxy.

[0200] In a preferred embodiment, R 3-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; the heteroatom of the 3- to 6-membered heterocycloalkyl group is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3. 3-8 It is preferably a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of the heteroatom is 1.

[0201] In a preferred embodiment, each R a and each R b are independently H or unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl. a and each R b Independently preferably H.

[0202] In a preferred embodiment, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene group; the 5- to 12-membered cycloalkylene group is a spirocyclic ring, a cyclic ring or a bridged ring; the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring; the heteroatom of the 5- to 12-membered heterocycloalkylene group is N, S or O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 and C1-C6 alkyl which is independently halogen, hydroxy or unsubstituted or substituted by one or more halogens.

[0203] In a preferred embodiment, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene group; the 5- to 12-membered cycloalkylene group is a spirocyclic ring, a cyclic ring or a bridged ring; the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring; the heteroatom of the 5- to 12-membered heterocycloalkylene group is N, S or O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 and C1-C6 alkyl which is independently deuterium, halogen, hydroxyl or unsubstituted or substituted by one or more halogens.

[0204] In a preferred embodiment, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 7 to 11 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 7 to 11 membered heterocycloalkylene; the 7 to 11 membered heterocycloalkylene is a spiro ring; the 7 to 11 membered heterocycloalkylene is a spiro ring; the heteroatom of the 7 to 11 membered heterocycloalkylene is N, and the number of heteroatoms is 1 or 2; each L0 -2 are independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 and C1-C6 alkyl which is independently halogen, hydroxy or unsubstituted or substituted by one or more halogens.

[0205] In a preferred embodiment, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 7 to 11 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3substituted 7 to 11 membered heterocycloalkylene; the 7 to 11 membered heterocycloalkylene is a spiro ring; the 7 to 11 membered heterocycloalkylene is a spiro ring or a cyclic ring; the heteroatom of the 7 to 11 membered heterocycloalkylene is N, and the number of heteroatoms is 1 or 2; each L0 -2 are independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 is independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens. In a preferred embodiment, L0 is a 7- to 11-membered cycloalkylene or a 7- to 11-membered heterocycloalkylene; the 7- to 11-membered cycloalkylene is a spiro ring; the 7- to 11-membered heterocycloalkylene is a spiro ring; the heteroatom of the 7- to 11-membered heterocycloalkylene is N, and the number of heteroatoms is 1.

[0206] In a preferred embodiment, L0 is a 7- to 11-membered cycloalkylene group or a 7- to 11-membered heterocycloalkylene group; the 7- to 11-membered cycloalkylene group is a spiro ring; the 7- to 11-membered heterocycloalkylene group is a spiro ring or a cyclohexane ring; the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1 or 2.

[0207] In a preferred embodiment, L0 is an 8- to 11-membered cycloalkylene group or an 8- to 11-membered heterocycloalkylene group; the 8- to 11-membered cycloalkylene group is a spiro ring; the 8- to 11-membered heterocycloalkylene group is a spiro ring or a cyclocyclic ring; the heteroatom of the 8- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1. Preferably, the 8- to 11-membered cycloalkylene group can be The 8- to 11-membered heterocycloalkylene group may be The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0208] In a preferred embodiment, L0 is a 9- to 11-membered heterospirocyclic group; the heteroatom of the 9- to 11-membered heterospirocyclic group is N, and the number of heteroatoms is 1. Preferably, the 9- to 11-membered heterospirocyclic group is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0209] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not substituted or replaced by one or more L2 1-3 Replaced m is an integer of 1-4, q is an integer of 1-6, X is absent or O; Cy 1 is a 4- to 11-membered heterocyclic ring or a 4- to 11-membered cycloalkane; 2 It is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring; the heteroatoms of the 4- to 11-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3.

[0210] In a preferred embodiment, preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist,

[0211] In a preferred embodiment, preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, The a' end faces L0, and the b' end faces LLM.

[0212] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced or not substituted or replaced by one or more L2 1-2 Replaced m is 1 or 2, q is 1 or 2, X is absent or O; Cy 1 It is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 11-membered heterocycle is N and / or O, and the number of heteroatoms is 1 or 2; the 4- to 11-membered heterocycle is a monocyclic, bridged or spirocyclic ring; the 4- to 11-membered cycloalkane is a monocyclic, bridged or spirocyclic ring.

[0213] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not substituted or replaced by one or more L2 1-3 Replaced m is 1 or 2, q is 1 or 2, X is absent or O; Cy 1 is a 4- to 11-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 11-membered heterocyclic ring is N and / or O, and the number of heteroatoms is 1 or 2; the 4- to 11-membered heterocyclic ring is a monocyclic ring, a bridged ring or a spirocyclic ring; the 4- to 6-membered cycloalkane is a monocyclic ring. 2 is a 5- to 6-membered heteroaromatic ring; the heteroatom of the 5- to 6-membered heteroaromatic ring is N and / or O, and the number of heteroatoms is 1 or 2. In a preferred embodiment, when the 4- to 11-membered heterocyclic ring is a monocyclic ring, the 4- to 11-membered heterocyclic ring is a 3- to 6-membered heterocyclic ring; the heteroatom of the 4- to 11-membered heterocyclic ring is N or O, and the number of heteroatoms is 1 or 2.

[0214] In a preferred embodiment, when the 4- to 11-membered heterocycle is a spirocycle, the 4- to 11-membered heterocycle is a 4,6-azaspirocycle, a 6,6-azaspirocycle or a 4,4-azaspirocycle.

[0215] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced or not substituted or replaced by one or more L2 1-2 Replaced m is 1 or 2, q is 1, X is absent or O; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocyclic ring is a 6-membered monocyclic ring or a 4,6-azaspirocyclic ring; R c For H.

[0216] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not substituted or replaced by one or more L2 1-3 Replaced m is 1 or 2, q is 1, X is absent or O; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocyclic ring is a 6-membered monocyclic ring, a 4,4-azaspiro ring or a 4,6-azaspiro ring; R c H, Cy 2 is a 5-membered heteroaromatic ring, wherein the heteroatom of the 5-membered heteroaromatic ring is N, the number of heteroatoms is 2, and the 5-membered heteroaromatic ring is preferably a pyrazole ring. -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, m is 1 or 2, q is 1, X is absent; Cy 1 is a 4- to 6-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 6-membered cycloalkane is a 6-membered monocyclic ring; R c For H.

[0217] In a preferred embodiment, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, m is 1 or 2, q is 1, X is absent; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 6-membered cycloalkane is a 6-membered monocyclic ring; R c H, Cy 2 It is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is N, and the number of heteroatoms is 2, such as a pyrazole ring.

[0218] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is unsubstituted or replaced by one or more L2 1-2 Replaced Cyclo 1 Preferably, L2 is -L2-1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is an unsubstituted cyclic Cy 1 , Cy 1 It is piperidinyl or piperazinyl.

[0219] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 Not present; L2 -2 、L2 -3 and L2 -4 Independently or not substituted or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl.

[0220] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently or not substituted or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl.

[0221] In a preferred embodiment, each L2 1-2 are independently halogen or hydroxy.

[0222] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not substituted or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; the 4- to 6-membered heterocyclic ring is a monocyclic ring.

[0223] In a preferred embodiment, in L2, R c It is H or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, more preferably H.

[0224] In a preferred embodiment, the ring Cy 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 6-membered heterocyclic ring, wherein the heteroatom of the 5- to 6-membered heterocyclic ring is N, S or O, and the number of the heteroatom is 1. 3 Preferably it is unsubstituted or substituted with multiple Cy 3-1 The substituted 5- to 6-membered heterocyclic ring has 1 heteroatom N.

[0225] In a preferred embodiment, each Cy 3-1 In a preferred embodiment, the ring Cy 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl, wherein the heteroatom of the 5- to 8-membered heterocyclic ring is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3. 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl group, wherein the heteroatom of the 5- to 8-membered heterocyclic ring is N, S or O, and the number of the heteroatom is 1.

[0226] In a preferred embodiment, each Cy 4-1 They are independently C1-C6 alkyl, hydroxy or oxo, preferably oxo.

[0227] In a preferred embodiment, the five-membered and six-membered compound as shown in formula I is a compound as shown in formula Ia, Ib, Id, Ig, Ih or Ii

[0228] In a preferred embodiment, the five-membered and six-membered compound as shown in formula I is a compound as shown in formula Ia, Ib, Id, Ig, Ih, Ii, Ik, Im or In

[0229]

[0230] In a preferred embodiment, LLM is Preferably p is 0 or 1, p is 0 or 1 or More preferably For example

[0231] In a preferred embodiment, LLM is Preferably p is 0 or 1, p is 0 or 1, p is 0 or 1 or More preferably For example

[0232] In a preferred embodiment, LLM is P is 0 or 1, for example Another example

[0233] In a preferred embodiment, R 1 for Preferably In a preferred embodiment, R 3 is methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, carboxyl, fluorine, Preferably, methoxy,

[0234] In a preferred embodiment, for For example

[0235] In a preferred embodiment, in the compound shown in formula I, for X is N or CH, and X1 is S or O.

[0236] In a preferred embodiment, in the compound shown in formula I, for

[0237]

[0238] In a preferred embodiment, in the compound shown in formula I, for

[0239] In a preferred embodiment, in the compound shown in formula I, for

[0240] In a preferred embodiment, in the compound shown in formula I, for

[0241] In a preferred embodiment, in the compound shown in formula I, for

[0242] In a preferred embodiment, in the compound shown in formula I, for

[0243] In a preferred embodiment, in the compound shown in formula I, for

[0244] In a preferred embodiment, L0 is

[0245] In a preferred embodiment, L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0246] In a preferred embodiment, L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0247] In a preferred embodiment, L0 for The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0248] In a preferred embodiment, L2 is

[0249]

[0250]

[0251] In a preferred embodiment, L2 is

[0252]

[0253] Among them, the a' end is connected to L0, and the b' end is connected to LLM.

[0254] In a preferred embodiment, when L0 is (Further L0 is unsubstituted or replaced by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene), L2 is

[0255]

[0256]

[0257] In a preferred embodiment, when L0 is (Further L0 is unsubstituted or replaced by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene), L2 is

[0258]

[0259] The a' end of L2 is connected to L0, and the b' end of L2 is connected to LLM.

[0260] In a preferred embodiment, when R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0261] In a preferred embodiment, when R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0262] In a preferred embodiment, when R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2.

[0263] In a preferred embodiment, when R 1 for When L2- The a' end of L2 is connected to L0, and the b' end of L2 is connected to LLM.

[0264] In a preferred embodiment, when R 1 for When L2- The a' end of L2 is connected to L0, and the b' end of L2 is connected to LLM.

[0265] In a preferred embodiment, when R 1 for When L2- The a' end of L2 is connected to L0, and the b' end of L2 is connected to LLM.

[0266] In a preferred embodiment, -L0-L2- is Preferably

[0267] In a preferred embodiment, -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM.

[0268] In a preferred embodiment, when for When -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM; preferably The a' end is connected to the ring Cy, and the b' end is connected to LLM.

[0269] In a preferred embodiment, when for When -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM.

[0270] In a preferred embodiment, when for -L0-L2- The a' end is connected to the ring Cy, and the b' end is connected to LLM.

[0271] In a preferred embodiment, the compound shown in formula I is a compound shown in formula Id,

[0272]

[0273] Among them, R 1 For one or more R 1-1 substituted pyridyl or one or more R 1-1 Replaced

[0274] When R 1For one or more R 1-1 When the pyridyl group is substituted, each R 1-1 Independently for one or more R 1-1-4 Substituted C1-C6 alkyl;

[0275] When R 1 For one or more R 1-1 Replaced When each R 1-1 is unsubstituted or substituted with one or more R 1-1-1 A substituted 7- to 8-membered heterocycloalkyl group; wherein the heteroatom of the 7- to 8-membered heterocycloalkyl group is selected from N or O, and the number of heteroatoms is 2;

[0276] Each R 1-1-4 are independently halogen; each R 1-1-1 is independently a C1-C6 alkyl group substituted by one or more halogens;

[0277] R 2 is hydrogen;

[0278] R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy;

[0279] Each R 3-4 are independently deuterium, halogen or hydroxyl; each R 3-7 independently for deuterium;

[0280] L0 is a 9- to 11-membered heterospirocyclic group; the heteroatom of the 9- to 11-membered heterospirocyclic group is N, and the number of heteroatoms is 1;

[0281] L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not substituted or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; the 4- to 6-membered heterocyclic ring is a monocyclic ring; each L2 1-2 are independently hydroxyl groups;

[0282] LLM

[0283] Cyclo 3 is unsubstituted or substituted with multiple Cy 3-1 A substituted 5- to 6-membered heterocyclic ring, wherein the heteroatom of the 5- to 6-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1; Cy 3-1 are independently oxo;

[0284] Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl, wherein the heteroatom of the 5- to 8-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1; Cy 4-1 are independently oxo;

[0285] Each R 5 are independently halogen;

[0286] p is 0, 1, 2 or 3.

[0287] In a preferred embodiment, R 1 For one or more R 1-1 substituted pyridyl or one or more R 1-1 Replaced

[0288] In a preferred embodiment, when R 1 For one or more R 1-1 When the pyridyl group is substituted, each R 1-1 Independently for one or more R 1-1-4 Substituted C1-C6 alkyl.

[0289] In a preferred embodiment, when R 1 For one or more R 1-1 Replaced When each R 1-1 is unsubstituted or substituted with one or more R 1-1-1 Substituted 7- to 8-membered heterocycloalkyl; the heteroatom of the 7- to 8-membered heterocycloalkyl is selected from N or O, and the number of heteroatoms is 2.

[0290] In a preferred embodiment, each R 1-1-4 are independently fluorine, chlorine or bromine, preferably fluorine.

[0291] In a preferred embodiment, when R 1-1 Independently for multiple R 1-1-4 In the case of a substituted C1-C6 alkyl group, the plurality is 2 or 3, preferably 3.

[0292] In a preferred embodiment, each R 1-1-1are independently C1-C6 alkyl substituted by one or more halogens.

[0293] In a preferred embodiment, R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy.

[0294] In a preferred embodiment, each R 3-4 are independently deuterium, halogen or hydroxy.

[0295] In a preferred embodiment, each R 3-7 Independently for deuterium.

[0296] In a preferred embodiment, when R 3 For multiple R 3-4 When the C1-C6 alkyl group is substituted, at least one R 3-4 It is hydroxy, deuterium and hydroxy, or halogen and hydroxy.

[0297] In a preferred embodiment, L0 is a 9- to 11-membered spirocyclic group; the heteroatom of the 9- to 11-membered spirocyclic group is N, and the number of the heteroatom is 1.

[0298] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not substituted or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; the 4- to 6-membered heterocyclic ring is a monocyclic ring.

[0299] In a preferred embodiment, each L2 1-2 are independently hydroxyl.

[0300] In a preferred embodiment, the compound shown in formula I is a compound shown in formula Id,

[0301]

[0302] Among them, R 1 is unsubstituted or substituted with one or more R 1-1A substituted 5- to 9-membered heteroaryl group, wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0303] Each R 1-1 is unsubstituted or substituted with one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11 membered heterocycloalkyl or unsubstituted or substituted by one or more R 1-1-7 Substituted 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2;

[0304] Each R 1-1-1 , R 1-1-4 and R 1-1-7 is independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens;

[0305] R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy or unsubstituted or with one or more R 3-1 Substituted tetrahydropyrrolyl;

[0306] Each R 3-1 are independently deuterium, halogen or hydroxyl, each R 3-4 are independently deuterium, halogen or hydroxyl, each R 3-7 are independently deuterium or hydroxyl;

[0307] L0 is an 8- to 11-membered cycloalkylene group or an 8- to 11-membered heterocycloalkylene group; the 8- to 11-membered cycloalkylene group is a spiro ring; the 8- to 11-membered heterocycloalkylene group is a spiro ring or a fused ring; the heteroatom of the 8- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1.

[0308] L2 is one of the following:

[0309] Case (1) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is unsubstituted or replaced by one or more L2 1-2 Substituted Cyclic1 , Cy 1 is piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy;

[0310] Case (2) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 Not present; L2 -2 、L2 -3 and L2 -4 Independently or not replaced or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy;

[0311] Case (3) L2 is -L2- 1 -L2- 2 -L2- 3 -L2- 4 -;L2- 1 、L2- 2 、L2- 3 and L2- 4 Independently or not substituted or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy;

[0312] LLM p is 0 or 1.

[0313] In a preferred embodiment, the compound as shown in formula I is any of the following compounds:

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320] In a preferred embodiment, for

[0321]

[0322] In a preferred embodiment, for

[0323] In a preferred embodiment, for

[0324] In a preferred embodiment, for

[0325]

[0326] In a preferred embodiment, for

[0327] In a preferred embodiment, for

[0328] In a preferred embodiment, for

[0329]

[0330] In a preferred embodiment, for

[0331]

[0332] In a preferred embodiment, for

[0333]

[0334] In a preferred embodiment, for

[0335] In a preferred embodiment, for

[0336] In a preferred embodiment, for

[0337]

[0338] In a preferred embodiment, for

[0339] In a preferred embodiment, for

[0340] In a preferred embodiment, for

[0341] In a preferred embodiment, for

[0342] In a preferred embodiment, the pharmaceutically acceptable salt of the compound shown in I-12 is

[0343]

[0344] In a preferred embodiment, For compounds with a retention time of 2.262 min or 3.319 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / (MeOH:MeCN=1:1)=50 / 50; flow rate: 120 mL / min.

[0345] In a preferred embodiment, For compounds with a retention time of 12.068 min or 14.283 min under the following conditions, chromatographic column: IC 25 x 250 mm, 10 um (Daicel); mobile phase: HEX (0.1% DEA): EtOH (0.1% DEA): = 50:50; flow rate: 50 mL / min.

[0346] In a preferred embodiment, For compounds with a retention time of 1.759 min or 2.520 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel), mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50, flow rate: 120 mL / min.

[0347] In a preferred embodiment, For compounds with a retention time of 1.299 min or 1.936 min under the following conditions, chromatographic column: AS25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH): MeCN = 1:1] = 40 / 60; flow rate: 100 mL / min.

[0348] In a preferred embodiment, For compounds with a retention time of 2.309 min or 3.384 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50; flow rate: 120 mL / min.

[0349] The present invention also provides a pharmaceutical composition, which comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in Formula I, or a pharmaceutically acceptable salt or isotope compound thereof.

[0350] In a preferred embodiment, in the pharmaceutical composition, the substance Z is an effective amount of substance Z.

[0351] In a preferred embodiment, the pharmaceutical composition is used to treat and / or prevent Myd88 and / or IRAK4 related diseases.

[0352] The present invention also provides an application of a substance Z in the preparation of an IRAK4 degrader and a drug for treating and / or preventing Myd88 and / or IRAK4 related diseases, wherein the substance Z is a compound as shown in formula I, or a pharmaceutically acceptable salt or isotope compound thereof.

[0353] The present invention also provides a method for treating and / or preventing Myd88 and / or IRAK4 related diseases, comprising administering an effective amount of substance Z to a patient, wherein substance Z is a compound as shown in formula I, or a pharmaceutically acceptable salt or isotope compound thereof.

[0354] In a preferred embodiment, the IRAK4-related diseases include one or more of autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases, and central nervous system diseases.

[0355] In a preferred embodiment, the IRAK4-related diseases include one or more of chronic lung diseases, autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases, and central nervous system diseases.

[0356] In a preferred embodiment, the autoimmune diseases include psoriasis and rheumatoid arthritis.

[0357] In a preferred embodiment, the autoimmune diseases include psoriasis, systemic lupus erythematosus and rheumatoid arthritis.

[0358] In a preferred embodiment, the inflammatory disease includes ulcerative colitis.

[0359] In a preferred embodiment, the inflammatory disease includes inflammatory bowel disease, such as ulcerative colitis.

[0360] In a preferred embodiment, the tumor may be a hematological tumor or a solid tumor.

[0361] In a preferred embodiment, the blood tumor includes large B-cell lymphoma, acute and chronic lymphocytic leukemia;

[0362] In a preferred embodiment, the solid tumors include colon cancer and skin cancer caused by MYD88 mutation.

[0363] In a preferred embodiment, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis.

[0364] In a preferred embodiment, the central nervous system disease includes primary central nervous system lymphoma.

[0365] The present invention also provides an application of a substance Z or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the substance Z is a compound as shown in formula I, a pharmaceutically acceptable salt or isotope compound thereof; the drug is used to treat one or more of autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases and central nervous system diseases.

[0366] In a preferred embodiment, the autoimmune disease, inflammatory disease, tumor, cardiovascular and cerebrovascular disease and central nervous system disease are as described in any embodiment of the present invention.

[0367] The present invention also provides a compound as shown in formula II or III, a salt thereof, a boc-protected compound thereof or an isotope compound thereof,

[0368]

[0369] R 1 , R 2 , R 3 , Q, Y, ring Cy, L0 and L2 are as described in any of the preceding items;

[0370] Preferably, the compound as shown in formula II or III is any of the following compounds:

[0371]

[0372]

[0373]

[0374]

[0375] The present invention also provides a use of the compound as shown in formula II or III as described above, its salt, boc-protected compound or isotope compound in the preparation of the compound as shown in any of the above items, its pharmaceutically acceptable salt or isotope compound.

[0376] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0377] The terms "compound" and "pharmaceutically acceptable salt" may exist in the form of a single tautomer or a mixture thereof if tautomers exist, preferably in a form in which the more stable tautomer is predominant.

[0378] If a linking group is indicated as "absent", the structures on both sides of the linking group are directly connected by a single bond, for example -ABC-. ​​When B does not exist, -ABC- is -AC-.

[0379] the term Indicates presence or absence.

[0380] The term "oxo" refers to the replacement of hydrogen or lone pair electrons on non-oxygen atoms with oxygen, e.g. After being oxidized After being oxidized

[0381] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0382] The term "cycloalkyl" refers to a cycloalkyl radical having a specified number of carbon atoms (e.g., C3 to C 10 ) is a saturated monocyclic cyclic group consisting of only carbon atoms. The monocyclic alkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0383] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1 to C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0384] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 11 members, and also 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), wherein the heteroatoms may be connected to other groups as a linking group, or may not be connected to other groups (e.g., piperidinyl may be The heterocycloalkyl group includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0385] The term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), wherein the heteroatoms may be connected to other groups as a linking group or may not be connected to other groups (e.g., the piperidine ring may be etc.) which are monocyclic, fused, bridged or spirocyclic, and each ring is saturated. Heterocycloalkyl includes but is not limited to azetidine ring, tetrahydropyrrole ring, tetrahydrofuran ring, morpholine ring, piperidinyl ring.

[0386] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0387] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaromatic ring is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaromatic rings include, but are not limited to, furan rings, pyrrole rings, thiophene rings, pyrazole rings, imidazole rings, oxazole rings, thiazole rings, pyridine rings, pyrimidine rings, indole rings, and the like.

[0388] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, CH3-C(=O)- refers to acetyl.

[0389] In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to the acetyl group.

[0390] The term "cycloalkylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "cycloalkyl".

[0391] The term "heterocycloalkylene" is a divalent group which is attached to the rest of the molecule by two single bonds, and the rest is the same as the definition of the term "heterocycloalkyl".

[0392] The term "isotopic compound" refers to a compound in which one or more atoms have an isotopic abundance that differs from its natural abundance. For example, one or more atoms in a compound has been replaced by an atom of a lower mass number that occurs naturally - a hydrogen atom in a compound has been replaced by deuterium, or a C has been replaced by 13 C replacement.

[0393] The term "plurality" refers to 2, 3, 4 or 5.

[0394] The term "boc protection" generally refers to N protection with a boc group.

[0395] The substituents such as the heterocycle, aromatic ring, heteroaryl, aryl, heterocycloalkyl, alkoxy, alkyl, cycloalkyl, etc. described in the present invention, if they are used as connecting units to connect different components of the compound respectively, may also be referred to as sub-heterocycles, sub-aromatic rings, sub-heteroaryls, sub-aryls, sub-heterocycloalkyls, sub-alkyloxys, sub-alkyls, and sub-cycloalkyls.

[0396] When any variable (such as the group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other. 1-1 Substituted C6~C 10 Aryl refers to C6~C 10 The aromatic group will be 3 R 1-1 Replacement, 3 R's 1-1 The definitions are independent of each other and do not affect each other.

[0397] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, acetates, trifluoroacetates, sulfates, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0398] The term "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base, and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include but are not limited to hydrochloride monohydrate.

[0399] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).

[0400] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0401] The term "prevention" refers to reducing the risk of developing a disease.

[0402] The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0403] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0404] The reagents and raw materials used in the present invention are commercially available.

[0405] The positive and progressive effects of the present invention are: the compounds of the present invention have an inhibitory or / and degradation effect on IRAK4, and can almost completely degrade the IRAK4 protein at a lower drug concentration. The compounds of the present invention can also inhibit the scaffold function of the Myddosome complex. The compounds of the present invention have potential clinical application value and are expected to be applicable to various IRAK4-related immune diseases and various blood diseases and solid tumors caused by Myd88 mutations. DETAILED DESCRIPTION

[0406] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0407] Example 1. Synthesis of Compound I-1

[0408] Synthesis I-1

[0409]

[0410] Step 1: Synthesis of I-1-A

[0411] A mixed solution of 7-tert-butoxycarbonyl-7-azaspiro[3.5]-2-nonanol (600 mg, 2.49 mmol), 4-dimethylaminopyridine (60.75 mg, 497.25 μmol, 83.68 μL), triethylamine (503.17 mg, 4.97 mmol, 693.07 μL) and dichloromethane (1.35 mL) was stirred to dissolve, p-toluenesulfonyl chloride (521.40 mg, 2.73 mmol) was added and the mixture was heated to 40°C and stirred for 18 hours until the reaction was complete. Water (30 mL) was added to the reaction system for dilution, and the mixture was extracted with dichloromethane (20 mL x 3) under stirring. The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain I-1-A (1 g, crude product), MS (ESI) m / z: 396.2 [M+H] + .

[0412] Step 2: Synthesis of I-1-1

[0413] A mixed solution of 6-methoxy-5-nitro-2H-indazole (2 g, 10.35 mmol), Pd / C (0.3 g, 10% purity) and methanol (30 mL) was stirred and replaced with hydrogen three times, and then stirred and reacted under hydrogen atmosphere at 25°C for 18 hours until the reaction was complete. The mixed solution was filtered through diatomaceous earth to remove the catalyst, and the filter cake was washed with methanol (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain a brown solid product I-1-1 (1.59 g, crude product), MS (ESI) m / z: 164.1 [M+H] + , directly used in the next step.

[0414] Step 3: Synthesis of I-1-2

[0415] 2,4,6-tripropyl-2-(2-(trifluoromethyl)pyridine-2-carboxylic acid) (2.05 g, 10.72 mmol), diisopropylethylamine (3.78 g, 29.23 mmol, 5.09 mL) and tetrahydrofuran (25 mL) were added dropwise at 0°C under stirring.

[0416] 1,3,5,2,4,6-trioxophosphine 2,4,6-trioxide (7.44 g, 11.69 mmol, 50% purity), after the addition, the reaction system was stirred at 15°C under nitrogen protection for 2 hours until the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x5), and the combined organic phase was washed with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a brown solid product I-1-2 (3.08 g, crude product), MS (ESI) m / z: 337.1 [M+H] + , directly used in the next step.

[0417] Step 4: Synthesis of I-1-3

[0418] A mixed solution of I-1-A (500 mg, 1.49 mmol), I-1-2 (705.71 mg, 1.78 mmol), cesium carbonate (968.93 mg, 2.97 mmol) and N,N-dimethylformamide (4 mL) was stirred at 90 ° C for 5 hours until the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (30 mL), stirred and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give I-1-3 (250 mg, 446.76 μmol, yield 30.05%), MS (ESI) m / z: 560.2 [M+H] + .

[0419] Step 5: Synthesis of I-1-4

[0420] A mixed solution of I-1-3 (250 mg, 446.76 μmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was spin-dried, and the crude product was purified by C18 column chromatography to obtain a yellow solid I-1-4 (200 mg, 435.29 μmol, yield 97.43%), MS (ESI) m / z: 460.2 [M+H] + .

[0421] Step 6: Synthesis of I-1-5

[0422] A mixed solution of I-1-4 (25.00 mg, 54.41 μmol), 1-Boc-4-piperidinic acid (12.47 mg, 54.41 μmol), diisopropylethylamine (35.16 mg, 272.06 μmol, 47.39 μL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.83 mg, 65.29 μmol) and N,N-dimethylformamide (2 mL) was added to the reaction flask and stirred at room temperature for 12 hours until the reaction was complete. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by TLC to give I-1-5 (36 mg, 53.67 μmol, yield 98.64%), MS (ESI) m / z: 671.3 [M+H] + .

[0423] Step 7: Synthesis of I-1-6

[0424] Trifluoroacetic acid (2 mL) was added dropwise to a mixed solution of I-1-5 (36.00 mg, 53.67 μmol) and dichloromethane (2 mL) under stirring at 0°C, and the mixture was reacted at room temperature for 1 hour until complete. The reaction solution was spin-dried to obtain I-1-6 (30 mg, crude trifluoroacetate salt), MS (ESI) m / z: 571.6 [M+H] + , directly used in the next reaction.

[0425] Step 8: Synthesis of I-1

[0426] A mixed solution of I-1-6 (30.00 mg, 52.58 μmol), 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (14.52 mg, 52.58 μmol), diisopropylethylamine (33.98 mg, 262.88 μmol, 45.79 μL) and N,N-dimethylformamide (2 mL) was placed at 100 ° C for 2 hours to complete. The reaction solution was diluted with water (20 mL), stirred and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by thin layer preparative chromatography to obtain I-1 (23 mg, 27.26 μmol, yield 51.85%), MS (ESI) m / z: 827.9 [M+H] + , 1HNMR(500MHz,DMSO-d6)δ11.08(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H),8.37(s,1H) ,8.22(d,J=8.0Hz,1H),7.67(d,J=8.5Hz,1H),7.33(s,1H),7.25(d,J=8.5Hz,1H),7.21(s,1H),5.24–5.12(m,1H),5.07(dd, J=13.0,5.0Hz,1H),4.07(d,J=12.5Hz,2H),3.99(s,3H),3.60–3.38(m,4H),3.15–3.05(m,2H),3.04–2.95(m,1H),2.94–2.8 3(m,1H),2.66–2.52(m,2H),2.50–2.46(m,2H),2.46–2.38(m,2H),2.06–1.98(m,1H),1.81–1.67(m,4H),1.67–1.54(m,4H).

[0427] Compounds I-2, I-3, I-4, I-5 and I-8 can be prepared by referring to the method of Example 1 above, and their structures and characterization data are shown in the following table:

[0428]

[0429]

[0430] Example 2, Synthesis II-1

[0431]

[0432] Step 1: Synthesis of II-1-A1

[0433] 2-(2,6-dioxy-3-piperidinyl)-5-fluoro-isoindole-1,3-dione (247.18 mg, 894.85 μmol) and tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol) were dissolved in dimethyl sulfoxide (3 mL), and diisopropylethylamine (346.95 mg, 2.68 mmol, 467.59 μL) was weighed and added to the reaction system, and the mixed solution was stirred at 100°C for 2 hours until the reaction was complete. Water (50 mL) was added to the reaction system for dilution, and ethyl acetate (50 mL x 3) was stirred for extraction, and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Silica gel column chromatography (dichloromethane: methanol = 20: 1) was used to purify the yellow solid product II-1-A1 (260 mg, 587.62 μmol, yield 65.67%), MS (ESI) m / z: 443.2 [M+H] + .

[0434] Step 2: Synthesis of II-1-A

[0435] II-1-A1 (260 mg, 587.62 μmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid-dioxane (4 M, 2 mL) was added dropwise under stirring at 0°C. After the addition, the mixed solution was stirred at 25°C for 2 hours until the reaction was complete. The reaction system was filtered, washed with dichloromethane (10 mL), and the filter cake was dried to obtain a white solid product II-1-A (204 mg, 538.52 μmol, yield 91.65%), MS (ESI) m / z: 343.2 [M+H] + .

[0436] Step 3: Synthesis II-1-1

[0437] A mixed solution of I-1-2 (1.02 g, 3.03 mmol), 4-methylsulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.10 g, 3.94 mmol), cesium carbonate (1.98 g, 6.07 mmol) and N, N-dimethylformamide (10 mL) was stirred at 70 ° C under nitrogen protection for 2 hours until the reaction was complete. Water (30 mL) was added to the reaction mixture, and extracted with ethyl acetate (20 mL x3), and the combined organic phase was washed with water (20 mL x3) and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a crude product. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1 elution) to obtain an off-white solid product II-1-1 (0.35 g, 673.70 μmol, yield 22.21%), MS (ESI) m / z: 520.2 [M+H] + .

[0438] Step 4: Synthesis II-1-2

[0439] II-1-1 (0.35 g, 673.70 μmol) was dissolved in dichloromethane (5 mL), and hydrochloric acid-dioxane (4 M, 7.9 mL) was added dropwise under stirring at 0°C. After the addition, the mixed solution was stirred at 25°C for 2 hours until the reaction was complete. The reaction system was filtered, washed with dichloromethane (10 mL), and the filter cake was dried to obtain a white solid product II-1-2 (280 mg, 667.62 μmol, yield 99.10%), MS (ESI) m / z: 420.2 [M+H] + .

[0440] Step 5: Synthesis II-1-3

[0441] II-1-2 (120 mg, 286.12 μmol) was dissolved in N, N-dimethylformamide (2 mL), and potassium carbonate (79.09 mg, 572.25 μmol) and ethyl 2-bromoacetate (71.67 mg, 429.19 μmol, 47.59 μL) were added, and the reaction system was stirred at 25 ° C for 6 hours until the reaction was complete. Water (50 mL) was added to the reaction system for dilution, and ethyl acetate (50 mL x 3) was stirred for extraction, and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. Silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) was purified to obtain a yellow solid II-1-3 (80 mg, 158.26 μmol, yield 55.31%), MS (ESI) m / z: 506.2 [M+H] + .

[0442] Step 6: Synthesis II-1-4

[0443] A mixed solution of II-1-3 (100 mg, 197.83 μmol), water (1 mL), lithium hydroxide (4.74 mg, 197.83 μmol) and methanol (2 mL) was stirred at room temperature for 1 hour until the reaction was complete, and the methanol was removed by distillation under reduced pressure. Dilute hydrochloric acid (2 M) was added to the system to adjust the pH to about 6-7, and purified by C18 reverse phase chromatography and freeze-dried to obtain a yellow solid II-1-4 (30 mg, 62.84 μmol, yield 31.76%), MS (ESI) m / z: 478.2 [M+H] + .

[0444] Step 7: Synthesis II-1

[0445] A mixed solution of II-1-4 (15 mg, 31.42 μmol), II-1-A (12.91 mg, 34.07 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.92 mg, 47.13 μmol), diisopropylethylamine (12.18 mg, 94.25 μmol, 16.42 μL) and N,N-dimethylformamide (1 mL) was reacted at 25 ° C under nitrogen protection for 2 hours until the reaction was complete. Water (25 mL) was added to the reaction mixture, extracted with ethyl acetate (25 mL x 3), and the combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by C18 column chromatography to obtain a yellow solid product II-1 (6 mg, 7.41 μmol, yield 23.58%), MS (ESI) m / z: 802.8 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.50(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.40(t,J=8.0Hz,1H),8.37(s,1H),8. 22(dd,J=8.0,1.0Hz,1H),7.71(d,J=8.5Hz,1H),7.39(d,J=2.0Hz,1H),7.29(dd,J=8.5,2.0Hz,1H),7.17(s,1H),5.08(dd,J=1 3.0,5.5Hz,1H),4.46–4.36(m,1H),3.98(s,3H),3.83–3.72(m,2H),3.70–3.61(m,2H),3.61–3.53(m,2H),3.52–3.43(m,2H),3 .29(s,2H),3.04–2.94(m,2H),2.93–2.85(m,1H),2.62–2.52(m,2H),2.33–2.24(m,2H),2.19–2.07(m,4H),2.05–2.00(m,1H).

[0446] Compounds II-5 and II-6 can be prepared by referring to the method of Example 2 above, and their structures and characterization data are shown in the following table:

[0447]

[0448]

[0449] Example 3, Synthesis of I-9

[0450]

[0451] Step 1: Synthesis (int-F-1)

[0452] DIPEA (4.7 g, 36.2 mmol) and tert-butyl piperidine-4-carboxylate (4.0 g, 21.6 mmol) were added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (5.0 g, 18.0 mmol) in anhydrous DMSO (20.0 mL), and the reaction mixture was stirred at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=5 / 1) to obtain a yellow solid product int-F-1 (7.5 g, yield 94.2%), MS (ESI) m / z: 442.2 [M+H] +.

[0453] Step 2: Synthesis (int-F)

[0454] TFA (20 mL) was added dropwise to a DCM (50 mL) solution of int-F-1 (5 g, 11.3 mmol) at 0°C, and the mixture was stirred at 25°C for 16 hours. Ether was added to the reaction solution under stirring, and the precipitated solid was filtered, and the filter cake was washed with ether to obtain a yellow solid product int-F (3.7 g, yield 84.9%), MS (ESI) m / z: 386.1 [M+H] +.

[0455] Step 3: Synthesis (I-9-1)

[0456] 6-Bromo-5-nitro-2H-indazole (1 g, 4.13 mmol) and I-1-A (2.45 g, 6.20 mmol) were dissolved in DMF (20 mL), and Cs2CO3 (1.35 g, 4.13 mmol) and KI (685.87 mg, 4.13 mmol) were added under stirring, and the reaction solution was stirred at 100 ° C for 2 hours. Water (50 mL) was added to the reaction system, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EA = 1: 1) to give a light yellow solid I-9-1 (500 mg, yield 26.01%), MS (ESI) m / z: 465.1 [M + H] +.

[0457] Step 4: Synthesis (I-9-2)

[0458] I-9-1 (250 mg, 537.24 μmol) and morpholine (936.09 mg, 10.74 mmol) were dissolved in 1,4-dioxane (2 mL), and CuI (51.16 mg, 268.62 μmol) and K3PO4 (456.15 mg, 2.15 mmol) were added under stirring, and the mixture was reacted at 90 ° C for 6 hours under nitrogen protection. Saturated ammonium chloride solution was added to the reaction system, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a light yellow solid I-9-2 (70 mg, yield 27.63%), MS (ESI) m / z: 472.2 [M+H] +.

[0459] Step 5: Synthesis (I-9-3)

[0460] I-9-2 (70 mg, 148.45 μmol) was dissolved in MeOH (2 mL), wet Pd / C (70 mg, 10% w / w) was added and hydrogen was replaced three times, and the mixture was reacted at 25°C under a hydrogen environment for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was rinsed three times with ethyl acetate (30 mL), and the filtrate was collected. The solvent was distilled off under reduced pressure to obtain the product I-9-3 (60 mg, yield 91.53%) as a white solid, MS (ESI) m / z: 442.3 [M+H] +.

[0461] Step 6: Synthesis (I-9-4)

[0462] 6-(Trifluoromethyl)pyridine-2-carboxylic acid (25 mg, 130.82 μmol) and I-9-3 (57.76 mg, 130.82 μmol) were dissolved in DMF (1 mL), and DIPEA (50.72 mg, 392.45 μmol) and HATU (74.61 mg, 196.22 μmol) were added under stirring, and the mixture was reacted at 25°C for 2 hours. Water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a light yellow solid product I-9-4 (50 mg, yield 62.18%), MS (ESI) m / z: 615.3 [M+H] +.

[0463] Step 7: Synthesis (I-9-5)

[0464] I-9-4 (70 mg, 113.88 μmol) was dissolved in DCM (3 mL), and HCl-dioxane solution (4 M, 284.71 μL) was added dropwise under stirring, and the reaction was continued at 25° C. for 2 hours. The reaction solution was filtered, and the filter cake was washed three times with DCM (30 mL), and dried to obtain a white solid product I-9-5 (50 mg, yield 79.68%, hydrochloride), MS (ESI) m / z: 515.2 [M+H] +.

[0465] Step 8: Synthesis (I-9)

[0466] DIPEA (28.15 mg, 217.78 μmol) and HATU (41.40 mg, 108.89 μmol) were added to a solution of I-9-5 (40 mg, 72.59 μmol, hydrochloride), int-F (33.57 mg, 87.11 μmol) and DMF (1.5 mL), and the resulting mixture was stirred at 25 ° C for 1 hour. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM: MeOH = 20: 1) to give a yellow solid product I-9 (23 mg, yield 35.93%), MS (ESI) m / z: 882.7 [M + H] +. 1H NMR (500MHz, DMSO-d6) δ11.15(s,1H),11.14(s,1H),8.85(s,1H),8.56(d,J=7.5Hz,1H),8.49–8.46(m,2H),8.29(d,J=8.5Hz ,1H),7.73(d,J=8.5Hz,1H),7.62(s,1H),7.39(s,1H),7.31(d,J=8.5Hz,1H),5.29–5.25(m,1H),5.13(dd,J=12.5,5.5Hz,1H) ,4.15–4.10(m,2H),3.96–3.92(m,4H),3.63–3.47(m,4H),3.19–3.13(m,2H),3.09–3.04(m,1H),3.01–2.98(m,4H),2.96–2. 91(m,1H),2.71–2.65(m,1H),2.65–2.60(m,1H),2.53–2.45(m,3H),2.11–2.03(m,2H),1.82–1.74(m,4H),1.72–1.64(m,4H).

[0467] Compound I-10 can be prepared by referring to the method of Example 3 above, and its structure and characterization data are shown in the following table:

[0468]

[0469] Example 4: Synthesis of I-12F

[0470]

[0471] Step 1: Synthesis (I-12F-1)

[0472] At 0 ° C, TsOH (627 mg, 3.3 mmol) was added to a solution of 6-bromo-5-nitro-1H-indazole (4 g, 16.7 mmol) and 3,4-dihydro-2H-pyran (DHP, 2.8 g, 33.3 mmol) in DCM (50 mL), and the mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was diluted with H2O (120 mL) and extracted with EA (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give a yellow solid product I-12F-1 (4.8 g, yield 88%), MS (ESI) m / z: 326.0 [M+H] + .

[0473] Step 2: Synthesis (I-12F-2)

[0474] Tributyl (1-ethoxyvinyl) stannane (5.45 g, 15.1 mmol) and TEA (3.2 g, 31.5 mmol) were added to a solution of I-12F-1 (4.1 g, 15.6 mmol) in 1,4-dioxane (15 mL), and the mixture was stirred at 25 ° C for 15 minutes under a nitrogen atmosphere, and then Pd (PPh3) 2Cl2 (0.9 g, 1.3 mmol) was added, and the resulting mixture was stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature and diluted with saturated potassium fluoride aqueous solution (50 mL). The resulting mixture was filtered and the filtrate was extracted with EtOAc (60 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give a yellow oily product I-12F-2 (2.9 g, yield 72.7%), MS (ESI) m / z: 318.3 [M+H] + .

[0475] Step 3: Synthesis (I-12F-3)

[0476] TsOH (0.15 g, 0.8 mmol) was added to a solution of I-12F-2 (2.5 g, 7.9 mmol), acetone (15 mL) and water (15 mL), and the mixture was stirred at 50 ° C for 2 hours. Diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid product I-12F-3 (1.8 g, yield 78.8%), MS (ESI) m / z: 290.1 ​​[M+H] + .

[0477] Step 4: Synthesis (I-12F-4)

[0478] At 25 ° C, trifluoromethyltrimethylsilane (2.04 mL, 13.84 mmol) in THF (27.6 mL) was added to a solution of I-12F-3 (2.0 g, 6.92 mmol) in THF (20 mL), stirred for 15 minutes, and then TBAF (6.92 mL, 6.92 mmol) was added, and the mixture was microwaved at room temperature for 16 hours. The reaction system was poured into a saturated NH4Cl solution and then extracted with ethyl acetate (50 mL x2). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give a yellow solid product I-12F-4 (1.4 g, yield 22.5%), MS (ESI) m / z: 360.1 [M + H] + .

[0479] Step 5: Synthesis (I-12F-5)

[0480] At 25°C, wet Pd / C (0.3 g, 10% purity) was added to a solution of I-12F-4 (0.6 g, 1.7 mmol) and MeOH (10 mL). The mixture was stirred and replaced with H2 three times and then stirred for 16 hours under H2 environment. The resulting mixture was filtered and concentrated to obtain a brown solid product I-12F-5 (0.5 g, yield 91%), MS (ESI) m / z: 330.2 [M+H] + .

[0481] Step 6: Synthesis (I-12F-6)

[0482] A mixture of I-12F-5 (1 g, 3.04 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (696.38 mg, 3.64 mmol), HATU (1.39 g, 3.64 mool), DIPEA (784.90 mg, 6.07 mmol, 1.06 mL) and DMF (10 mL) was stirred at 25 ° C for 3 hours until the reaction was complete. The reaction was quenched with water and the aqueous layer was extracted with EA (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and eluted with PE / EA (0-45%) to give a white solid product I-12F-6 (1.4 g, yield 91.77%), MS (ESI) m / z: 503.3 [M+H] + .

[0483] Step 7: Synthesis (I-12F-7)

[0484] A mixture of I-12F-6 (0.7 g, 1.39 mmol) and HCl-dioxane solution (4.0 M, 1.39 mmol, 2 mL) was stirred at 25 ° C for 16 hours. The resulting mixture was concentrated to dryness under reduced pressure to obtain a white solid product I-12F-7 (0.4 g, yield 63.13%, hydrochloride), MS (ESI) m / z: 419.3 [M+H] + .

[0485] Step 8: Synthesis (I-12F-8)

[0486] A mixture of I-12F-7 (1 g, 2.20 mmol), I-1-A (1.30 g, 3.30 mmol), Cs2CO3 (3.58 g, 10.99 mmol) and KI (365.03 mg, 2.20 mmol) in DMF (10 mL) was stirred at 90 ° C under nitrogen protection for 4 hours. The reaction was quenched with water (50 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by reverse phase C18 column chromatography (mobile phase: MeCN and water containing 0.1% HCOOH, gradient from 1% to 70% in 60 minutes; detector: UV 254 nm) to give a white solid product I-12F-8 (0.21 g, yield 14.88%), MS (ESI) m / z: 642.5 [M+H] + .

[0487] Step 9: Synthesis (I-12F-9)

[0488] I-12F-8 (0.1 g, 155.86 μmol) was dissolved in DCM (2 mL), and then TFA (1.49 g, 13.07 mmol, 1 mL) was added, and the mixture was stirred at 25 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure to give a white solid product I-12F-9 (0.1 g, crude, TFA salt), MS (ESI) m / z: 542.3 [M+H] + .

[0489] Step 10: Synthesis (I-12F)

[0490] I-12F-9 (0.084 g, 128.14 μmol, A), int-F (74.07 mg, 192.22 μmol), HATU (63.34 mg, 166.59 μmol) and DIPEA (33.12 mg, 256.29 μmol, 44.64 μL) were dissolved in DMF (1.21 mL), and the mixture was stirred at 25° C. for 2 hours. The reaction solution was purified by reverse phase C18 column chromatography (mobile phase: MeCN and water containing 0.1% HCOOH, gradient from 1% to 60% in 10 minutes; detector: UV 254 nm) to obtain a yellow solid product I-12F (0.032 g, yield 25.37%, formate), MS (ESI) m / z: 909.6 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.28(s,1H),11.08(s,1H),8.83(s,1H),8.48(s,1H),8.44(d,J=7.5Hz,1H),8.37(t,J =7.5Hz,1H),8.17(d,J=7.5Hz,1H),7.87(s,1H),7.76(s,1H),7.67(d,J=8.5Hz,1H),7.33(s,1H),7.25(d,J=9.0 Hz,1H),5.35–5.20(m,2H),5.07(dd,J=12.5,5.5Hz,1H),4.07(d,J=12.5Hz,2H),3.58-3.52(m,4H),3.12–3.01 (m,3H),2.94–2.83(m,2H),2.65–2.54(m,3H),2.36(s,2H),2.04–1.99(m,1H),1.97(s,3H),1.69–1.57(m,10H).

[0491] Compounds I-7, I-13, I-14, I-16, I-17, I-19 and I-20 can be prepared by referring to the methods of Examples 1 and 4 above, and their structures and characterization data are shown in the following table:

[0492]

[0493]

[0494]

[0495] Example 5: Synthesis of I-22

[0496]

[0497] Step 1: Synthesis (I-22-1)

[0498] CD3-I (31 g, 214.2 mmol) was added to a DMF (400 mL) solution of 2-fluoro-4-hydroxybenzaldehyde (25 g, 178.4 mmol) and K2CO3 (49.3 g, 356.9 mmol) at 0 ° C under nitrogen, and the mixture was stirred at 25 ° C for 16 hours. The mixture was quenched with NH4Cl solution (saturated, 400 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid product I-22-1 (27 g, yield 95.7%), MS (ESI) m / z: 158.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.21(s,1H),7.82(t,J=8.4Hz,1H),6.78(dd,J=8.8,2.4Hz,1H),6.64(dd,J=12.4,2.4Hz,1H).

[0499] Step 2: Synthesis (I-22-2)

[0500] At 0 ° C, I-22-1 (25 g, 163 mmol) was added to a solution of KNO3 (18 g, 179 mmol) and concentrated H2SO4 (130 mL) in batches, and the mixture was stirred at 25 ° C for 2 hours after the addition was completed in 0.5 hours. The reaction mixture was quenched with ice water, filtered, washed with H2O and the filter cake was dried in vacuo to give a yellow solid product I-22-2 (30 g, yield 93.2%), MS (ESI) m / z: 203.2 [M+H] + . 1 HNMR (400MHz, CDCl3) δ10.22(s,1H),8.46(d,J=7.2Hz,1H),6.87(d,J=11.6Hz,1H).

[0501] Step 3: Synthesis (I-22-3)

[0502] A solution of I-22-2 (27 g, 133.5 mmol), hydrazine hydrate (13.4 g, 267.1 mmol) and DMF (60 mL) was stirred at 140 ° C for 2 hours. After cooling to room temperature, the reaction mixture was washed with ice water to obtain a yellow solid product I-22-3 (30 g, yield 97%), MS (ESI) m / z: 197.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),8.41(s,1H),8.20(s,1H),7.21(s,1H).

[0503] Step 4: Synthesis (I-22-4)

[0504] A mixed solution of I-22-3 (16 g, 81.6 mmol), a THF (1 L) solution containing wet Pd / C (3 g, 10% purity) and DMF (100 mL) was stirred at 25 ° C for 16 hours under a hydrogen atmosphere. The reaction system was filtered through celite and washed with THF (1 L), and the filtrate was distilled under reduced pressure to obtain a brown solid product I-22-4 (11.5 g, yield 84.9%), MS (ESI) m / z: 167.2 [M+H] + .

[0505] Step 5: Synthesis (I-22-5)

[0506] A mixed solution of I-22-4 (23 g, 138 mmol), HATU (56 g, 162 mmol), DIEA (32 g, 277 mmol) and DMF (100 mL) was stirred at 25 ° C for 10 minutes, and then a solution of 6-(trifluoromethyl)picolinic acid (23 g, 135 mmol) in DMF (20 mL) was added at 0 ° C, and the resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with H2O (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was concentrated under reduced pressure to give a brown solid product I-22-5 (24 g, yield 51.1%), MS (ESI) m / z: 340.1 [M+H] + .

[0507] Step 6: Synthesis (I-22-6)

[0508] A solution of I-22-5 (24 g, 70.8 mmol), I-1-A (42 g, 106.2 mmol), Cs2CO3 (69 g, 212.4 mmol), KI (11.8 g, 70.8 mmol) and DMF (120 mL) was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (PE / EtOAc=1 / 1) to give a yellow solid product I-22-6 (5 g, yield 13%), MS (ESI) m / z: 563.2 [M+H] + .

[0509] Step 7: Synthesis (I-22-7)

[0510] At 25 ° C, a solution of I-22-6 (5 g, 8.9 mmol) and HCl-dioxane (1M, 100 mL) was stirred for 1 hour, and ether was added to the reaction mixture under stirring. After standing, the supernatant was removed, and the reaction mixture was repeated three times to remove the residual HCl in the reaction mixture to obtain a white solid product I-22-7 (4 g, yield 97%), MS (ESI) m / z: 463.2 [M+H] + .

[0511] Step 8: Synthesis (I-22)

[0512] A solution of int-F (2.9 g, 7.5 mmol), DIEA (3.9 g, 30.0 mmol), HATU (3.4 g, 9.0 mmol) and DMF (20 mL) was stirred at 25 ° C for 10 minutes, and then a DMF (10 mL) solution containing I-22-7 (3.7 g, 7.5 mmol) was added at 0 ° C, and the resulting mixture was stirred for 2 hours until the reaction was complete. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column chromatography to obtain a yellow solid product I-22 (2.1 g, yield 32%), MS (ESI) m / z: 830.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.51(s,1H),8.69(s,1H),8.52–8.33(m,3H),8.22(d ,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.33(s,1H),7.29–7.17(m,2H),5.231–5.12(m,1H),5. 07(dd,J=12.8,5.2Hz,1H),4.07(d,J=13.2Hz,2H),3.58–3.31(m,4H),3.10–3.05(m,3H),2. 92–2.84(m,1H),2.61–2.54(m,2H),2.48–2.35(m,4H),2.07–1.96(m,1H),1.77–1.53(m,8H).

[0513] Example 6, Synthesis of I-23

[0514]

[0515] Step 1: Synthesis (I-23-1)

[0516] Dissolve 5-amino-2H-indazole-6-carboxylic acid methyl ester (5g, 26mmol) in tetrahydrofuran (50mL), slowly add DIPEA (27g, 209mmol), then add T3P (propylphosphoric anhydride, 25g, 78.6mmol), and then add 6-(trifluoromethyl)picolinic acid (7.5g, 39mmol) to the reaction solution. After the addition is complete, the reaction solution is stirred at 25°C for 16 hours. Add water to the reaction system, precipitate solids, filter, and vacuum dry the filter cake to obtain a light yellow solid product I-23-1 (9.3g, yield 98%). MS (ESI) m / z: 365.3 [M+H] + .

[0517] Step 2: Synthesis (I-23-2)

[0518] A solution of I-23-1 (5 g, 13.72 mmol), I-1-A (10.86 g, 27.45 mmol), Cs2CO3 (13.4 g, 41.2 mmol), KI (2.28 g, 13.72 mmol) and DMF (50 mL) was stirred at 50 ° C for 16 hours. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (PE / EtOAc=1 / 1) to give a brown solid product I-23-2 (1.0 g, yield 12.3%), MS (ESI) m / z: 588.2 [M+H] + .

[0519] Step 3: Synthesis (I-23-3)

[0520] At 0 ° C, (methyl-D3) magnesium iodide (14.5 mL, 14.5 mmol) was added dropwise to a solution of I-23-2 (850 mg, 1.45 mmol) in THF (40 mL), and the mixture was stirred at 25 ° C for 16 hours. The reaction solution was poured into water and then extracted with EtOAc (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc=2 / 1) to obtain a yellow solid product I-23-3 (100 mg, yield 11.6%), MS (ESI) m / z: 594.4 [M+H] + .

[0521] Step 4: Synthesis (I-23-4)

[0522] At 0°C, TFA (2 mL) was added dropwise to a DCM (5 mL) solution of I-23-3 (100 mg, 0.17 mmol), and the mixture was stirred at 25°C for 2 hours. Ether was added to the reaction mixture under stirring, and the supernatant was removed after standing. The residual TFA in the reaction solution was removed three times, and vacuum dried to obtain a yellow solid product I-23-4 (80 mg, yield 95.2%), MS (ESI) m / z: 494.3 [M+H] + .

[0523] Step 5: Synthesis (I-23)

[0524] At 0°C, DIEA (53 mg, 0.42 mmol) and I-23-4 (100 mg, 0.21 mmol) were added to a solution of int-F (80 mg, 0.21 mmol), HATU (92 mg, 0.24 mmol) and DMF (5 mL), and the mixture was stirred at 25°C for 16 hours. Water (10 mL) was added and extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give a white solid product I-23 (24.05 mg, yield 13.9%), MS (ESI) m / z: 861.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),11.11(s,1H),8.77(s,1H),8.50(d,J=7.6Hz,1H),8.46–8.37(m,2H ),8.20(d,J=7.6Hz,1H),7.71(d,J=8.4Hz,1H),7.65(s,1H),7.37(s,1H),7.29(d,J=8.4Hz,1H),5.98(s,1 H),5.35–5.21(m,1H),5.11(m,1H),4.11(d,J=11.6Hz,2H),3.61–3.46(m,6H),3.16–3.04(m,2H),3.04–2. 96(m,1H),2.95–2.81(m,1H),2.69–2.55(m,2H),2.47–2.36(m,2H),2.10–1.96(m,1H).1.84–1.57(m,8H).

[0525] Compounds I-24 to I-29, I-31 to I-38, I-48, I-51, I-53, and I-56 were prepared by referring to the methods of Examples 1, 3, 5, and 6, and their structures and characterization data are shown in the following table:

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535] Example 7, Synthesis of I-30

[0536]

[0537] Step 1: Synthesis (I-30-1)

[0538] Under nitrogen protection, 4-bromo-2-methoxy-5-methyl-aniline (1g, 4.63mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (1.06g, 5.55mmol), DIPEA (1.20g, 9.26mmol, 1.61mL) and anhydrous THF (15mL) were added to the reaction bottle, cooled to 0°C and T3P (2.95g, 9.26mmol) was slowly added dropwise, and the reaction was stirred at 25°C for 1 hour. H2O (60mL) was added to the reaction system, the product precipitated, filtered, the filter cake was washed with water, and vacuum dried to obtain a white solid product I-30-1 (1.77g, yield 98.16%), MS (ESI) m / z: 389.2 [M+H] + .

[0539] Step 2: Synthesis (I-30-2)

[0540] Under nitrogen protection, I-30-1 (1.77 g, 4.54 mmol), phenyl formate (1.1 g, 9.08 mmol), Pd(OAc)2 (palladium acetate, 101 mg, 0.45 mmol), P(t-Bu)3.HBF4 (tri-tert-butylphosphine tetrafluoroborate, 516.4 mg, 1.78 mmol), Et3N (triethylamine, 917.08 mg, 9.08 mmol), acetonitrile (3 mL) were added to the reaction bottle, and the temperature was raised to 80 ° C to react overnight. Return to room temperature, filter, and concentrate the filtrate under reduced pressure. Add ethyl acetate to dilute, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by reverse phase C18 column chromatography (mobile phase 0-60% water / acetonitrile) to give a white solid product I-30-2 (1.3 g, yield 70%), MS (ESI) m / z: 431.1 [M+H] + .

[0541] Step 3: Synthesis (I-30-3)

[0542] I-30-2 (1.3 g, 3.2 mmol), potassium carbonate (1.77 g, 12.8 mmol) and methanol (4 mL) were added to the reaction flask and reacted at room temperature for 2 hours. The product was precipitated by adding water, filtered, and the filter cake was washed with water. The filter cake was vacuum dried to obtain a crude product. The crude product was purified by reverse phase C18 column chromatography (mobile phase 0-60% water / acetonitrile) to obtain a white solid product I-30-3 (900 mg, yield 75%), MS (ESI) m / z: 369.1 [M+H] + .

[0543] Step 4: Synthesis (I-30-4)

[0544] Under nitrogen protection, I-30-3 (900 mg, 2.4 mmol), NBS (512.6 mg, 2.88 mmol), AIBN (39 mg, 0.24 mmol) and CCl4 (9 mL) were added to the reaction bottle and heated to 80 ° C for 5 hours. After returning to room temperature, the reaction solution was filtered, H2O (30 mL) was added to the filtrate, extracted with EA (25 mL x 3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase C18 column chromatography and eluted with (MeCN / H2O+1‰HCOOH) to obtain the desired white solid product I-30-4 (802 mg, yield 76%), MS (ESI) m / z: 447.1 [M+H] + .

[0545] Step 5: Synthesis (I-30-5)

[0546] A mixed solution of I-30-4 (300 mg, 670.84 μmol), 2-amino-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (177.35 mg, 737.92 μmol), DIPEA (260.10 mg, 2.01 mmol, 350.53 μL) and ACN (4 mL) was stirred at 25 ° C for 3 hours. H2O (20 mL) was added to the reaction solution, extracted with EA (15 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM: MeOH = 30: 1) to give a brown solid product I-30-5 (135 mg, yield 35.02%), MS (ESI) m / z: 575.3 [M + H] + .

[0547] Step 6: Synthesis (I-30-6)

[0548] I-30-5 (135 mg, 234.95 μmol) was dissolved in DCM (3 mL), TFA (1.5 mL) was added, and stirred at 25 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain a white solid product I-30-6 (86 mg, yield 70.32%, TFA salt), MS (ESI) m / z: 475.2 [M+H] + .

[0549] Step 7: Synthesis (I-30)

[0550] A mixed solution of I-30-6 (40 mg, 76.85 μmol), int-F (32.58 mg, 84.53 μmol), HATU (35.06 mg, 92.22 μmol), DIPEA (39.73 mg, 307.40 μmol, 53.54 μL) and DMF (2 mL) was stirred at 25 ° C for 1 hour. H2O (25 mL) was added to the reaction solution, extracted with EA (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM: MeOH = 20: 1) to obtain a yellow solid product I-30 (27 mg, yield 40.90%). 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.58(s,1H),8.67(s,1H),8.48(d,J=7.5Hz,1H),8.42(t,J=8.0Hz,1H),8.25(d,J=7.5Hz,1H),7. 66(d,J=8.5Hz,1H),7.36(s,1H),7.33(d,J=1.5Hz,1H),7.25(dd,J=8.5,2.0Hz,1H),5.07(dd,J=13.0,5.5Hz,1H),4.85–4.77(m,1H),4. 59(s,2H),4.10–4.03(m,2H),4.02(s,3H),3.57–3.50(m,1H),3.50–3.41(m,2H),3.40–3.36(m,1H),3.13–3.05(m,2H),3.04–2.97(m,1H ),2.93–2.84(m,1H),2.66–2.52(m,3H),2.23–2.09(m,4H),2.05–1.98(m,1H),1.74–1.66(m,3H),1.66–1.56(m,4H),1.54–1.49(m,1H).

[0551] Example 8, Synthesis of I-41

[0552]

[0553] Step 1: Synthesis (I-41-1)

[0554] Under nitrogen protection, a mixture of 6-methoxy-5-nitro-2H-indazole (1.17 g, 6.07 mmol), DMF (12 mL), cesium carbonate (4.94 g, 15.17 mmol) and I-1-A (3 g, 7.59 mmol) was stirred at 90 ° C for 3 hours. After returning to room temperature, H2O (60 mL) was added to the reaction mixture, and extracted with DCM (35 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM / MeOH=98 / 2) to give a white solid product I-41-1 (770 mg, yield 24.38%), MS (ESI) m / z: 417.5 [M+H] + .

[0555] Step 2: Synthesis (I-41-2)

[0556] Under hydrogen atmosphere, I-41-1 (770 mg, 1.85 mmol) was dissolved in MeOH (7 mL), and a catalyst wet Pd / C (80 mg, 10% purity) was added, and the mixture was reacted at 25°C for 4 hours. The reaction solution was filtered through diatomaceous earth to remove the catalyst, and the filtrate was concentrated under reduced pressure to obtain a yellow solid product II-41-2 (500 mg, yield 69.97%), MS (ESI) m / z: 387.2 [M+H] + .

[0557] Step 3: Synthesis (I-41-3)

[0558] A mixed solution of II-41-2 (50 mg, 129.37 μmol), 6-morpholinopyridine-2-carboxylic acid (26.94 mg, 129.37 μmol), HATU (49.19 mg, 129.37 μmol), DIPEA (33.44 mg, 258.74 μmol, 45.07 μL) and DMF (2 mL) was stirred at 25 ° C for 2 hours. H2O (30 mL) was added to the reaction solution, extracted with EA (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography to obtain a white solid product II-41-3 (64 mg, yield 85.78%), MS (ESI) m / z: 577.5 [M+H] + .

[0559] Step 4: Synthesis (I-41-4)

[0560] A mixed solution of I-41-3 (63 mg, 109.25 μmol), TFA (2 mL) and DCM (2 mL) was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to give a yellow oily product I-41-4 (64 mg, crude, TFA salt), MS (ESI) m / z: 477.3 [M+H] + .

[0561] Step 5: Synthesis (I-41)

[0562] A mixed solution of I-41-4 (52 mg, 109.11 μmol), int-F (42.05 mg, 109.11 μmol), HATU (41.49 mg, 109.11 μmol), DIPEA (28.20 mg, 218.23 μmol, 38.01 μL) and DMF (2 mL) was stirred at 25 ° C for 2 hours. H2O (30 mL) was added to the reaction solution, extracted with EA (20 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by preparative thin layer chromatography to obtain a yellow solid product I-41 (28 mg, yield 29.80%), MS (ESI) m / z: 844.6 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ11.08(s,1H),10.79(s,1H),8.64(s,1H),8.33(s,1H),7.84–7.78(m,1H),7.67(d,J=8.5Hz,1H),7 .46(d,J=7.0Hz,1H),7.33(s,1H),7.25(d,J=8.5Hz,1H),7.18(s,1H),7.16(d,J=8.5Hz,1H),5.22–5.12(m,1H),5.07(dd, J=12.5,5.5Hz,1H),4.11–4.03(m,2H),3.97(s,3H),3.84–3.78(m,4H),3.69–3.59(m,4H),3.56–3.39(m,4H),3.15–3.05( m,2H),3.04–2.95(m,1H),2.93–2.84(m,1H),2.68–2.53(m,2H),2.48–2.32(m,4H),2.05–1.99(m,1H),1.75–1.57(m,8H).

[0563] Compounds I-42, I-44, I-46, I-47, I-49, I-50, I-52, I-54 and I-55 were prepared by the method of Example 8, and their structures and characterization data are shown in the following table:

[0564]

[0565]

[0566]

[0567]

[0568] Example 9: Synthesis of I-43

[0569]

[0570] Step 1: Synthesis (I-43-1)

[0571] A mixture of 5-fluoroisobenzofuran-1,3-dione (0.9 g, 8.6 mmol), 6-aminopyridazin-3(2H)-one (1.3 g, 7.8 mmol), NaOAc (1.3 g, 15.5 mmol) and HOAc (7 mL) was stirred at 80°C for 16 hours. The mixture was returned to room temperature and concentrated under reduced pressure. The residue was poured into water and stirred. Solids precipitated, filtered, washed with ether, and the filter cake was dried under vacuum to obtain a white solid product I-43-1 (1.2 g, yield 55%), MS (ESI) m / z: 260.2 [M+H] + .

[0572] Step 2: Synthesis (I-43-2)

[0573] To a solution of I-43-1 (1.1 g, 4.4 mmol) in anhydrous DMSO (10.0 mL) was added DIEA (1.14 g, 8.8 mmol) and tert-butyl piperidine-4-carboxylate (0.82 g, 4.4 mmol) and reacted at 90 ° C for 2 hours. Return to room temperature, dilute the reaction mixture with water (100 mL), and extract with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse C18 column chromatography to obtain a yellow solid product I-43-2 (200 mg, yield 11%), MS (ESI) m / z: 425.3 [M+H] + .

[0574] Step 3: Synthesis (I-43-3)

[0575] At 0°C, TFA (1 mL) was added dropwise to a solution of I-43-2 (200 mg, 0.47 mmol) and DCM (5 mL), and the mixture was stirred at 25°C for 16 hours. Ether was added to precipitate a solid, and the mixture was allowed to stand and the supernatant was removed, which was repeated three times. The yellow solid product I-43-3 (180 mg, yield 99%) was obtained by vacuum drying. MS (ESI) m / z: 369.1 [M+H] + .

[0576] Step 4: Synthesis (I-43)

[0577] A mixed solution of I-43-3 (60 mg, 0.14 mmol), I-1-4 (52 mg, 0.14 mmol), HCTU (67 mg, 0.16 mmol), TEA (142 mg, 1.4 mmol) and DMF (3 mL) was stirred at 25 ° C for 1 hour. The reaction solution was purified by preparative HPLC to obtain a yellow solid product I-43 (11.2 mg, yield 10%), MS (ESI) m / z: 810.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.69(s,1H),8.47(d,J=7.5Hz,1H),8.44–8.39(m,1H),8.38(d,J=1. 0Hz,1H),8.22(dd,J=7.5,1.0Hz,1H),7.74(d,J=8.5Hz,1H),7.56(d,J=9.5Hz,1H),7.40(d,J=1.5Hz,1H),7 .33–7.28 (m, 1H), 7.21 (s, 1H), 7.06 (d, J = 9.5 Hz, 1H), 5.21–5.14 (m, 1H), 4.20–4.07 (m, 3H), 3.99 (s, 3H), 3.59–3.38 (m, 4H), 3.13–3.02 (m, 3H), 2.70–2.65 (m, 1H) 2.49–2.36 (m, 4H), 1.84–1.49 (m, 8H). Example 10 Synthesis of I-45

[0578]

[0579] Step 1: Synthesis (I-45-1)

[0580] Under nitrogen atmosphere at 0°C, add (2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl) allyl carbonate (10.6 g, 53.1 mmol) to a solution of K2CO3 (18.35 g, 132.8 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (10 g, 44.25 mmol) in acetone / H2O (120 / 40 mL), and stir at 25°C for 16 hours. The reaction system was diluted with ethyl acetate (500 mL), washed with 3N HCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification by rapid silica gel column chromatography gave a yellow solid product I-45-1 (13.0 g, yield 94%), 1 H NMR (400MHz, CDCl3) δ6.00–5.87(m,1H),5.31–5.20(m,2H),4.59–4.57(m,2H),3.65(s,4H),3.46–3.38(m,4H),1.74–1.70(m,4H),1.43(s,9H).

[0581] Step 2: Synthesis (I-45-2)

[0582] Add TFA (24 mL) to a DCM (240 mL) solution of I-45-1 (12.2 g, 39.0 mmol) at 0°C and react at 25°C for 2 hours. Add ether to precipitate a solid, let stand, remove the supernatant, and repeat three times. Vacuum dry to obtain a brown solid product I-45-2 (10 g, yield 100%). 1 H NMR (400MHz, DMSO-d6) δ5.97–5.87(m,1H),5.29–5.17(m,2H),4.53–4.51(m,2H),3.73(t,J=6.4Hz,4H),1.78–1.66(m,4H).

[0583] Step 3: Synthesis (I-45-3)

[0584] At 0 ° C, 6-chloropyridin-3-ol (22 g, 170 mmol) was added in batches to a solution of KNO3 (31 g, 308 mmol) and concentrated H2SO4 (250 mL). The addition was completed after 0.5 hours, and the resulting mixture was stirred at 25 ° C for 2 hours. Quenched with ice water, the solid was filtered, washed with H2O and the filter cake was dried in vacuo to obtain a yellow solid product I-45-3 (20 g, yield 69%), MS (ESI) m / z: 175.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.92 (s, 1H), 7.73 (q, J = 8.8Hz, 2H).

[0585] Step 4: Synthesis (I-45-4)

[0586] Under nitrogen atmosphere, Fe (25.4 g, 453 mmol) was added to a solution of I-45-3 (15 g, 90 mmol) and NH4Cl (24 g, 453 mmol) in MeOH / H2O (150 mL / 50 mL), and the mixture was reacted at 70 °C for 4 hours. After returning to room temperature, water (300 mL) was added for dilution, and the solution was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EtOAc=5 / 1) to obtain a yellow solid product I-45-4 (5 g, yield 24%), MS (ESI) m / z: 145.0 [M+H] + .

[0587] Step 5: Synthesis (I-45-5)

[0588] Under nitrogen atmosphere, I-45-4 (7 g, 48 mmol), potassium O-ethyldithiocarbonate (10.8 g, 68 mmol) in pyridine (80 mL) were stirred at 110 ° C for 16 hours. The reaction system was returned to room temperature and diluted with ice water (100 mL), acidified to pH = 3-4 with dilute hydrochloric acid (4 M) under stirring, and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid product I-45-5 (4 g, yield 45%), MS (ESI) m / z: 186.1 [M+H] + .

[0589] Step 6: Synthesis (I-45-6)

[0590] To a solution of I-45-5 (6 g, 32 mmol) and EtOAc (60 mL) was added iodomethane (9 g, 64 mmol) and K2CO3 (8.8 g, 64 mmol), the resulting mixture was sealed and stirred at 25 ° C under nitrogen protection for 2 hours. The reaction solution was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc=10 / 1) to give a yellow solid product I-45-6 (4 g, yield 62.5%), MS (ESI) m / z: 200.9 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.58 (d, J = 8.4Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 2.73 (s, 3H).

[0591] Step 7: Synthesis (I-45-7)

[0592] Under nitrogen atmosphere, a solution of I-45-6 (4.2 g, 21 mmol), I-45-2 (22 g, 105 mmol), DIEA (13.6 g, 105 mol) and 1,4-dioxane (40 mL) was stirred at 110 ° C for 16 hours. The reaction solution was diluted with H2O (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc=3 / 1) to obtain a yellow solid product I-45-7 (5 g, yield 65%), MS (ESI) m / z: 363.1 [M+H] + .

[0593] Step 8: Synthesis (I-45-8)

[0594] At -30 ℃ to -20 ℃, slowly add concentrated H2SO4 (10 mL) and concentrated HNO4 (10 mL) solution to a solution of I-45-7 (5 g, 13.7 mmol) and concentrated H2SO4 (40 mL) under stirring, and the addition is completed after 2 hours. The reaction solution is stirred for 20 minutes, and then ice water is added to quench the reaction. The solid is filtered, washed with H2O, and the filter cake is dried in vacuo to obtain a yellow solid product I-45-8 (2.2 g, yield 50%), MS (ESI) m / z: 324.1 [M+H] + .

[0595] Step 9: Synthesis (I-45-9)

[0596] To a solution of I-45-8 (2.2 g, 6.8 mmol), DMAP (0.08 g, 0.6 mmol), TEA (2.06 g, 20.4 mmol) and THF (20 mL) was added di-tert-butyl dicarbonate (2.22 g, 10 mmol) at 0 ° C and the resulting mixture was stirred for 1 hour until the reaction was complete. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (PE / EtOAc=1 / 1) to give a yellow solid product I-45-9 (600 mg, yield 21%), MS (ESI) m / z: 424.0 [M+H] + .

[0597] Step 10: Synthesis (I-45-10)

[0598] A mixture of I-45-9 (600 mg, 1.4 mmol), (R)-pyrrolidin-3-ol (699 mg, 5.66 mmol), DIEA (362 mg, 2.8 mmol) and toluene (10 mL) was sealed and stirred at 110 ° C under nitrogen protection for 16 hours. After returning to room temperature, the mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (PE / EtOAc=1 / 1) to give a yellow solid product I-45-10 (350 mg, yield 52.6%), MS (ESI) m / z: 475.3 [M+H] + .

[0599] Step 11: Synthesis (I-45-11)

[0600] Wet Pd / C (35 mg, 10% purity) was added to a solution of I-45-10 (350 mg, 0.73 mmol) in MeOH (2 mL), and stirred at 25 ° C for 4 hours under a hydrogen atmosphere. The reaction system was filtered through diatomaceous earth, and the filter cake was washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give a green solid product I-45-11 (200 mg, yield 61.5%), MS (ESI) m / z: 445.2 [M+H] + .

[0601] Step 12: Synthesis (I-45-12)

[0602] A mixture of 6-(trifluoromethyl)picolinic acid (51.5 mg, 0.27 mmol), I-45-11 (120 mg, 0.27 mmol), HOBT (54.6 mg, 0.4 mmol), EDCI (52 mg, 0.4 mol), DMAP (6.6 mg, 0.05 mmol) and DMF (2 mL) was stirred at 25 ° C for 16 hours. The reaction solution was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative thin layer chromatography (PE / EtOAc=3 / 1) to give a yellow solid product I-45-12 (50 mg, yield 30%), MS (ESI) m / z: 618.1 [M+H] + .

[0603] Step 13: Synthesis (I-45-13)

[0604] I-45-12 (50 mg, 0.08 mmol) was added to HCl-dioxane (1 M, 3 mL) at 0 ° C, and the reaction mixture was stirred at 25 ° C for 1 hour. Ether was added to the reaction mixture under stirring, and the supernatant was removed after standing. This was repeated three times to obtain a yellow solid product I-45-13 (35 mg, yield 85.3%), MS (ESI) m / z: 518.2 [M+H] + .

[0605] Step 14: Synthesis (I-45)

[0606] A mixed solution of int-F (28.3 mg, 0.073 mmol), TEA (30 mg, 0.294 mmol), I-45-13 (38 mg, 0.073 mmol), HCTU (33.4 mg, 0.080 mmol) and DMF (20 mL) was stirred at 25 ° C for 16 hours until the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain a yellow solid product I-45 (23 mg, yield 35%), MS (ESI) m / z: 885.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.17(s,1H),8.51–8.32(m,2H),8.19(dd,J=7.5,1.0Hz,1H), 8.01(s,1H),7.66(d,J=8.5Hz,1H),7.33(d,J=1.5Hz,1H),7.24(dd,J=8.5,2.0Hz,1H),5.06(dd,J=1 3.0,5.5Hz,1H),4.88–4.81(m,1H),4.29(s,1H),4.08–4.01(m,6H),3.71–3.50(m,4H),3.48–3.33(m ,4H),3.08–3.01(m,4H),2.67–2.56(m,1H),2.70–2.53(m,2H),2.07–1.89(m,2H),1.86–1.58(m,8H).

[0607] Example 11, Synthesis of Compound II-2

[0608]

[0609] Step 1: Synthesis (int-G-1)

[0610] A mixed solution of 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindole-1,3-dione (1 g, 3.62 mmol), tert-butyl piperazine-1-carboxylate (809.14 mg, 4.34 mmol), DIPEA (935.80 mg, 7.24 mmol, 1.26 mL) and DMSO (10 mL) was stirred at 100°C for 2 hours. After returning to room temperature, water (60 mL) was added under stirring, and a solid precipitated. The solid was filtered and dried to obtain a white solid product int-G-1 (1.2 g, crude product), MS (ESI) m / z: 443.3 [M+H] + .

[0611] Step 2: Synthesis (int-G)

[0612] A mixed solution of int-G-1 (35 mg, 79.10 μmol), TFA (1 mL) and DCM (1 mL) was stirred at 25 °C for 1 hour, and the mixture was concentrated under reduced pressure to obtain a yellow solid product int-G (25 mg, yield 69.25%, TFA salt) which was directly used for the next step reaction, MS (ESI) m / z: 343.2 [M+H] + .

[0613] Step 3: Synthesis (II-2-1)

[0614] 5-Nitro-6-(trifluoromethoxy)-2H-indazole (250 mg, 1.01 mmol) was dissolved in MeOH (3 mL), and a catalyst wet Pd / C (26.14 mg, 10% purity) was added. The mixed solution was replaced with hydrogen three times under stirring, and the hydrogen environment was kept stirring for 2 hours. The reaction solution was filtered through diatomaceous earth to remove the catalyst, and the filtrate was dried to obtain a brown solid product II-2-1 (211 mg, yield 96.05%), MS (ESI) m / z: 218.1 [M+H] + .

[0615] Step 4: Synthesis (II-2-2)

[0616] A mixed solution of II-2-1 (320 mg, 1.47 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (309.79 mg, 1.62 mmol), DMF (5 mL), HATU (840.49 mg, 2.21 mmol) and DIPEA (380.91 mg, 2.95 mmol, 513.35 μL) was stirred at 25 ° C for 6 hours until the reaction was complete. Water (30 mL) was added to the reaction solution, extracted with EA (50 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to give a brown solid product II-2-2 (295 mg, yield 51.30%), MS (ESI) m / z: 391.2 [M + H] + .

[0617] Step 5: Synthesis (II-2-3)

[0618] A mixed solution of II-2-2 (100 mg, 256.25 μmol), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (143.17 mg, 512.51 μmol), NaOH (20.50 mg, 512.51 μmol) and DMF (3 mL) was stirred at 110 ° C for 6 hours. Water (30 mL) was added to the reaction solution, extracted with EA (30 mL x 3), and the combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE: EA = 3: 1) to give a brown solid product II-2-3 (71 mg, yield 48.31%), MS (ESI) m / z: 574.5 [M + H] + .

[0619] Step 6: Synthesis (II-2-4)

[0620] II-2-3 (71 mg, 123.80 μmol) was dissolved in DCM (5 mL), and HCl-dioxane solution (4 M, 309.51 μL) was added dropwise to the mixture at 25 ° C. After the addition, the reaction solution was stirred for 2 hours. Water (30 mL) was added to the reaction solution, and the pH was adjusted to neutral with saturated NaHCO3, and then extracted with DCM (20 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a white solid product II-2-4 (48 mg, yield 81.90%), MS (ESI) m / z: 474.1 [M+H] + .

[0621] Step 7: Synthesis (II-2-5)

[0622] A mixture of II-2-4 (48 mg, 101.40 μmol), tert-butyl 2-bromoacetate (23.73 mg, 121.68 μmol), DIPEA (26.21 mg, 202.80 μmol, 35.32 μL) and DMF (2 mL) was stirred at 25 ° C for 2 hours. Water (20 mL) was added to the reaction solution, extracted with EA (20 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give a white solid product II-2-5 (45 mg, yield 75.54%), MS (ESI) m / z: 588.5 [M + H] + .

[0623] Step 8: Synthesis (II-2-6)

[0624] A mixed solution of II-2-5 (45 mg, 76.59 μmol), DCM (1.5 mL) and TFA (1.5 mL) was stirred at 25 ° C for 2 hours. The mixture was repeatedly concentrated under reduced pressure to remove the solvent to obtain a white solid product II-2-6 (24 mg, yield 58.96%), MS (ESI) m / z: 532.1 [M+H] + .

[0625] Step 9: Synthesis (II-2)

[0626] A mixed solution of II-2-6 (24 mg, 45.16 μmol), int-G (22.67 mg, 49.68 μmol, TFA salt), DMF (2 mL), DIPEA (17.51 ​​mg, 135.49 μmol, 23.60 μL) and HATU (25.76 mg, 67.74 μmol) was stirred at 25 ° C for 2 hours. Water (20 mL) was added, extracted with EA (20 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography to obtain a yellow solid product II-2 (23 mg, yield 58.32%), MS (ESI) m / z: 856.3 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ11.08(s,1H),10.39(s,1H),8.69(s,1H),8.62(s,1H),8.47(d,J=7.5Hz,1H),8.42(t,J=8.0Hz,1H),8 .24(dd,J=7.5,1.0Hz,1H),7.82(s,1H),7.72(d,J=8.5Hz,1H),7.39(d,J=2.0Hz,1H),7.29(dd,J=8.5,2.0Hz,1H),5.08(dd,J= 13.0,5.5Hz,1H),4.57–4.50(m,1H),3.80–3.75(m,2H),3.65–3.60(m,2H),3.60–3.55(m,2H),3.52–3.47(m,2H),3.01(d,J=1 1.0Hz,2H),2.93–2.84(m,1H),2.66–2.59(m,1H),2.59–2.53(m,1H),2.37–2.24(m,3H),2.17–2.09(m,4H),2.06–1.94(m,2H).

[0627] Compounds II-4, II-7, II-10, II-12, II-13, II-16, II-17, II-20 and II-21 were prepared by the methods of Example 2 and Example 11, and their structures and characterization data are shown in the following table:

[0628]

[0629]

[0630]

[0631]

[0632] Example 12: Synthesis of I-57 and I-58

[0633]

[0634] I-1 (100 mg) was chirally separated by SFC (supercritical fluid chromatography) to obtain yellow solid I-57 (47 mg) and yellow solid I-58 (44 mg).

[0635] I-57 or I-58: Chiral HPLC: optical purity (ee value) = 100%, RT = 2.262 min. MS (ESI) m / z: 827.8 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H),8.38(s ,1H),8.22(d,J=8.0Hz,1H),7.67(d,J=8.5Hz,1H),7.34(s,1H),7.25(d,J=8.5Hz,1H),7.22(s,1H),5.24–5.12(m,1H), 5.07(dd,J=13.0,5.0Hz,1H),4.07(d,J=12.5Hz,2H),3.99(s,3H),3.60–3.38(m,4H),3.13–3.07(m,2H),3.04–2.97(m, 1H),2.92–2.84(m,1H),2.66–2.52(m,2H),2.49–2.36(m,4H),2.04–1.98(m,1H),1.75–1.67(m,4H),1.66–1.56(m,4H).

[0636] I-57 or I-58: Chiral HPLC: optical purity (ee value) = 99.64%, RT = 3.319 min. MS (ESI) m / z: 827.8 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H),8. 38(s,1H),8.22(d,J=8.0Hz,1H),7.67(d,J=8.5Hz,1H),7.34(s,1H),7.25(d,J=8.5Hz,1H),7.22(s,1H),5.24–5.1 3(m,1H),5.07(dd,J=13.0,5.0Hz,1H),4.07(d,J=12.5Hz,2H),3.99(s,3H),3.59–3.39(m,4H),3.13–3.07(m,2H), 3.04–2.97(m,1H),2.92–2.83(m,1H),2.66–2.52(m,2H),2.49–2.36(m,4H),2.04–1.98(m,1H),1.75–1.56(m,8H).

[0637] The SFC splitting conditions are as follows:

[0638] Instrument: SFC-150 (Waters)

[0639] Chromatographic column: IH 25x 250mm, 10um (Daicel)

[0640] Column temperature: 35°C

[0641] Mobile phase: CO2 / (MeOH:MeCN=1:1)=50 / 50

[0642] Flow rate: 120mL / min

[0643] Back pressure: 100bar

[0644] Detection wavelength: 214nm

[0645] Cycle time: 8.2min

[0646] Sample solution: 100 mg of sample was dissolved in 25 mL of methanol / dichloromethane

[0647] Injection volume: 4.0mL

[0648] Example 13: Synthesis of I-59 and I-60

[0649]

[0650] I-4 (50 mg) was chiral resolved by SFC to obtain yellow solid I-59 (17.4 mg) and yellow solid I-60 (15.9 mg).

[0651] I-59 or I-60: Chiral HPLC: optical purity (ee value) = 99.64%, RT = 12.068 min. MS (ESI) m / z: 841.9 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H ),8.38(s,1H),8.22(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.22(s,1H),7.03(d,J=7.0Hz,1H),6.99(s,1H), 6.88(d,J=8.0Hz,1H),5.20–5.14(m,1H),5.03(dd,J=13.0,5.5Hz,1H),3.99(s,3H),3.54–3.37(m,5H),2.91 –2.83(m,1H),2.68–2.51(m,3H),2.47–2.35(m,3H),2.04–1.95(m,3H),1.74–1.52(m,8H),1.34–1.22(m,3H).

[0652] I-59 or I-60: Chiral HPLC: optical purity (ee value) = 97.76%, RT = 14.283 min. MS (ESI) m / z: 841.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz,1H ),8.38(s,1H),8.22(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.22(s,1H),7.04(d,J=7.0Hz,1H),6.99(s,1H), 6.88(d,J=8.0Hz,1H),5.20–5.14(m,1H),5.03(dd,J=13.0,5.5Hz,1H),3.99(s,3H),3.52–3.37(m,5H),2.91 –2.83(m,1H),2.68–2.51(m,3H),2.47–2.35(m,3H),2.04–1.95(m,3H),1.75–1.53(m,8H),1.32–1.25(m,3H).

[0653] The SFC splitting conditions are as follows:

[0654] Instrument: Gilson-281

[0655] Chromatographic column: IC 25x 250mm, 10um (Daicel)

[0656] Mobile phase: HEX (0.1% DEA): EtOH (0.1% DEA): = 50:50

[0657] Flow rate: 50mL / min

[0658] Single needle running time: 30min

[0659] Injection volume: 3mL

[0660] Sample solution: 50 mg sample dissolved in 35 mL methanol

[0661] Example 14: Synthesis of I-61 and I-62

[0662]

[0663] I-8 (100 mg) was subjected to SFC chiral separation to obtain yellow solid I-61 (40.6 mg) and yellow solid I-62 (41.2 mg).

[0664] I-61 or I-62: Chiral HPLC: optical purity (ee value) = 100%, RT = 1.759 min. MS (ESI) m / z: 845.8 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz, 1H),8.38(s,1H),8.22(d,J=8.0Hz,1H),7.71(d,J=11.0Hz,1H),7.44(d,J=7.0Hz,1H),7.22(s,1H),5.21– 5.15(m,1H),5.11(dd,J=13.0,5.5Hz,1H),3.99(s,3H),3.64(d,J=11.5Hz,2H),3.58–3.39(m,4H),3.05–2 .97(m,2H),2.94–2.86(m,2H),2.64–2.53(m,2H),2.49–2.36(m,4H),2.10–2.01(m,1H),1.79–1.57(m,8H).

[0665] I-61 or I-62: Chiral HPLC: optical purity (ee value) = 99.74%, RT = 2.520 min. MS (ESI) m / z: 845.8 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ11.12(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=8.0Hz,1H),8.41(t,J=8.0Hz, 1H),8.38(s,1H),8.23(d,J=8.0Hz,1H),7.71(d,J=11.0Hz,1H),7.44(d,J=7.0Hz,1H),7.22(s,1H),5.21– 5.15(m,1H),5.11(dd,J=13.0,5.5Hz,1H),3.99(s,3H),3.64(d,J=11.5Hz,2H),3.57–3.39(m,4H),3.05–2 .97(m,2H),2.94–2.85(m,2H),2.64–2.52(m,2H),2.49–2.36(m,4H),2.10–2.02(m,1H),1.79–1.57(m,8H).

[0666] The SFC splitting conditions are as follows:

[0667] Instrument: SFC-150 (Waters)

[0668] Chromatographic column: IH 25x 250mm, 10um (Daicel)

[0669] Column temperature: 35°C

[0670] Mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50

[0671] Flow rate: 120mL / min

[0672] Back pressure: 100bar

[0673] Detection wavelength: 214nm

[0674] Cycle time: 6.15min

[0675] Sample solution: 100 mg sample dissolved in 18 mL methanol

[0676] Injection volume: 4.0mL

[0677] Example 15: Synthesis of I-63 and I-64

[0678]

[0679] I-5 (20 mg) was chiral separated by SFC to obtain yellow solid I-63 (5.7 mg) and yellow solid I-64 (3.9 mg).

[0680] I-63 or I-64: Chiral HPLC: optical purity (ee value) = 100%, RT = 1.299 min. MS (ESI) m / z: 855.9 [M+H] + .

[0681] I-63 or I-64: Chiral HPLC: optical purity (ee value) = 99.98%, RT = 1.936 min. MS (ESI) m / z: 855.9 [M+H] + .

[0682] The SFC splitting conditions are as follows:

[0683] Instrument: SFC-150 (Waters)

[0684] Chromatographic column: AS25x 250mm, 10um (Daicel)

[0685] Column temperature: 35°C

[0686] Mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH):MeCN=1:1]=40 / 60

[0687] Flow rate: 100mL / min

[0688] Back pressure: 100bar

[0689] Detection wavelength: 214nm

[0690] Cycle time: 7.1min

[0691] Sample solution: 20 mg sample dissolved in 35 mL methanol

[0692] Injection volume: 4.9 mL

[0693] Example 16: Synthesis of I-65 and I-66

[0694]

[0695] I-22 (100 mg) was chiral resolved by SFC to obtain yellow solid I-65 (48.2 mg) and yellow solid I-66 (46.6 mg).

[0696] I-65 or I-66: Chiral HPLC: optical purity (ee value) = 100%, RT = 2.309 min. MS (ESI) m / z: 830.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.51(s,1H),8.69(s,1H),8.47–8.38(m,3H),8.22(d ,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.34(s,1H),7.26–7.21(m,2H),5.21–5.15(m,1H),5. 07(dd,J=12.8,5.2Hz,1H),4.07(d,J=13.2Hz,2H),3.56–3.38(m,4H),3.10–2.97(m,3H),2. 92–2.84(m,1H),2.64–2.54(m,2H),2.48–2.36(m,4H),2.07–1.96(m,1H),1.77–1.53(m,8H).

[0697] I-65 or I-66: Chiral HPLC: optical purity (ee value) = 99.70%, RT = 3.384 min. MS (ESI) m / z: 830.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.51(s,1H),8.69(s,1H),8.47–8.38(m,3H),8.22(d ,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.34(s,1H),7.26–7.21(m,2H),5.20–5.15(m,1H),5. 07(dd,J=12.8,5.2Hz,1H),4.07(d,J=13.2Hz,2H),3.56–3.41(m,4H),3.10–2.97(m,3H),2. 92–2.85(m,1H),2.64–2.51(m,2H),2.48–2.36(m,4H),2.04–1.99(m,1H),1.75–1.53(m,8H).

[0698] The SFC splitting conditions are as follows:

[0699] Instrument: SFC-150 (Waters)

[0700] Chromatographic column: IH 25x 250mm, 10um (Daicel)

[0701] Column temperature: 35°C

[0702] Mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50

[0703] Flow rate: 120mL / min

[0704] Back pressure: 100bar

[0705] Detection wavelength: 214nm

[0706] Cycle time: 8.65min

[0707] Sample solution: 100 mg sample dissolved in 35 mL methanol

[0708] Injection volume: 4.8 mL.

[0709] Application Examples

[0710] 1. Evaluation of the Inhibition of Kinase Activity by Compounds

[0711] A fluorescent microfluidics mobility shift assay-based assay to determine the IC of compounds against competitive ATP binding to the kinase IRAK4 50 The initial detection concentration of the compound was 10 μM, and it was diluted 4 times down to 0.38 nM, and the detection was performed in duplicate wells. Among them, commercial staurosporine was used as the standard control in this experiment.

[0712] 1.1 Reagents and consumables information is as follows:

[0713]

[0714] 1.2 Experimental operation method

[0715] 1) IRAK4 kinase was dissolved in kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM DTT and 0.01% Brij-35) to a final concentration of 6 nM.

[0716] 2) Dissolve the substrate peptide FAM-P8 and ATP in the above kinase buffer. The final concentrations of the substrate peptide FAM-P8 and ATP of IRAK4 are 3 μM and 10 μM, respectively.

[0717] 3) Compound dilution: The compound was first diluted to 50 μM, and then diluted with DMSO 4 times in a gradient. The solution without compound and kinase was the blank control, corresponding to the "minimum value" shown below; the solution without compound but with kinase, adenosine 5'-triphosphate disodium salt hydrate, DMSO and buffer was the positive control, corresponding to the "maximum value" shown below.

[0718] 4) Kinase reaction and termination: 10 μL of kinase buffer was added to a 384-well plate containing 5 μL of the test compound and incubated at room temperature for 10 minutes. Another 10 μL of buffer containing substrate peptide and adenosine 5'-triphosphate disodium salt hydrate was added to a 384-well plate. After incubation at 28°C for one hour, 25 μL of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent #3 and 0.015% Brij-35) was added to each well to terminate the reaction.

[0719] 5) Data reading: The conversion rate data was read using the CaliperEZ ReaderⅡ instrument, and the setting conditions were: downstream voltage -500V, upstream voltage -2250V, reference pressure -0.5PSI, screening pressure -1.2PSI.

[0720] 6) Data calculation: Copy the conversion rate data from CaliperEZ ReaderⅡ and convert the conversion rate into inhibition rate data. The calculation formula is as follows:

[0721] Inhibition percentage (%) = (maximum value - conversion rate) / (maximum value - minimum value) * 100%

[0722] IC fitting using XLFit excel add-in version 5.4.0.8 50 value,

[0723] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope)

[0724] Kinase activity data are shown in Table 1 or 2

[0725] Table 1

[0726]

[0727] Table 2

[0728]

[0729]

[0730] IRAK4 assay:IC 50 <100nM:++++;≥100nM,<1μM:+++;≥1μM,<10μM:++;≥10μM:+

[0731] 2. LPS stimulates THP-1 to release cytokines

[0732] 2.1 Experimental Materials

[0733]

[0734] 2. PROTAC-induced IRAK4 protein degradation detection in THP-1

[0735] 2.1. Based on the Western Blot experimental method, the THP-1 cell samples treated with gel electrophoresis were stained with specific antibodies, and the degradation activity of the compound on the IRAK4 protein in THP-1 cells was determined by analyzing the location and depth of staining. The compound detection concentrations included 0μM, 0.3μM, 1μM and 3μM, and the compound was used to treat the cells for 8 hours, 16 hours, 24 hours, and 48 hours. Among them, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was the internal reference protein of this experiment.

[0736] 2.2. The information of cells, reagents and consumables is as follows:

[0737]

[0738]

[0739] 2.3 Equipment

[0740]

[0741]

[0742] 2.4. Reagent preparation method

[0743] Electrophoresis buffer: Dilute 50 mL of MOPSSDS Running Buffer (20x) and 50 mL of 20×TBS Tween-20 buffer to 1 L with deionized water as electrophoresis buffer;

[0744] 5% skim milk (w / v): Prepare 5% skim milk by diluting 2.5 g skim milk with 50 mL 1× TBS Tween-20 buffer.

[0745] 5% BSA (w / v): dilute 2.5 g BSA with 50 mL 1×TBS Tween-20 buffer to prepare 5% BSA;

[0746] Dilute the Anti-IRAK4 antibody at 1:1000 with 5% BSA to prepare the primary antibody working solution;

[0747] Dilute Goat Anti-Rabbit IgG H&L (HRP) at 1:2000 with 5% BSA to prepare the secondary antibody working solution;

[0748] Dilute Goat Anti-Mouse IgG H&L (HRP) at 1:2000 with 5% BSA to prepare the secondary antibody working solution.

[0749] THP-1 cells were plated in 6-well plates at a density of 1.5x106 cells per ml and incubated in a cell culture incubator set at 37°C and 5% CO2 for 2 hours. The compounds were diluted with DMSO to 0.6mM, 0.2mM and 0.06mM, respectively, and 10μL of compound solution was added to the corresponding wells, and the cells were cultured in the incubator for 16 hours, 24 hours and 48 hours, respectively. The drug-treated THP-1 cells in the wells were collected, and 120μL of RIPA lysis buffer containing protease inhibitors, phosphatase inhibitor solution II and phosphatase inhibitor solution III was added. After lysing the cells on wet ice for 30 minutes, the cell lysate was centrifuged at high speed and low temperature for 5 minutes, and the supernatant was collected. The protein concentration of the cell samples was determined according to the instructions in the kit PierceTM BCA Protein Assay Kit.

[0750] Use lysis buffer and 1M DTT Adjust the sample concentration to a consistent level using LDS sample buffer. Heat the sample at 95°C for 5 minutes and centrifuge at low temperature and high speed. Add 20 μL of the prepared protein sample and 4 μL of PageRuler Prestained Protein Ladder to the gel wells. Run the gel at 80V for 0.5 hours, then adjust the voltage to 120V and continue running the gel for 1.5 hours. Take out the gel and transfer the proteins in the gel to the IBlotTM 2 transfer membrane set at 20V. After the transfer is successful, cut the bands at 65kDa-40kDa and 40kDa-30kDa respectively. Block the membrane with 5% skim milk at room temperature for 1 hour. Wash the membrane three times with 1x TBST and incubate it with IRAK4 antibody working solution at 4°C overnight. Discard the IRAK4 antibody working solution, wash the membrane three times with 1x concentration TBST, incubate the corresponding membrane with Goat Anti-RabbitIgG H&L (HRP) working solution and Goat Anti-Mouse IgG H&L (HRP) working solution at room temperature for 1 hour, discard the antibody working solution, and wash the membrane three times with 1x concentration TBST. Refer to the kit SuperSignal TMWest FemtoMaximum Sensitivity Substrate instruction manual: Mix the reagents in the kit in equal volume ratio to prepare a luminescent liquid mixture. After incubating the membrane for 1 minute, take out the membrane for exposure.

[0751] The drug concentration was 1 μM, and the results of protein immunoblotting 24 hours after administration are shown in Table 3:

[0752] Table 3

[0753]

[0754]

[0755] The concentration of IRAK4 that degraded 50% by western blot 24 hours after administration is shown in Table 4:

[0756] Table 4

[0757]

Claims

1. A compound as shown in formula I, or a pharmaceutically acceptable salt or isotope compound thereof; Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring; the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; for or Q is C or N; E is CH or N; Y is C or N; R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl, or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , cyano, nitro, unsubstituted or replaced by one or more R 1 -1-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-1-3 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R 1-1-8 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 are independently deuterium, halogen, oxo, hydroxyl, -SO2-R a 、-SO-R a , C1-C6 alkoxy, cyano, nitro, unsubstituted or substituted with one or more halogens, 1-1-1-1 substituted 3- to 11-membered heterocycloalkyl, unsubstituted or substituted by one or more halogen or deuterium C1-C6 alkyl, 3- to 10-membered cycloalkyl, unsubstituted or substituted by one or more R 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R 1-1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen, oxo, hydroxy, C1-C6 alkoxy or C1-C6 alkyl; R 2 is hydrogen, hydroxy, cyano, halogen, unsubstituted or replaced by one or more R 2-3 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-2 Substituted C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-1 substituted 5- to 10-membered heteroaryl or unsubstituted or replaced by one or more R 2-4 substituted 4- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 2-1 , R 2-2 , R 2-3 and R 2-4 are independently halogen, hydroxy, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted with one or more halogens, or C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens; R 3 is hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, -SO2-R a 、-SO-R a , unsubstituted or substituted with one or more R 3-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 substituted 3- to 10-membered cycloalkyl, unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-5 substituted 6 to 10 membered aryl, unsubstituted or substituted with one or more R 3-6 substituted 5- to 10-membered heteroaryl, 3-8 Substituted hydroxyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or -O-COR a The heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently deuterium, halogen, oxo, hydroxy, unsubstituted or substituted with one or more R 3-1-1 substituted 3- to 11-membered heterocycloalkyl, Cyano, unsubstituted or substituted with one or more R 3-1-3 Substituted alkoxy, unsubstituted or substituted with one or more R 3-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-1-5 Substituted 3- to 10-membered cycloalkyl, -SO2-R a 、-SO-R a , 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; R 3-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 is independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, halogen, oxo or hydroxy; Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl; or R a and R b Together with the atoms connected thereto, a 3- to 11-membered heterocyclic ring is formed; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene; the 5- to 12-membered cycloalkylene is bicyclic or polycyclic; the 5- to 12-membered heterocycloalkylene is a monocyclic, bicyclic or polycyclic compound; the heteroatoms of the 5- to 12-membered cycloalkylene are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently deuterium, hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted with one or more halogen or deuterium, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens or deuterium; each L0 -3 are independently deuterium, hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted with one or more halogen or deuterium, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens or deuterium; L2 is the connecting subunit; When L0 is When L2 contains at least one or more of the following fragments: Not substituted or replaced by one or more L2 1-1 Replaced a and b are independently 1 or 2, m is an integer of 1-4, q is an integer of 1-6, and X is O; L2 1-1 is halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or Each R c are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl; Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; LLM Cyclo 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 3-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo; Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 12-membered heterocycloalkyl, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 4-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo; Cyclo 5 is unsubstituted or replaced by one or more Cy 5-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 5-1 are independently C1-C6 alkyl, hydroxy or oxo; Cyclo 6 is unsubstituted or replaced by one or more Cy 6-1 Substituted 6- to 10-membered aromatic ring; Cy 6-1 are independently C1-C6 alkyl, hydroxyl or halogen; Cyclo 7 is unsubstituted or replaced by one or more Cy 7-1 A substituted 5- to 9-membered heteroaromatic ring; the heteroatoms of the 5- to 9-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 7-1 are independently C1-C6 alkyl, hydroxyl or halogen; R 4 are independently hydrogen, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; p is 0, 1, 2 or 3; Each R 5 are independently halogen; L3 is unsubstituted or replaced by one or more L3 -1 Replaced in, m is an integer of 1-4, q is an integer of 1-6, and X is absent or 0; L3 -1 and C1-C6 alkyl which is independently halogen or unsubstituted or substituted by one or more halogens.

2. A compound as shown in formula I, or a pharmaceutically acceptable salt or isotope compound thereof; Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring; the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; for or Q is C or N; E is CH or N; Y is C or N; R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl, or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , cyano, nitro, unsubstituted or replaced by one or more R 1 -1-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-1-3 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or substituted with one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R 1-1-8 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 are independently halogen, oxo, hydroxyl, -SO2-R a 、-SO-R a , C1-C6 alkoxy, cyano, nitro, unsubstituted or substituted with one or more halogens, 1 -1-1-1 substituted 3- to 11-membered heterocycloalkyl, unsubstituted or substituted by one or more halogen C1-C6 alkyl, 3- to 10-membered cycloalkyl, unsubstituted or substituted by one or more R 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R 1-1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen, oxo, hydroxy, C1-C6 alkoxy or C1-C6 alkyl; R 2 is hydrogen, hydroxy, cyano, halogen, unsubstituted or replaced by one or more R 2-3 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 2-2 Substituted C1-C6 alkoxy, unsubstituted or substituted with one or more R 2-1 substituted 5- to 10-membered heteroaryl or unsubstituted or replaced by one or more R 2-4 substituted 4- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 2-1 , R 2-2 , R 2-3 and R 2-4 are independently halogen, hydroxy, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted with one or more halogens, or C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens; R 3 is hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, -SO2-R a 、-SO-R a , unsubstituted or substituted with one or more R 3-1 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 substituted 3- to 10-membered cycloalkyl, unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-5 substituted 6 to 10 membered aryl, unsubstituted or substituted with one or more R 3-6 substituted 5- to 10-membered heteroaryl, 3-8 Substituted hydroxyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or -O-COR a The heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently deuterium, halogen, oxo, hydroxy, unsubstituted or substituted with one or more R 3-1-1 substituted 3- to 11-membered heterocycloalkyl, Cyano, unsubstituted or substituted with one or more R 3-1-3 Substituted alkoxy, unsubstituted or substituted with one or more R 3-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-1-5 Substituted 3- to 10-membered cycloalkyl, -SO2-R a 、-SO-R a , 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; R 3-8 is a 3- to 10-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 11-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 is independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, halogen, oxo or hydroxy; Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl; or R a and R b Together with the atoms connected thereto, a 3- to 11-membered heterocyclic ring is formed; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene; the 5- to 12-membered cycloalkylene is bicyclic or polycyclic; the 5- to 12-membered heterocycloalkylene is a monocyclic, bicyclic or polycyclic compound; the heteroatoms of the 5- to 12-membered cycloalkylene are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently hydroxy, halogen, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; each L0 -3 are independently hydroxy, halogen, unsubstituted A or C1-C6 alkoxy substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; L2 is the connecting subunit; When L0 is When L2 contains at least one or more of the following fragments: Not substituted or replaced by one or more L2 1-1 Replaced a and b are independently 1 or 2, m is an integer of 1-4, q is an integer of 1-6, and X is O; L2 1-1 is halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or Each R c are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl; Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; LLM Cyclo 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 3-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo; Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 12-membered heterocycloalkyl, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 4-1 are independently C1-C6 alkyl, halogen, hydroxy or oxo; Cyclo 5 is unsubstituted or replaced by one or more Cy 5-1 A substituted 5- to 12-membered heterocyclic ring, wherein the heteroatoms of the 5- to 12-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 5-1 are independently C1-C6 alkyl, hydroxy or oxo; Cyclo 6 is unsubstituted or replaced by one or more Cy 6-1 Substituted 6- to 10-membered aromatic ring; Cy 6-1 are independently C1-C6 alkyl, hydroxyl or halogen; Cyclo 7 is unsubstituted or replaced by one or more Cy 7-1 A substituted 5- to 9-membered heteroaromatic ring; the heteroatoms of the 5- to 9-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cy 7-1 are independently C1-C6 alkyl, hydroxyl or halogen; R 4 are independently hydrogen, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; p is 0, 1, 2 or 3; Each R 5 are independently halogen; L3 is unsubstituted or replaced by one or more L3 -1 Replaced in, m is an integer of 1-4, q is an integer of 1-6, and X is absent or 0; L3 -1 and C1-C6 alkyl which is independently halogen or unsubstituted or substituted by one or more halogens.

3. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: LLM is a ligase binding group; the ligase may be an E3 ligase, preferably VHL, CRBN, MDM2, cIAP, Cereblon, XIAP, E3A, APC, UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, S MURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHI P / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb1 / MIB1, Mind Bomb 2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3, more preferably VHL, CRBN, MDM2 or cIAP; and / or, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not replaced or replaced by one or more L2 1-3 Replaced m is an integer of 1-4, q is an integer of 1-6, X is absent or O; Cy 1 is a 4- to 12-membered heterocyclic ring or a 3- to 12-membered cycloalkane; 2 is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring; the heteroatoms of the 4- to 12-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; L2 1-1 and L2 1-2 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, Hydroxyl, oxo or L2 1-3 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, cyano, Not substituted or replaced by one or more L2 1-3-1 Substituted 3 to 10 membered cycloalkyl, unsubstituted or substituted with one or more L2 1-3-2 substituted 3- to 11-membered heterocycloalkyl, -SO2-R a 、-SO-R a , or hydroxyl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each L2 1-3-1 and L2 1-3-2 are independently halogen, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, hydroxy, oxo or Each R c are independently H, unsubstituted or substituted with one or more R c-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R c-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R c-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R c-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R c-5 substituted 5- to 10-membered heteroaryl; Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Each R a and each R b are independently H, unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R a-2 Substituted 3 to 10 membered cycloalkyl, unsubstituted or replaced by one or more R a-3 substituted 3 to 11 membered heterocycloalkyl, unsubstituted or replaced by one or more R a-4 substituted 6 to 10 membered aryl, or unsubstituted or replaced by one or more R a-5 substituted 5- to 10-membered heteroaryl; Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5 independently halogen, cyano, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 11-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3.

4. The compound of formula I as claimed in claim 3, or its pharmaceutically acceptable salt or isotope compound, characterized in that: When the ring Cy is a 5-membered heterocyclic ring, the heteroatom of the 5-membered heterocyclic ring is O, the number of heteroatom is 1, and the 5-membered heterocyclic ring is preferably a tetrahydrofuran ring; and / or, when the ring Cy is a 5-membered heteroaromatic ring, the heteroatoms of the 5-membered heteroaromatic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the 5-membered heteroaromatic ring is preferably a pyrrole ring, a pyrazole ring, a thiazole ring, an oxazole ring or an imidazole ring; and / or, when R 1 is unsubstituted or substituted with one or more R 1-1 When the 5- to 10-membered heteroaryl is substituted, the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3; the 5- to 10-membered heteroaryl may be oxazolyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl or pyrazolopyrimidinyl, for example, pyridyl, oxazolyl, pyrazolyl or and / or, when R 1 is unsubstituted or substituted with one or more R 1-2 When the substituted 6- to 10-membered aryl group is a substituted 6- to 10-membered aryl group, the 6- to 10-membered aryl group is preferably a phenyl group or a naphthyl group; and / or, when each R 1-1 and R 1-2 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine; for example, fluorine; and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-1 In the case of a substituted 3- to 11-membered heterocycloalkyl, the 3- to 11-membered heterocycloalkyl is a 4- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; each R 1-1-1 Preferably, the 3- to 11-membered heterocycloalkyl radical is independently halogen, hydroxy, oxo, C1-C6 alkoxy radical which is unsubstituted or substituted by one or more halogen radicals, or C1-C6 alkyl radical which is unsubstituted or substituted by one or more halogen radicals; the 3- to 11-membered heterocycloalkyl radical is preferably piperazinyl, piperazinylene, piperidinyl, tetrahydropyrrolyl, oxetanyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-3 When the C1-C6 alkoxy is substituted, the C1-C6 alkoxy may be a C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; each R 1-1-3 Independently preferably halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-4 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; each R 1-1-4 Independently preferably halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-5 When the 3- to 10-membered cycloalkyl group is substituted, the 3- to 10-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each R 1-1-5 Independently preferably halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-7 When the 5- to 10-membered heteroaryl is substituted, the heteroatom of the 5- to 10-membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; each R 1-1-7 independently preferably halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; the 5- to 10-membered heteroaryl may be pyridyl, pyridylene, pyridazinyl, pyrazinyl, pyrimidinyl or triazinyl, for example pyridyl or pyridylene; and / or, when each R 1-1 and R 1-2 are independently unsubstituted or substituted with one or more R 1-1-8 When the 6- to 10-membered aryl group is substituted, the 6- to 10-membered aryl group is phenyl or naphthyl; each R 1-1-8 Independently preferably halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, when each R 1-1-1 and R 1-1-7 When independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and / or, when each R 1-1-4 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when R 2 When halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; and / or, when R 2 is unsubstituted or substituted with one or more R 2-1 When the substituted 5- to 10-membered heteroaryl group is a substituted 5- to 10-membered heteroaryl group, the heteroatom of the 5- to 10-membered heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3; the 5- to 10-membered heteroaryl group is preferably a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group or a triazinyl group, for example, a pyridyl group; and / or, when R 2 is unsubstituted or substituted with one or more R 2-2 In the case of a substituted C1-C6 alkoxy group, the C1-C6 alkoxy group is a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; and / or, when R 2 is unsubstituted or substituted with one or more R 2-3 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; and / or, when R 2 is unsubstituted or substituted with one or more R 2-4 When the 4- to 10-membered heterocycloalkyl is substituted, the 4- to 10-membered heterocycloalkyl is a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 4- to 10-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 4- to 10-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocycloalkyl is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example and / or, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine; for example, fluorine; and / or, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the halogen may be fluorine, chlorine, bromine or iodine; for example, fluorine; and / or, when each R 2-1 , R 2-2 , R 2-3 and R 2-4 When independently C1-C6 alkoxy, the C1-C6 alkoxy is C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as methoxy; the halogen may be fluorine, chlorine, bromine or iodine; such as fluorine; and / or, when R 3 When halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when R 3 is unsubstituted or substituted with one or more R 3-1 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl is a 3- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are preferably N and / or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl is preferably piperidinyl, tetrahydropyrrolyl, tetrahydropyrrolylene, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, morpholinyl, tetrahydropyranyl, oxetanyl, azabicyclo[2.2.1]heptyl or diazabicyclo[2.2.1]heptyl; each R 3-1 is independently preferably halogen, oxo or hydroxy, such as hydroxy; the unsubstituted or substituted with one or more R 3-1 The substituted 3 to 8 membered heterocycloalkyl group is preferably and / or, when R 3 is unsubstituted or substituted with one or more R 3-2 When the 3- to 10-membered cycloalkyl is substituted, the 3- to 10-membered cycloalkyl is C3-C6 cycloalkyl, which may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl, cyclobutyl or cyclohexyl; each R 3-2 is independently preferably halogen or hydroxy; unsubstituted or substituted by one or more R 3-2 The substituted 3- to 10-membered cycloalkyl group is preferably and / or, when R 3 is unsubstituted or substituted with one or more R 3-4 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, tert-butyl, n-pentyl, isopentyl, primary pentyl, secondary pentyl, tert-pentyl or neopentyl, and may be methyl, ethyl, propyl, isopropyl or isopentyl; each R 3-4 Preferably, deuterium, halogen, hydroxyl, -SO2-R a or R a is a C1-C6 alkyl group (preferably, each R 3-4 are independently preferably halogen, hydroxyl, -SO2-R a or R a is C1-C6 alkyl), R b is hydrogen; the unsubstituted or replaced by one or more R 3-4 The substituted C1-C6 alkyl group may be and / or, when R 3 is unsubstituted or substituted with one or more R 3-7 When the C1-C6 alkoxy is substituted, the C1-C6 alkoxy is a C1-C4 alkoxy, which may be a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1-butoxy, 2-butoxy or 3-butoxy, and may also be a methoxy, ethoxy or isopropoxy; each R 3-7 Preferably, each R 3-7 is independently preferably halogen); said unsubstituted or substituted with one or more R 3-7 The substituted C1-C6 alkoxy group is preferably a methoxy group, Isopropoxy or trifluoromethoxy; and / or, when R 3 For R 3-8 When the hydroxyl group is substituted, R 3-8 is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, wherein the heteroatom of the 3- to 6-membered heterocycloalkyl is oxygen and the number of heteroatoms is 1; 3-8 The substituted hydroxyl group is preferably and / or, when R 3 for When R a is H; and / or, when each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 are independently unsubstituted or substituted with one or more R 3-1-1 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl is a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are preferably N and / or O, and the number of heteroatoms is 1 or 2; the unsubstituted or substituted with one or more R 3-1-1 The substituted 3- to 11-membered heterocycloalkyl is preferably tetrahydropyrrolyl, oxetanyl or contains one oxygen and / or one azoheptanyl, for example and / or, when each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 When they are independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-butyl, 2-butyl or t-butyl, and may also be methyl or ethyl; and / or, when each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when L0 is unsubstituted or replaced by one or more L0 -2 When the 5- to 12-membered cycloalkylene is substituted, the 5- to 12-membered cycloalkylene is a spirocyclic, bridged or fused cyclic, and may be a, b, c and d are independently 0, 1 or 2; for example Another example The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, when L0 is unsubstituted or replaced by one or more L0 -3 When the 5- to 12-membered heterocycloalkylene is substituted, the 5- to 12-membered heterocycloalkylene is a monocyclic, spirocyclic, bridged or fused ring, and may be U and V are independently CH or N, and at least one is N, and a, b, c and d are independently 0, 1 or 2; for example Another example The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, when each L0 -2 When independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-butyl, sec-butyl or tert-butyl, and may also be methyl, ethyl or isopropyl; the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when each L0 -2 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; And / or, when each L0 -2 When independently C1-C6 alkoxy is unsubstituted or substituted by one or more halogens, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when each L0 -2 When the C1-C6 alkoxy group is independently unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a t-butoxy group, and may also be a methoxy group, an ethoxy group or an isopropoxy group; and / or, when each L0 -3 When independently unsubstituted or substituted by one or more halogen C1-C6 alkyl, the C1-C6 alkyl is C1-C4 alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-butyl, sec-butyl or tert-butyl, and may also be methyl, ethyl or isopropyl; the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine; And / or, when each L0 -3 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, when each L0 -3 When independently C1-C6 alkoxy is unsubstituted or substituted by one or more halogens, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; And / or, when each L0 -3 When the C1-C6 alkoxy group is independently unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a t-butoxy group, and may also be a methoxy group, an ethoxy group or an isopropoxy group; and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-2 When the 3- to 10-membered cycloalkyl is substituted, the 3- to 10-membered cycloalkyl is a 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-3 When the 3- to 11-membered heterocycloalkyl is substituted, the 3- to 11-membered heterocycloalkyl is a 5- to 8-membered heterocycloalkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl are N, S or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-3 When the substituted 3- to 11-membered heterocycloalkyl group is a 5- to 8-membered heterocycloalkyl group, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are N, S or O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocycloalkyl group is preferably piperazinyl, piperidinyl, tetrahydropyrrolyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl; and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-4 When the substituted 6- to 10-membered aryl group is a substituted 6- to 10-membered aryl group, the 6- to 10-membered aryl group is a benzene ring or a naphthalene ring; and / or, when each R a and each R b are independently unsubstituted or substituted with one or more R a-5 When the 5- to 10-membered heteroaryl is substituted, the 5- to 10-membered heteroaryl is a 5-membered heteroaryl or a 6-membered heteroaryl; the 6-membered heteroaryl is preferably a pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl or triazinyl; the 5-membered heteroaryl is preferably a pyrazolyl, thiazolyl or imidazolyl; and / or, in the ring Cy 3 wherein the 5- to 12-membered heterocyclic ring is a 5- to 6-membered heterocyclic ring, the heteroatom of the 5- to 12-membered heterocyclic ring is preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring; And / or, in Cy 3-1 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, in the ring Cy 4 wherein the 5- to 12-membered heterocyclic ring is a 5- to 6-membered heterocyclic ring, the heteroatom of the 5- to 6-membered heterocyclic ring is preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, such as a piperidine ring; And / or, in Cy 4-1 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, in the ring Cy 5 wherein the 5- to 12-membered heterocyclic ring is a 5- to 6-membered heterocyclic ring, the heteroatom of the 5- to 12-membered heterocyclic ring is preferably N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring; And / or, in Cy 5-1 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; And / or, in Cy 6 wherein the 6- to 10-membered aromatic ring is a benzene ring or a naphthalene ring; And / or, in Cy 6-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; And / or, in Cy 6-1 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, in the ring Cy 7 In the embodiment, the 5- to 9-membered heteroaromatic ring is a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring is preferably a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring; the 5-membered heteroaromatic ring is preferably a pyrazole ring, an oxazole ring, a thiazole ring or an imidazole ring, for example And / or, in Cy 7-1 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; And / or, in Cy 7-1 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group; and / or, in R 4 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group, or may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, or may be a tert-butyl group; and / or, in R 4 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; and / or, in R 5 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; and / or, at L3 -1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a priming-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group; And / or, when the ring Cy 1 When it is a 5- to 12-membered heterocyclic ring; the heteroatom of the 5- to 12-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1 or 2; the 5- to 12-membered heterocyclic ring may be an oxetane ring, a diazaspiro[3.3]heptane, a tetrahydrofuran ring, a piperidine ring, a piperazine ring, a diazaspiro[3.5]nonane, an azaspiro[3.3]heptane, a diazaspiro[5.5]undecane, an azaspiro[3.5]nonane or an azaspiro[5.5]undecane; And / or, when the ring Cy 1 When it is a 3- to 12-membered cycloalkane; the 3- to 12-membered cycloalkane is a 3- to 6-membered cycloalkane, such as cyclohexane; And / or, when the ring Cy 2 When it is a 5- to 10-membered heteroaromatic ring; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the 5- to 10-membered heteroaromatic ring is preferably a 5- or 6-membered heteroaromatic ring; the 6-membered heteroaromatic ring is preferably a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring; the 5-membered heteroaromatic ring is preferably a pyrazole ring, a thiazole ring or an imidazole ring; and / or, at L2 1-1 and L2 1-2 In the above, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, at L2 1-1 and L2 1-2 In the above, the C1-C6 alkoxy group is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, and may also be a methoxy group, an ethoxy group or an isopropoxy group; and / or, at L2 1-1 and L2 1-2 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine; and / or, at L2 1-3 wherein the halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; and / or, at L2 1-3 In the C1-C6 alkyl group which is unsubstituted or substituted by one or more halogens, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a 1-butyl group, a 2-butyl group or a t-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; the halogen group is preferably a fluorine group, a chlorine group, a bromine group or an iodine group, such as a fluorine group or a chlorine group; and / or, at L2 1-3 In the C1-C6 alkoxy group which is unsubstituted or substituted by one or more halogens, the C1-C6 alkoxy group is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a t-butoxy group, and may also be a methoxy group, an ethoxy group or an isopropoxy group; the halogen group is preferably fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; and / or, when L2 1-3 wherein said unsubstituted or replaced by one or more L2 1-3-1 In the substituted 3- to 10-membered cycloalkyl, the 3- to 10-membered cycloalkyl is a C3-C6 cycloalkyl, which may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl, cyclobutyl or cyclohexyl; each L2 1-3-1 independently preferably halogen or hydroxy; and / or, at L2 1-3 wherein said unsubstituted or replaced by one or more L2 1-3-2 In the substituted 3- to 11-membered heterocycloalkyl, the 3- to 11-membered heterocyclic ring is a 4- to 9-membered heterocyclic ring, and the heteroatoms of the 4- to 9-membered heterocyclic ring are preferably one or more of N, S and O, and the number of heteroatoms is 1 or 2; the 3- to 11-membered heterocyclic ring may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, such as a piperidine ring; and / or, at L2 1-3-1 and L2 1-3-2 In the above, the C1-C6 alkoxy group is a C1-C4 alkoxy group, which may be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a 1-butoxy group, a 2-butoxy group or a 3-butoxy group, and may also be a methoxy group, an ethoxy group or an isopropoxy group; and / or, when R c is unsubstituted or substituted with one or more R c-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is a C1-C4 alkyl group, which may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, and may also be a methyl group, an ethyl group or an isopropyl group; and / or, in LLM, p is 0 or 1; and / or, in L2, m is 1 or 2; and / or, in L2, q is 1 or 2; and / or, in L3, m is 1 or 2; and / or, in L3, q is 1 or 2; and / or, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 wherein the 6- to 10-membered aryl groups are independently phenyl or naphthyl; and / or, in R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 wherein the C1-C6 alkoxy group is independently a C1-C4 alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, and also such as methoxy; and / or, in R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the halogen may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; and / or, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the C1-C6 alkyl group is independently a C1-C4 alkyl group, which may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a pri-butyl group, a sec-butyl group or a tert-butyl group, or a methyl group, an ethyl group or an isopropyl group; and / or, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the 3- to 11-membered heterocycloalkyl group is independently a 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, an 8-membered heterocycloalkyl group or a 7-membered heterocycloalkyl group, the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the 6-membered heterocycloalkyl group is preferably a piperazinyl group, a morpholinyl group or a piperidinyl group, for example The 5-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, for example The 8-membered heterocycloalkyl group is preferably azabicyclo[2.2.2]octyl or -azabicyclo[3.2.1]octyl, for example The 7-membered heterocycloalkyl group is preferably azaspiro[3.3]heptyl or azabicyclo[2.2.1]heptyl, for example and / or, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 wherein the 3 to 10-membered cycloalkyl group is independently a 3 to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and / or, in R c , R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 3-1-1 , R 3-1-4 , R 3-1-5 , R 1-1-1-1 , R 1-1-1-2 , R 1-1-1-3 , R a-1 , R a-2 , R a-3 , R a-4 , R a-5 , R c-1 , R c-2 , R c-3 , R c-4 and R c-5 In the above, the 5- to 10-membered heteroaryl group is independently a 5-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered and 5-membered heteroaryl group; the 6-membered heteroaryl group is preferably a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group, or a triazinyl group; the 5-membered heteroaryl ring is preferably a pyrazolyl group, an oxazolyl group, a thiazolyl group, or an imidazolyl group, for example The 5- to 9-membered heteroaryl group is preferably pyrazolyl, thiazolyl, imidazolyl, tetrahydropyrrolothiazolyl or tetrahydropyrrolopyrazolyl, for example 5. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl or unsubstituted or substituted by one or more R 1-2 substituted 6- to 10-membered aryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3; R 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 substituted 5 to 9 membered heteroaryl or unsubstituted or substituted by one or more R 1-2 substituted 6- to 10-membered aryl; the heteroatoms of the 5- to 9-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3; R 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 A substituted 5- to 9-membered heteroaryl group, wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or both of N and O, and the number of heteroatoms is 1, 2 or 3; and / or, each R 1-1 and R 1-2 are independently halogen, hydroxyl, -SO2-R a 、-SO-R a , unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl, or unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11-membered heterocycloalkyl; the heteroatoms of the 5 to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, each R 1-1 and R 1-2 are independently halogen, hydroxyl, SO2-R a 、-SO-R a , unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, or unsubstituted or replaced by one or more R 1-1-7 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; each R 1-1 and R 1-2 are independently preferably halogen, unsubstituted or substituted with one or more R 1-1-7 substituted 5- to 6-membered heteroaryl or unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl; the heteroatom of the 5- to 6-membered heteroaryl is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; and / or, each R 1-1-4 are independently halogen, and the halogen is preferably fluorine; and / or, each R 1-1-7 are independently halogen, hydroxy, C1-C6 alkoxy which is unsubstituted or substituted by one or more halogens, cyano, nitro, C1-C6 alkyl which is unsubstituted or substituted by one or more halogens, 1-1-1-2 substituted 6 to 10 membered aryl, or unsubstituted or substituted by one or more R 1-1-1-3 substituted 5- to 10-membered heteroaryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; each R 1-1-7 Independently preferably C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen or C1-C6 alkyl; and / or, R 2 is hydrogen; and / or, R 3 is hydrogen, hydroxyl, halogen, cyano, unsubstituted or substituted with one or more R 3-1 substituted 3 to 10 membered heterocycloalkyl, unsubstituted or substituted with one or more R 3-2 Substituted 3 to 8 membered cycloalkyl, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or R 3-8 substituted hydroxyl; the heteroatoms of the 3- to 10-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 3 Preferably, halogen, unsubstituted or substituted with one or more R 3-1 substituted 3 to 6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, or R 3-8 substituted hydroxyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; preferably, R 3 is hydrogen, hydroxy, halogen, cyano, unsubstituted or replaced by one or more R 3-1 substituted 3 to 10 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 Substituted 3 to 8 membered cycloalkyl, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or R 3-8 substituted hydroxyl; the heteroatoms of the 3- to 10-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3; R 3 Preferably, it is unsubstituted or substituted with one or more R 3-1 substituted 3 to 6 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-2 Substituted C3-C6 cycloalkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy, unsubstituted or replaced by one or more R 3-4 Substituted C1-C6 alkyl, or R 3-8 Substituted hydroxyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; and / or, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently deuterium, oxo, hydroxyl, halogen, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; preferably, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently oxo, hydroxy, halogen, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; each R 3-1 are independently preferably hydroxy or halogen; each R 3-2 is independently preferably hydroxyl; each R 3-4 are independently preferably deuterium, halogen or hydroxyl, more preferably hydroxyl; each R 3-7 are independently preferably deuterium or halogen, more preferably halogen; and / or, R 3-8 is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group; the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; R 3-8 It is preferably a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; the heteroatom of the 3- to 6-membered heterocycloalkyl is selected from one or both of N and O, and the number of the heteroatom is 1; and / or, each R a and each R b are independently H or unsubstituted or substituted with one or more R a-1 Substituted C1-C6 alkyl; each R a and each R b Independently preferably H; and / or, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene group; the 5- to 12-membered cycloalkylene group is a spirocyclic ring, a cyclic ring or a bridged ring; the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring; the heteroatom of the 5- to 12-membered heterocycloalkylene group is N, S or O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 are independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; Preferably, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 5 to 12 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene group; the 5- to 12-membered cycloalkylene group is a spirocyclic ring, a cyclic ring or a bridged ring; the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring; the heteroatom of the 5- to 12-membered heterocycloalkylene group is N, S or O, and the number of heteroatoms is 1, 2 or 3; each L0 -2 are independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 are independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; preferably, L0 is unsubstituted or substituted by one or more L0 -2 Substituted 7 to 11 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 7 to 11 membered heterocycloalkylene; the 7 to 11 membered heterocycloalkylene is a spiro ring; the 7 to 11 membered heterocycloalkylene is a spiro ring; the heteroatom of the 7 to 11 membered heterocycloalkylene is N, and the number of heteroatoms is 1 or 2; each L0 -2 are independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 is independently halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; more preferably, L0 is 7 to 11-membered cycloalkylene or 7 to 11-membered heterocycloalkylene; the 7 to 11-membered cycloalkylene is a spiro ring; the 7 to 11-membered heterocycloalkylene is a spiro ring; the heteroatom of the 7 to 11-membered heterocycloalkylene is N, and the number of heteroatoms is 1; and / or, in L2, R c is H or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; more preferably H; and / or, Cy 3 is unsubstituted or replaced by one or more Cy 3-1 A substituted 5- to 6-membered heterocyclic ring, wherein the heteroatom of the 5- to 6-membered heterocyclic ring is N, S or O, and the number of the heteroatom is 1; Cy 3 Preferably it is unsubstituted or substituted with multiple Cy 3-1 A substituted 5- to 6-membered heterocyclic ring, wherein the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of the heteroatom is 1; and / or, each Cy 3-1 are independently oxo; and / or, cyclic Cy 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl, wherein the heteroatoms of the 5- to 8-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; Cyclo 4 Preferably it is unsubstituted or substituted with one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl group, wherein the heteroatom of the 5- to 8-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1; and / or, each Cy 4-1 They are independently C1-C6 alkyl, hydroxy or oxo, preferably oxo.

6. The compound of formula I as claimed in claim 3, or its pharmaceutically acceptable salt or isotope compound, characterized in that: L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not replaced or replaced by one or more L2 1-3 Replaced m is an integer of 1-4, q is an integer of 1-6, X is absent or O; Cy 1 is a 4- to 11-membered heterocyclic ring or a 4- to 11-membered cycloalkane; 2 is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring; the heteroatoms of the 4- to 11-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaromatic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, The a' end faces L0, and the b' end faces LLM.

7. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5- to 10-membered heteroaryl or unsubstituted or substituted by one or more R 1-2 substituted 6- to 10-membered aryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; R 1 Preferably, it is unsubstituted or substituted with one or more R 1-1 substituted 5- to 6-membered heteroaryl or unsubstituted or replaced by one or more R 1-2 A substituted 6- to 10-membered aryl group; the heteroatom of the 5- to 6-membered heteroaryl group is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; and / or, each R 1-1 and R 1-2 are independently halogen, unsubstituted or substituted with one or more R 1-1-7 substituted 5- to 6-membered heteroaryl or unsubstituted or replaced by one or more R 1-1-4 Substituted C1-C6 alkyl, or unsubstituted or replaced by one or more R 1-1-1 substituted 5- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 6-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5- to 10-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; each R 1-1 are independently preferably unsubstituted or substituted with one or more R 1-1-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 1-1-1 Substituted 5- to 10-membered heterocycloalkyl; the heteroatoms of the 5- to 10-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; and / or, L0 is unsubstituted or replaced by one or more L0 -2 Substituted 7 to 11 membered cycloalkylene or unsubstituted or substituted by one or more L0 -3 substituted 7 to 11 membered heterocycloalkylene; the 7 to 11 membered heterocycloalkylene is a spiro ring; the 7 to 11 membered heterocycloalkylene is a spiro ring or a cyclic ring; the heteroatom of the 7 to 11 membered heterocycloalkylene is N, and the number of heteroatoms is 1 or 2; each L0 -2 are independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted with one or more halogens; each L0 -3 is independently deuterium, halogen, hydroxyl or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; preferably, L0 is a 7- to 11-membered cycloalkylene group or a 7- to 11-membered heterocycloalkylene group; the 7- to 11-membered cycloalkylene group is a spiro ring; the 7- to 11-membered heterocycloalkylene group is a spiro ring or a cyclohexane ring; the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1 or 2.

8. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: R 1 For one or more R 1-1 substituted pyridyl or one or more R 1-1 Replaced and / or, each R 1-1 are independently unsubstituted or substituted with one or more R 1-1-4 substituted C1-C6 alkyl; or, each R 1-1 are independently unsubstituted or substituted with one or more R 1-1-1 A substituted 7- to 8-membered heterocycloalkyl group; wherein the heteroatom of the 7- to 8-membered heterocycloalkyl group is selected from N or O, and the number of heteroatoms is 2; and / or, R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy; and / or, when R 3 For multiple R 3-4 When the C1-C6 alkyl group is substituted, at least one R 3-4 is hydroxy, deuterium and hydroxy, or halogen and hydroxy; and / or, L0 is a 9- to 11-membered heterospirocyclic group; the heteroatom of the 9- to 11-membered heterospirocyclic group is N, and the number of heteroatoms is 1; preferably, the 9- to 11-membered heterospirocyclic group is The a' end is connected to the ring Cy, and the b' end is connected to L2.

9. The compound of formula I as claimed in claim 3, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not replaced or replaced by one or more L2 1-3 Replaced m is 1 or 2, q is 1 or 2, X is absent or O; Cy 1 is a 4- to 11-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 11-membered heterocyclic ring is N and / or O, and the number of heteroatoms is 1 or 2; the 4- to 11-membered heterocyclic ring is a monocyclic ring, a bridged ring or a spirocyclic ring; the 4- to 6-membered cycloalkane is a monocyclic ring, and the ring Cy is 2 is a 5- to 6-membered heteroaromatic ring; the heteroatoms of the 5- to 6-membered heteroaromatic ring are N and / or O, and the number of heteroatoms is 1 or 2; preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced or not replaced or replaced by one or more L2 1-2 Replaced m is 1 or 2, q is 1 or 2, X is absent or O; Cy 1 is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 11-membered heterocycle is N and / or O, and the number of heteroatoms is 1 or 2; the 4- to 11-membered heterocycle is a monocyclic, bridged or spirocyclic ring; the 4- to 11-membered cycloalkane is a monocyclic, bridged or spirocyclic ring; and / or, when the 4- to 11-membered heterocycle is a monocyclic ring, the 4- to 11-membered heterocycle is a 3- to 6-membered heterocycle, the heteroatom of the 4- to 11-membered heterocycle is N or O, and the number of heteroatoms is 1 or 2; and / or, when the 4- to 11-membered heterocycle is a spirocycle, the 4- to 11-membered heterocycle is a 4,6-azaspirocycle, a 6,6-azaspirocycle or a 4,4-azaspirocycle; Preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, Not substituted or replaced by one or more L2 1-1 Replaced Not substituted or replaced by one or more L2 1-2 Replaced or not replaced or replaced by one or more L2 1-3 Replaced m is 1 or 2, q is 1, X is absent or O; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocyclic ring is a 6-membered monocyclic ring, a 4,4-azaspiro ring or a 4,6-azaspiro ring; R c H, Cy 2 is a 5-membered heteroaromatic ring, wherein the heteroatom of the 5-membered heteroaromatic ring is N, the number of heteroatoms is 2, and the 5-membered heteroaromatic ring is preferably a pyrazole ring; L2 -1 、L2 -2 、L2 -3 and L2 -4 independently preferably not present, Not substituted or replaced by one or more L2 1-1 Replaced or not replaced or replaced by one or more L2 1 -2 Replaced m is 1 or 2, q is 1, X is absent or O; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 10-membered heterocyclic ring is a 6-membered monocyclic ring or a 4,6-azaspirocyclic ring; R c is H; Preferably, L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently does not exist, m is 1 or 2, q is 1, X is absent; Cy 1 is a 4- to 10-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 6-membered cycloalkane is a 6-membered monocyclic ring; R c H, Cy 2 is a 5-membered heteroaromatic ring, wherein the heteroatom of the 5-membered heteroaromatic ring is N and the number of heteroatoms is 2, such as a pyrazole ring; L2 -1 、L2 -2 、L2 -3 and L2 -4 independently preferably not present, m is 1 or 2, q is 1, X is absent; Cy 1 is a 4- to 6-membered heterocyclic ring or a 4- to 6-membered cycloalkane; the heteroatom of the 4- to 10-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; the 4- to 6-membered cycloalkane is a 6-membered monocyclic ring; R c is H; More preferably, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not replaced or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; and the 4- to 6-membered heterocyclic ring is a monocyclic ring.

10. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The five-membered and six-membered compound as shown in Formula I is a compound as shown in Formula Ia, Ib, Id, Ig, Ih, Ii, Ik, Im, In, Io, Ip, Iq or Ir.

11. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: LLM Preferably or More preferably For example and / or, R 1 for Preferably and / or, R 3 is methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, carboxyl, fluorine, Preferably, methoxy, and / or, for For example and / or, L0 is Preferably, L0 is Wherein the a' end is connected to the ring Cy, and the b' end is connected to L2; preferably, L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, L2 is Preferably, L2 is Among them, the a' end is connected to L0, and the b' end is connected to LLM; And / or, when L0 is (Further L0 is unsubstituted or replaced by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene), L2 is Preferably, when L0 is (Further L0 is unsubstituted or replaced by one or more L0 -3 substituted 5- to 12-membered heterocycloalkylene), L2 is Among them, the a' end of L2 is connected to L0, and the b' end of L2 is connected to LLM; And / or, in the compound as shown in formula I, for X is N or CH, X1 is S or O; More preferably, in the compound as shown in formula I, for 12. The compound of formula I according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: When R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, when R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, when R 1 for When L0 is The a' end is connected to the ring Cy, and the b' end is connected to L2; and / or, when R 1 for When L2- The a' end is connected to L0, and the b' end is connected to LLM; and / or, when R 1 for When L2- The a' end is connected to L0, and the b' end is connected to LLM; and / or, when R 1 for When L2- The a' end is connected to L0, and the b' end is connected to LLM.

13. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: -L0-L2- The a' end is connected to the ring Cy, and the b' end is connected to LLM; Or -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM; Preferably The a' end is connected to the ring Cy, and the b' end is connected to LLM.

14. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: when for When -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM; preferably The a' end is connected to the ring Cy, and the b' end is connected to LLM; and / or when for When -L0-L2- is The a' end is connected to the ring Cy, and the b' end is connected to LLM; and / or when for -L0-L2- The a' end is connected to the ring Cy, and the b' end is connected to LLM.

15. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in formula I is a compound shown in formula Id, Among them, R 1 For one or more R 1-1 substituted pyridyl or one or more R 1-1 Replaced When R 1 For one or more R 1-1 When the pyridyl group is substituted, each R 1-1 Independently for one or more R 1-1-4 Substituted C1-C6 alkyl; When R 1 For one or more R 1-1 Replaced When each R 1-1 is unsubstituted or substituted with one or more R 1-1-1 A substituted 7- to 8-membered heterocycloalkyl group; wherein the heteroatom of the 7- to 8-membered heterocycloalkyl group is selected from N or O, and the number of heteroatoms is 2; Each R 1-1-4 are independently halogen; each R 1-1-1 is independently a C1-C6 alkyl group substituted by one or more halogens; R 2 is hydrogen; R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy; Each R 3-4 are independently deuterium, halogen or hydroxyl; each R 3-7 independently for deuterium; L0 is a 9- to 11-membered heterospirocyclic group; the heteroatom of the 9- to 11-membered heterospirocyclic group is N, and the number of heteroatoms is 1; L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not replaced or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; the 4- to 6-membered heterocyclic ring is a monocyclic ring; each L2 1-2 are independently hydroxyl groups; LLM Cyclo 3 is unsubstituted or substituted with multiple Cy 3-1 A substituted 5- to 6-membered heterocyclic ring, wherein the heteroatom of the 5- to 6-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1; Cy 3-1 are independently oxo; Cyclo 4 is unsubstituted or replaced by one or more Cy 4-1 A substituted 5- to 8-membered heterocycloalkyl, wherein the heteroatom of the 5- to 8-membered heterocyclic ring is N, S or O, and the number of heteroatoms is 1; Cy 4-1 are independently oxo; Each R 5 are independently halogen; p is 0, 1, 2 or 3.

16. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: R 1 For one or more R 1-1 substituted pyridyl or one or more R 1-1 Replaced and / or, when R 1 For one or more R 1-1 When the pyridyl group is substituted, each R 1-1 Independently for one or more R 1-1-4 Substituted C1-C6 alkyl; and / or, when R 1 For one or more R 1-1 Replaced When each R 1-1 is unsubstituted or substituted with one or more R 1-1-1 A substituted 7- to 8-membered heterocycloalkyl group; wherein the heteroatom of the 7- to 8-membered heterocycloalkyl group is selected from N or O, and the number of heteroatoms is 2; and / or, each R 1-1-4 are independently fluorine, chlorine or bromine, preferably fluorine; and / or, when R 1-1 Independently for multiple R 1-1-4 When the substituted C1-C6 alkyl group is present, the plurality is 2 or 3, preferably 3; and / or, each R 1-1-1 is independently a C1-C6 alkyl group substituted by one or more halogens; and / or, R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy; and / or, each R 3-4 are independently deuterium, halogen or hydroxyl; and / or, each R 3-7 independently for deuterium; and / or, when R 3 For multiple R 3-4 When the C1-C6 alkyl group is substituted, at least one R 3-4 is hydroxy, deuterium and hydroxy, or halogen and hydroxy; And / or, L0 is a 9- to 11-membered heterospirocyclic group; the heteroatom of the 9- to 11-membered heterospirocyclic group is N, and the number of heteroatoms is 1; and / or, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or L2 -1 for L2 -2 、L2 -3 and L2 -4 Independently does not exist, or not replaced or replaced by one or more L2 1-2 Replaced Cyclo 1 is a 4- to 6-membered heterocyclic ring; the heteroatom of the 4- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1; the 4- to 6-membered heterocyclic ring is a monocyclic ring; and / or, each L2 1-2 are independently hydroxyl.

17. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: R 1 is unsubstituted or substituted with one or more R 1-1 substituted 5 to 9 membered heteroaryl, wherein the 5 to 9 membered heteroaryl is pyridyl, oxazolyl, pyrazolyl or and / or, each R 1-1 is unsubstituted or substituted with one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11 membered heterocycloalkyl or unsubstituted or substituted by one or more R 1-1-7 Substituted 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1, 2 or 3; and / or, each R 1-1-4 is independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, each R 1-1-7 is independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, each R 1-1-1 are independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; each R 1-1-1 Independently preferably C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; and / or, R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 3-7 Substituted C1-C6 alkoxy or unsubstituted or with one or more R 3-1 Substituted tetrahydropyrrolyl; and / or, each R 3-1 are independently deuterium, hydroxyl or halogen; and / or, each R 3-4 are independently deuterium, halogen or hydroxyl; and / or, each R 3-7 are independently deuterium or hydroxyl; and / or, L0 is an 8- to 11-membered cycloalkylene group or an 8- to 11-membered heterocycloalkylene group; the 8- to 11-membered cycloalkylene group is a spiro ring; the 8- to 11-membered heterocycloalkylene group is a spiro ring or a cyclic ring; the heteroatom of the 8- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1; preferably, the 8- to 11-membered cycloalkylene group is The 8- to 11-membered heterocycloalkylene group is The a' end is connected to the ring Cy, and the b' end is connected to L2; And / or, L2 is one of the following: Case (1) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is unsubstituted or replaced by one or more L2 1-2 Replaced Cyclo 1 is piperidinyl or piperazinyl; preferably, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is an unsubstituted cyclic Cy 1 , Cy 1 is piperidinyl or piperazinyl; Case (2) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 Not present; L2 -2 、L2 -3 and L2 -4 Independently or not replaced or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl; Case (3) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently or not replaced or replaced by one or more L2 1-2 Substituted Cyclic 1 , Cy 1 is cyclohexyl, piperidinyl or piperazinyl; and / or, each L2 1-2 are independently halogen or hydroxy; and / or, LLM for For example Another example 18. The compound of formula I as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound shown in formula I is a compound shown in formula Id, Among them, R 1 is unsubstituted or substituted with one or more R 1-1 A substituted 5- to 9-membered heteroaryl group, wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or both of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 1-1 is unsubstituted or substituted with one or more R 1-1-4 Substituted C1-C6 alkyl, unsubstituted or replaced by one or more R 1-1-1 substituted 3 to 11 membered heterocycloalkyl or unsubstituted or substituted by one or more R 1-1-7 Substituted 5- to 10-membered heteroaryl; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2; Each R 1-1-1 , R 1-1-4 and R 1-1-7 is independently halogen or C1-C6 alkyl which is unsubstituted or substituted by one or more halogens; R 3 is unsubstituted or substituted with one or more R 3-4 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-7 Substituted C1-C6 alkoxy or unsubstituted or with one or more R 3-1 Substituted tetrahydropyrrolyl; Each R 3-1 are independently deuterium, halogen or hydroxyl, each R 3-4 are independently deuterium, halogen or hydroxyl, each R 3-7 are independently deuterium or hydroxyl; L0 is an 8- to 11-membered cycloalkylene group or an 8- to 11-membered heterocycloalkylene group; the 8- to 11-membered cycloalkylene group is a spiro ring; the 8- to 11-membered heterocycloalkylene group is a spiro ring or a fused ring; the heteroatom of the 8- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1; L2 is one of the following: Case (1) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 and L2 -2 Not present; L2 -3 for L2 -4 is unsubstituted or replaced by one or more L2 1-2 Substituted ring Cy1, ring Cy1 is piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy; Case (2) L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -;L2 -1 Not present; L2 -2 、L2 -3 and L2 -4 Independently or not replaced or replaced by one or more L2 1-2 Substituted ring Cy1, ring Cy1 is cyclohexyl, piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy; Case (3) L2 is -L 2-1 -L 2-2 -L 2-3 -L 2-4 -;L2 -1 、L2 -2 、L2 -3 and L2 -4 Independently or not replaced or replaced by one or more L2 1-2 Substituted ring Cy1, ring Cy1 is cyclohexyl, piperidinyl or piperazinyl; each L2 1-2 are independently halogen or hydroxy; LLM 19. A compound, a pharmaceutically acceptable salt or isotope compound thereof, characterized in that: The compound is any of the following compounds:

20. The compound, pharmaceutically acceptable salt or isotope compound thereof according to claim 19, characterized in that: for or, For compounds with a retention time of 2.262 min or 3.319 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / (MeOH:MeCN=1:1)=50 / 50; flow rate: 120 mL / min; and / or, for or, For compounds with a retention time of 12.068 min or 14.283 min under the following conditions, chromatographic column: IC 25 x 250 mm, 10 um (Daicel); mobile phase: HEX (0.1% DEA): EtOH (0.1% DEA): = 50:50; flow rate: 50 mL / min; and / or, for or, For compounds with a retention time of 1.299 min or 1.936 min under the following conditions, chromatographic column: AS25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH): MeCN = 1:1] = 40 / 60; flow rate: 100 mL / min; and / or, for or, For compounds with a retention time of 1.759 min or 2.520 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel), mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50, flow rate: 120 mL / min; and / or, for or, For compounds with a retention time of 2.309 min or 3.384 min under the following conditions, chromatographic column: IH 25 x 250 mm, 10 um (Daicel); mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50; flow rate: 120 mL / min; and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for and / or, for And / or, the pharmaceutically acceptable salt of the compound as shown in I-12 is 21. A pharmaceutical composition comprising a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound as shown in formula I according to any one of claims 1 to 18, a pharmaceutically acceptable salt or isotope compound thereof, or a compound as described in claim 19 or 20, a pharmaceutically acceptable salt or isotope compound thereof.

22. Use of a substance Z or a pharmaceutical composition as claimed in claim 21 in the preparation of an IRAK4 degrader and a drug for treating and / or preventing Myd88 and / or IRAK4 related diseases, wherein the substance Z is a compound as shown in formula I as claimed in any one of claims 1 to 18, a pharmaceutically acceptable salt or isotope compound thereof, or a compound as claimed in claim 19 or 20, a pharmaceutically acceptable salt or isotope compound thereof; Preferably, the IRAK4-related diseases include one or more of chronic lung disease, autoimmune disease, inflammatory disease, tumor, cardiovascular and cerebrovascular disease and central nervous system disease; More preferably, the autoimmune disease is psoriasis, systemic lupus erythematosus and rheumatoid arthritis; More preferably, the inflammatory disease is inflammatory bowel disease, such as ulcerative colitis; More preferably, the tumor is a blood tumor or a solid tumor. The blood tumor may be large B-cell lymphoma or acute or chronic lymphocytic leukemia; the solid tumor may be intestinal cancer or skin cancer caused by MYD88 mutation. More preferably, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis; More preferably, the central nervous system disease is primary central nervous system lymphoma.

23. Use of a substance Z or a pharmaceutical composition as claimed in claim 21 in preparing a drug, wherein the substance Z is a compound as shown in formula I as claimed in any one of claims 1 to 18, a pharmaceutically acceptable salt or isotope compound thereof, or a compound as claimed in claim 19 or 20, a pharmaceutically acceptable salt or isotope compound thereof; the drug is used to treat one or more of autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases and central nervous system diseases; Preferably, the autoimmune disease is psoriasis, systemic lupus erythematosus and rheumatoid arthritis; Preferably, the inflammatory disease is inflammatory bowel disease, such as ulcerative colitis; Preferably, the tumor is a blood tumor or a solid tumor. The blood tumor may be large B-cell lymphoma or acute or chronic lymphocytic leukemia; the solid tumor may be intestinal cancer or skin cancer caused by MYD88 mutation. Preferably, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis; Preferably, the central nervous system disease is primary central nervous system lymphoma.

24. A compound of formula II or III, a salt or an isotope compound thereof, R 1 , R 2 , R 3 , Q, Y, ring Cy, L0 and L2 as described in any one of claims 1-20; Preferably, the compound as shown in formula II or III is any of the following compounds:

25. Use of a compound of formula II or III as claimed in claim 24, a salt thereof, a boc-protected compound or an isotope compound thereof in the preparation of a compound of formula I as claimed in any one of claims 1 to 18, a pharmaceutically acceptable salt or an isotope compound thereof, or a compound of claim 19 or 20, a pharmaceutically acceptable salt or an isotope compound halogen thereof.

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