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

Abstract

The present invention discloses a five-membered fused six-membered compound, a preparation method, a pharmaceutical composition, and applications. The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, or an isotope thereof. The compound of the present invention has an inhibitory and / or degrading effect on IRAK4. [Formula 1] TIFF2025525281000581.tif31170

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application No. 2022106755993, filed June 15, 2022, Chinese patent application No. 2022116279194, filed December 16, 2022, and Chinese patent application No. 202310658843X, filed June 5, 2023. This application references all of the above Chinese patent applications.

[0002] The present invention relates to five-membered fused six-membered compounds, preparation methods, pharmaceutical compositions and applications. [Background technology]

[0003] Kinases have been important therapeutic targets in 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 downstream of the toll-like receptor and IL-1R pathways, in which IRAK1 and IRAK4 possess kinase activity. IRAK4 acts upstream of the IRAK family kinase activation pathway and plays an important role in innate immune signaling (Science 1996, 271(5252):1128-31). TLR stimulation recruits myeloid differentiation primary response 88 (MYD88), which activates the receptor to form a complex called the myddosome, which then forms a complex with IRAK4, further activating IRAK1. TRAF6 is then activated by IRAK1, leading to the activation of the NF-κB and AMPK signaling pathways, ultimately resulting in the expression of proinflammatory cytokines (Molecules 2016, 21, 1529, J Biol Chem. 2018 Sep 28, 293(39):15195-15207, Eur J. Immunol. 2008. 38:614-618).

[0004] One very important feature of IRAK4 is its dual function in the TLR and IL-1R signaling pathways: scaffolding and kinase phosphorylation. The kinase domain (KD) provides kinase function, while the death domain (DD) provides scaffolding for the myddosome (Molecules 2016, 21(11), 1529). The myddosome is involved in multiple diseases, including autoimmune and inflammatory disorders, as well as cancer. For example, MYD88 gene mutations account for 39% of patients with activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) and 86%–100% of patients with several other types of B-cell malignancies and primary central nervous system lymphoma (Cell Chemical Biology 27, 1–10, December 17, 2020).

[0005] IRAK4 knockout mice and clinical pathological studies have shown that IRAK4 deficiency is not lethal per se, and individuals with IRAK4 gene mutations are also protected against chronic lung disease and inflammatory bowel disease (Eur. J. Immunol. 2008.38:614-618). IRAK4 inhibitors have been considered a target for treating immune diseases, such as the autoimmune diseases rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis (Expert Opinion on Therapeutic Patents Volume 29, 2019, Issue 4). IRAK4 is also a popular target for tumor treatment, and a few IRAK4 kinase inhibitors have entered clinical trials. However, these investigational drugs in clinical trials all inhibit IRAK4 kinase function (KD) and do not directly inhibit IRAK4 scaffolding function. It would be desirable for IRAK4-targeting protein degradation agents (PROTACs) to simultaneously eliminate both its kinase activity and scaffolding function, thereby resulting in 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

[0006] The present invention provides a five-membered fused six-membered compound, a preparation method, a pharmaceutical composition, and applications. The compound of the present invention has an inhibitory and / or degrading effect on IRAK4, and is expected to have potential clinical application value, improve patient prognosis, and reduce the possibility of drug resistance.

[0007] The present invention provides a compound of formula I, a pharmaceutically acceptable salt or isotopic compound thereof, [ka] Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein 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; [ka] teeth, [ka] and Q is C or N; E is CH or N; Y is C or N; R 1 is unsubstituted or one or more R 1-1 a 5- to 10-membered heteroaryl group substituted with, or unsubstituted or one or more R 1-2 wherein the heteroatoms in 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 a halogen, a hydroxy group, [ka] -SO2-R a , -SO-R a , a cyano group, a nitro group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-1-3 C1-C6 alkoxy group, unsubstituted or substituted with one or more R 1-1-4 a C1-C6 alkyl group substituted with [ka] Unsubstituted or one or more R 1-1-5 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R 1-1-7 wherein 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; and 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 1-1-1 , 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, hydroxy group, [ka] -SO2-R a , -SO-R a , an unsubstituted or one or more halogen-substituted C1-C6 alkoxy group, a cyano group, a nitro group, an unsubstituted or one or more R 1-1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with one or more halogens or deuterium, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens or deuterium, a 3- to 10-membered cycloalkyl group unsubstituted or substituted with one or more R 1-1-1-2 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R 1-1-1-3 wherein 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; and 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 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen, oxo, hydroxy, C1-C6 alkoxy, or C1-C6 alkyl; R 2is hydrogen, a hydroxy group, a cyano group, a halogen, unsubstituted or one or more R 2-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R 2-2 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 2-1 a 5- to 10-membered heteroaryl group or an unsubstituted or substituted with one or more R 2-4 wherein 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; and the heteroatoms of the 4- to 10-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 2-1 , R 2-2 , R 2-3 and R 2-4 are independently a halogen, a hydroxy group, a cyano group, a nitro group, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, [ka] or a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens; R 3 represents hydrogen, deuterium, halogen, cyano group, hydroxy group, nitro group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 3-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 3-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-5 a 6- to 10-membered aryl group, unsubstituted or substituted with one or more R 3-6 a 5- to 10-membered heteroaryl group substituted with R 3-8 a hydroxy group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group substituted with -O-COR a wherein 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; and 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 one or more R 3-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 3-1-3 an alkoxy group substituted with [ka] Unsubstituted or one or more R 3-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-1-5 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein 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; and 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; 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, wherein 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; and 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 are independently a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a halogen, an oxo, or a hydroxy group; Each R a and each R b are independently H, unsubstituted, or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R a-5 is a 5- to 10-membered heteroaryl group substituted with or R a and R b form a 3- to 11-membered heterocyclic ring together with the atoms to which they are attached, the heteroatoms of said 3- to 11-membered heterocycloalkyl group being selected from one or more of N, S and O, and the number of heteroatoms being 1, 2 or 3; Each Ra-1 , R a-2 , R a-3 , R a-4 and R a-5 are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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; L0 may be unsubstituted or one or more L0 -2 a 5- to 12-membered cycloalkylene group or an unsubstituted or -3 wherein the 5- to 12-membered cycloalkylene group is bicyclic or polycyclic, the 5- to 12-membered heterocycloalkylene group is monocyclic, bicyclic or polycyclic, the heteroatoms of the 5- to 12-membered cycloalkylene group are selected from one or more of N, S and O, the number of heteroatoms is 1, 2 or 3, and each L0 -2 are independently deuterium, a hydroxy group, a halogen, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens or deuterium, [ka] or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens or deuterium, and each L0 -3 are independently deuterium, a hydroxy group, a halogen, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens or deuterium, [ka] or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens or deuterium; L2 is a linker unit (connects LLM to L0), L0 is [ka] If so, L2 contains at least [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] wherein a and b are independently 1 or 2, m is an integer from 1 to 4, q is an integer from 1 to 6, X is O, and L2 1-1 represents a halogen, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, [ka] Hydroxy group, oxo or [ka] and Each R c are independently H, unsubstituted, or one or more R c-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R c-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R c-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R c-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R c-5 is a 5- to 10-membered heteroaryl group substituted with Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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; LLM is [ka] and Ring Cy 3 is unsubstituted or one or more Cy 3-1 wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and 3-1 are independently a C1-C6 alkyl group, halogen, hydroxy group, or oxo; Ring Cy 4 is unsubstituted or one or more Cy 4-1 wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and Cy 4-1 are independently a C1-C6 alkyl group, halogen, hydroxy group, or oxo; Ring Cy 5 is unsubstituted or one or more Cy 5-1 wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and 5-1 are independently a C1-C6 alkyl group, a hydroxy group, or an oxo group; Ring Cy 6 is unsubstituted or one or more Cy6-1 a 6- to 10-membered aromatic ring substituted with Cy 6-1 are independently a C1-C6 alkyl group, a hydroxy group, or a halogen; Ring Cy 7 is unsubstituted or one or more Cy 7-1 wherein 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; and Cy 7-1 are independently a C1-C6 alkyl group, a hydroxy group, or a halogen; R 4 are independently hydrogen, halogen, a hydroxy group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens; p is 0, 1, 2 or 3; Each R 5 are independently halogen; L3 is unsubstituted or one or more L3 -1 replaced with [ka] where m is an integer from 1 to 4, q is an integer from 1 to 6, X is absent or O, and L3 -1 are independently halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0008] The present invention provides a compound of formula I, a pharmaceutically acceptable salt or isotopic compound thereof, [ka] Ring Cy is a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein 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; [ka] teeth, [ka] and Q is C or N; E is CH or N; Y is C or N; R 1 is unsubstituted or one or more R 1-1 a 5- to 10-membered heteroaryl group substituted with, or unsubstituted or one or more R 1-2 wherein the heteroatoms in 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 a halogen, a hydroxy group, [ka] -SO2-R a , -SO-R a , a cyano group, a nitro group, unsubstituted or one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 1-1-3 C1-C6 alkoxy group, unsubstituted or substituted with one or more R 1-1-4 a C1-C6 alkyl group substituted with [ka] Unsubstituted or one or more R 1-1-5 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R 1-1-8 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R 1-1-7wherein 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; and 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 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 are independently a halogen, an oxo, a hydroxy group, [ka] -SO2-R a , -SO-R a , an unsubstituted or one or more halogen-substituted C1-C6 alkoxy group, a cyano group, a nitro group, an unsubstituted or one or more R 1-1-1-1 a 3- to 11-membered heterocycloalkyl group substituted with one or more halogens, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, a 3- to 10-membered cycloalkyl group unsubstituted or substituted with one or more R 1-1-1-2 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R 1-1-1-3 wherein 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; and 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 1-1-1-1 , 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, a hydroxy group, a cyano group, a halogen, unsubstituted or one or more R 2-3 C1-C6 alkyl group, unsubstituted or substituted with one or more R2-2 a C1-C6 alkoxy group substituted with [ka] Unsubstituted or one or more R 2-1 a 5- to 10-membered heteroaryl group or an unsubstituted or substituted with one or more R 2-4 wherein 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; and the heteroatoms of the 4- to 10-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 2-1 , R 2-2 , R 2-3 and R 2-4 are independently a halogen, a hydroxy group, a cyano group, a nitro group, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, [ka] or a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens; R 3 represents hydrogen, deuterium, halogen, cyano group, hydroxy group, nitro group, [ka] -SO2-R a , -SO-R a , [ka] Unsubstituted or one or more R 3-1 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 a 3- to 10-membered cycloalkyl group substituted with [ka] Unsubstituted or one or more R 3-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-5 a 6- to 10-membered aryl group, unsubstituted or substituted with one or more R 3-6 a 5- to 10-membered heteroaryl group substituted with R 3-8 a hydroxy group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group substituted with -O-COR a wherein 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; and 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 one or more R 3-1-1 a 3- to 11-membered heterocycloalkyl group substituted with [ka] Cyano group, unsubstituted or one or more R 3-1-3 an alkoxy group substituted with [ka] Unsubstituted or one or more R 3-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-1-5 a 3- to 10-membered cycloalkyl group substituted with -SO2-R a , -SO-R a , [ka] a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein 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; and 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; 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, wherein 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; and 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 are independently a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a halogen, an oxo, or a hydroxy group; Each R a and each R b are independently H, unsubstituted, or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R a-5 is a 5- to 10-membered heteroaryl group substituted with or R a and R b form a 3- to 11-membered heterocyclic ring together with the atoms to which they are attached, the heteroatoms of said 3- to 11-membered heterocycloalkyl group being selected from one or more of N, S and O, and the number of heteroatoms being 1, 2 or 3; Each Ra-1 , R a-2 , R a-3 , R a-4 and R a-5 are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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; L0 may be unsubstituted or one or more L0 -2 a 5- to 12-membered cycloalkylene group or an unsubstituted or -3 wherein the 5- to 12-membered cycloalkylene group is bicyclic or polycyclic, the 5- to 12-membered heterocycloalkylene group is monocyclic, bicyclic or polycyclic, the heteroatoms of the 5- to 12-membered cycloalkylene group are selected from one or more of N, S and O, the number of heteroatoms is 1, 2 or 3, and each L0 -2 are independently a hydroxy group, a halogen, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, [ka] or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, and each L0 -3 are independently a hydroxy group, a halogen, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, [ka] or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens; L2 is a linker unit (connects LLM to L0), L0 is [ka] If so, L2 contains at least [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] wherein a and b are independently 1 or 2, m is an integer from 1 to 4, q is an integer from 1 to 6, X is O, and L2 1-1 represents a halogen, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, [ka] Hydroxy group, oxo or [ka] and Each R c are independently H, unsubstituted, or one or more R c-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R c-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R c-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R c-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R c-5 is a 5- to 10-membered heteroaryl group substituted with Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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; LLM is [ka] and Ring Cy 3 is unsubstituted or one or more Cy 3-1 wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and 3-1 are independently a C1-C6 alkyl group, halogen, hydroxy group, or oxo; Ring Cy 4 is unsubstituted or one or more Cy 4-1 wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and Cy 4-1 are independently a C1-C6 alkyl group, halogen, hydroxy group, or oxo; Ring Cy 5 is unsubstituted or one or more Cy 5-1 wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, or 3; and 5-1 are independently a C1-C6 alkyl group, a hydroxy group, or an oxo group; Ring Cy 6 is unsubstituted or one or more Cy6-1 a 6- to 10-membered aromatic ring substituted with Cy 6-1 are independently a C1-C6 alkyl group, a hydroxy group, or a halogen; Ring Cy 7 is unsubstituted or one or more Cy 7-1 wherein 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; and Cy 7-1 are independently a C1-C6 alkyl group, a hydroxy group, or a halogen; R 4 are independently hydrogen, halogen, a hydroxy group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens; p is 0, 1, 2 or 3; Each R 5 are independently halogen; L3 is unsubstituted or one or more L3 -1 replaced with [ka] where m is an integer from 1 to 4, q is an integer from 1 to 6, X is absent or O, and L3 -1 are independently halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0009] In a preferred embodiment, in the five-membered fused six-membered compound represented by formula I, its pharmaceutically acceptable salt or isotope compound, the definitions of some groups may be as described below, and the definitions of other groups may be as described in any one of the above embodiments (hereinafter abbreviated as "in one embodiment"). LLM is a group that binds to a ligase, and 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, T OPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / g p78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / 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 Bomb 1 / 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.

[0010] In one 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 - and L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] Unsubstituted or one or more L2 1-2 replaced with [ka] or unsubstituted or one or more L2 1-3 replaced with [ka] wherein m is an integer of 1 to 4, q is an integer of 1 to 6, X is absent or O, and the ring Cy 1 is a 4- to 12-membered heterocycle or a 3- to 12-membered cycloalkane, and the ring Cy 2 is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring, wherein 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 a halogen, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, [ka] Hydroxy group, oxo or [ka] and L2 1-3 are independently a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, a cyano group, [ka] Unsubstituted or one or more L2 1-3-1 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more L 1-3-2 a 3- to 11-membered heterocycloalkyl group substituted with [ka] -SO2-R a , -SO-R a , [ka] or a hydroxy group, wherein 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 L2 1-3-1 and L2 1-3-2 are independently a halogen, a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, a hydroxy group, an oxo group, or [ka] and Each R c are independently H, unsubstituted, or one or more R c-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R c-2a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R c-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R c-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R c-5 is a 5- to 10-membered heteroaryl group substituted with Each R c-1 , R c-2 , R c-3 , R c-4 and R c-5 are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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 a and each R b are independently H, unsubstituted, or one or more R a-1 C1-C6 alkyl group, unsubstituted or substituted with one or more R a-2 a 3- to 10-membered cycloalkyl group, unsubstituted or substituted with one or more R a-3 a 3- to 11-membered heterocycloalkyl group, unsubstituted or substituted with one or more R a-4 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R a-5 is a 5- to 10-membered heteroaryl group substituted with Each R a-1 , R a-2 , R a-3 , R a-4 and R a-5are independently a halogen, a cyano group, a hydroxy group, a nitro group, a C-C alkyl group, a C-C alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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; and 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.

[0011] In a preferred embodiment, when the ring Cy is a 5-membered heterocycle, the heteroatom of the 5-membered heterocycle is O, the number of which is 1, and the 5-membered heterocycle is preferably a tetrahydrofuran ring.

[0012] In a preferred embodiment, when the ring Cy is a 5-membered heteroaromatic ring, the heteroatom of the 5-membered heteroaromatic ring is selected from one or two of N, S, and O, the number of heteroatoms is 1 or 2, and the 5-membered heteroaromatic ring is preferably a pyrrole ring, a pyrazole ring, a thiazole ring, an oxazole ring, or an imidazole ring.

[0013] In one preferred embodiment, R 1 is unsubstituted or one or more R 1-1 In the case where the 5- to 10-membered heteroaryl group is a 5- to 10-membered heteroaryl group substituted with, the heteroatoms of the 5- to 10-membered heteroaryl group are selected from one or two of N, O and S, and the number of heteroatoms is 1, 2 or 3, and the 5- to 10-membered heteroaryl group is an oxazolyl group, a pyrazolyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group, a triazinyl group or a pyrazolopyrimidinyl group, for example, a pyridyl group, an oxazolyl group, a pyrazolyl group or [ka] may be.

[0014] In one preferred embodiment, R 1 is unsubstituted or one or more R 1-2 When the 6- to 10-membered aryl group is substituted with , the 6- to 10-membered aryl group is preferably a phenyl group or a naphthyl group.

[0015] In one preferred embodiment, each R 1-1 and R 1-2 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0016] In one preferred embodiment, each R 1-1 and R 1-2 is independently unsubstituted or one or more R 1-1-1 In the case where the heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group may be a 4- to 8-membered heterocycloalkyl group, and 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, and each R 1-1-1 are independently preferably a halogen, a hydroxy group, an oxo group, a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, and the 3- to 11-membered heterocycloalkyl group is preferably a piperazinyl group, a piperazinylene group, a piperidinyl group, a tetrahydropyrrolyl group, an oxetanyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group, or an azabicyclo[2.2.1]heptyl group, for example [ka] is.

[0017] In one preferred embodiment, each R 1-1 and R 1-2is independently unsubstituted or one or more R 1-1-3 When R is a C1-C6 alkoxy group substituted with R, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, and each R 1-1-3 are independently preferably a halogen, a hydroxy group, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0018] In one preferred embodiment, each R 1-1 and R 1-2 is independently unsubstituted or one or more R 1-1-4 When R is a C1-C6 alkyl group substituted with R, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and each R 1-1-4 are independently preferably a halogen, a hydroxy group, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0019] In one preferred embodiment, each R 1-1 and R 1-2 is independently unsubstituted or one or more R 1-1-5 When R is a 3- to 10-membered cycloalkyl group substituted with R, the 3- to 10-membered cycloalkyl group may be a 3- to 6-membered cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and each R 1-1-5 are independently preferably a halogen, a hydroxy group, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0020] In one preferred embodiment, each R 1-1 and R 1-2 is independently unsubstituted or one or more R 1-1-7 In the case where the 5- to 10-membered heteroaryl group is a 5- to 10-membered heteroaryl group substituted with N, the number of heteroatoms is 1, 2, or 3, and each R 1-1-7 are independently preferably a halogen, a hydroxy group, a C1-C6 alkoxy group that is unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, and the 5- to 10-membered heteroaryl group may be a pyridyl group, a pyridylene group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group, or a triazinyl group, for example, a pyridyl group or a pyridylene group.

[0021] In one preferred embodiment, each R 1-1 and R 1-2 is independently unsubstituted or one or more R 1-1-8 When R is a 6- to 10-membered aryl group substituted with R, the 6- to 10-membered aryl group is preferably a phenyl group or a naphthyl group, and each R 1-1-8 are independently preferably a halogen, a hydroxy group, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0022] In one preferred embodiment, each R 1-1-1 and R 1-1-7 is independently a C1-C6 alkyl group that is unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0023] In one preferred embodiment, each R 1-1-4 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0024] In one preferred embodiment, R 2 When is a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0025] In one preferred embodiment, R 2 is unsubstituted or one or more R 2-1 When the 5- to 10-membered heteroaryl group is a 5- to 10-membered heteroaryl group substituted with N, the heteroatom of the 5- to 10-membered heteroaryl group is N, the number of heteroatoms is 1, 2 or 3, and 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.

[0026] In one preferred embodiment, R 2 is unsubstituted or one or more R 2-2 When the substituted C1-C6 alkoxy group is 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, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0027] In one preferred embodiment, R 2 is unsubstituted or one or more R 2-3 When it is a C1-C6 alkyl group substituted with , the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0028] In one preferred embodiment, R 2 is unsubstituted or one or more R 2-4In the case of a 4- to 10-membered heterocycloalkyl group substituted with a substituted 4- to 10-membered heterocycloalkyl group, the 4- to 10-membered heterocycloalkyl group may be a 5- to 8-membered heterocycloalkyl group, wherein the heteroatom of the 4- to 10-membered heterocycloalkyl group is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2, preferably the heteroatom of the 4- to 10-membered heterocycloalkyl group is N, S or O, and the number of heteroatoms is 1 or 2, and the 4- to 10-membered heterocycloalkyl group is preferably a piperazinyl group, a piperidinyl group, a tetrahydropyrrolyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group or an azabicyclo[2.2.1]heptyl group, for example [ka] is.

[0029] In one preferred embodiment, each R 2-1 , R 2-2 , R 2-3 and R 2-4 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0030] In one preferred embodiment, each R 2-1 , R 2-2 , R 2-3 and R 2-4 is independently a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and the halogen may be fluorine, chlorine, bromine, or iodine, such as fluorine.

[0031] In one preferred embodiment, each R 2-1 , R 2-2 , R 2-3 and R 2-4is 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, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, further for example a methoxy group, and the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0032] In one preferred embodiment, R 3 When is a halogen, said halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0033] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-1 In the case of a 3- to 11-membered heterocycloalkyl group substituted with R, the 3- to 11-membered heterocycloalkyl group may be a 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is 1 or 2, and the 3- to 11-membered heterocycloalkyl group is preferably a piperidinyl group, a tetrahydropyrrolyl group, a tetrahydropyrrolylene group, a 2-azaspiro[3.3]heptyl group, a 2-oxaspiro[3.3]heptyl group, a morpholinyl group, a tetrahydropyranyl group, an oxetanyl group, an azabicyclo[2.2.1]heptyl group, or a diazabicyclo[2.2.1]heptyl group, and each R 3-1 are independently preferably halogen, oxo or hydroxy groups, e.g., hydroxy groups, and the unsubstituted or one or more R 3-1 The 3- to 8-membered heterocycloalkyl group substituted with is preferably [ka] is.

[0034] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-2In the case where R is a 3- to 10-membered cycloalkyl group substituted with R, the 3- to 10-membered cycloalkyl group may be a C3-C6 cycloalkyl group, and may further be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, and each R 3-2 are independently preferably halogen or hydroxy groups, and are unsubstituted or one or more R 3-2 The 3 to 10 membered cycloalkyl group substituted with is preferably [ka] is.

[0035] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-4 When R is a C1-C6 alkyl group substituted with R, the C1-C6 alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group, and may also be a methyl group, an ethyl group, a propyl group, an isopropyl group, or an isopentyl group, and each R 3-4 are independently preferably halogen, a hydroxy group, -SO2-R a or [ka] and R a is a C1-C6 alkyl group, and R b is hydrogen, and the unsubstituted or one or more R 3-4 C1-C6 alkyl group substituted with [ka] may be.

[0036] In one preferred embodiment, R 3is unsubstituted or one or more R 3-4 When R is a C1-C6 alkyl group substituted with R, the C1-C6 alkyl group may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a primary pentyl group, a sec-pentyl group, a tert-pentyl group, or a neopentyl group, and may also be a methyl group, an ethyl group, a propyl group, an isopropyl group, or an isopentyl group, and each R 3-4 are independently preferably deuterium, halogen, a hydroxy group, -SO2-R a or [ka] and R a is a C1-C6 alkyl group, and R b is hydrogen, and the unsubstituted or one or more R 3-4 C1-C6 alkyl group substituted with [ka] may be.

[0037] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-7 When R is a C1-C6 alkoxy group substituted with R, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group; 3-7 are independently preferably halogen, and the unsubstituted or one or more R 3-7 The C1-C6 alkoxy group substituted with is preferably a methoxy group, [ka] It is an isopropoxy group or a trifluoromethoxy group.

[0038] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-7 When R is a C1-C6 alkoxy group substituted with R, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group; 3-7 are independently preferably deuterium or halogen, and the unsubstituted or one or more R 3-7 The C1-C6 alkoxy group substituted with is preferably a methoxy group, [ka] It is an isopropoxy group or a trifluoromethoxy group.

[0039] In one preferred embodiment, R 3 R 3-8 If R is a hydroxy group substituted with 3-8 may be 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 oxygen, the number of heteroatoms is 1, and the R 3-8 The hydroxy group substituted with is preferably [ka] is.

[0040] In one preferred embodiment, R 3 but [ka] If R a may be H.

[0041] In one preferred embodiment, each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0042] In one preferred embodiment, each R 3-1 , R 3-2 , R 3-4 , R 3-5 , R 3-6 and R 3-7 is independently unsubstituted or one or more R 3-1-1 In the case of a 3- to 11-membered heterocycloalkyl group substituted with one or more R, the 3- to 11-membered heterocycloalkyl group may be a 5- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 11-membered heterocycloalkyl group is preferably N and / or O, the number of heteroatoms is 1 or 2, and the unsubstituted or one or more R 3-1-1 The 3- to 11-membered heterocycloalkyl group substituted with is preferably a tetrahydropyrrolyl group, an oxetanyl group or a spiroheptyl group containing one oxygen and / or one nitrogen, e.g. [ka] is.

[0043] In one preferred embodiment, each R 3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 are independently a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, further 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 sec-butyl group or a tert-butyl group, further may be a methyl group or an ethyl group.

[0044] In one preferred embodiment, each R3-1-1 , R 3-1-3 , R 3-1-4 and R 3-1-5 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0045] In one preferred embodiment, L is unsubstituted or one or more L -2 In the case of a 5- to 12-membered cycloalkylene group substituted by [ka] and a, b, c and d are independently 0, 1 or 2, for example: [ka] is.

[0046] In one preferred embodiment, L is unsubstituted or one or more L -2 In the case of a 5- to 12-membered cycloalkylene group substituted by [ka] and a, b, c and d are independently 0, 1 or 2, for example: [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0047] In one preferred embodiment, L is unsubstituted or one or more L -3 In the case of a 5- to 12-membered heterocycloalkylene group substituted with [ka] wherein 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, e.g., [ka] is.

[0048] In one preferred embodiment, L is unsubstituted or one or more L -3 In the case of a 5- to 12-membered heterocycloalkylene group substituted with [ka] wherein 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, e.g., [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0049] In one preferred embodiment, each L0 -2 is independently a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group can be a C1-C4 alkyl group, further can 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 sec-butyl group or a tert-butyl group, further can be a methyl group, an ethyl group or an isopropyl group, and the halogen can be fluorine, chlorine, bromine or iodine, for example, fluorine.

[0050] In one preferred embodiment, each L0 -2is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0051] In one preferred embodiment, each L0 -2 is independently a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0052] In one preferred embodiment, each L0 -2 are independently a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a 1-butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group.

[0053] In one preferred embodiment, each L0 -3 is independently a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group can be a C1-C4 alkyl group, further can 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 sec-butyl group or a tert-butyl group, further can be a methyl group, an ethyl group or an isopropyl group, and the halogen can be fluorine, chlorine, bromine or iodine, for example, fluorine.

[0054] In one preferred embodiment, each L0 -3 is independently a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0055] In one preferred embodiment, each L0 -3is independently a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0056] In one preferred embodiment, each L0 -3 are independently a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a 1-butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group.

[0057] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-1 When the C1-C6 alkyl group is a C1-C6 alkyl group substituted with , the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further 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 sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0058] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-2 When it is a 3- to 10-membered cycloalkyl group substituted with , the 3- to 10-membered cycloalkyl group may be a 3- to 6-membered cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0059] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-3In the case of a 3- to 11-membered heterocycloalkyl group substituted with , the 3- to 11-membered heterocycloalkyl group may be a 5- to 8-membered heterocycloalkyl group, wherein the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2, preferably the heteroatom of the 3- to 11-membered heterocycloalkyl group is N, S or O, and the number of heteroatoms is 1 or 2, and the 3- to 11-membered heterocycloalkyl group is preferably a piperazinyl group, a piperidinyl group, a tetrahydropyrrolyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group or an azabicyclo[2.2.1]heptyl group, for example [ka] is.

[0060] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-3 In the case where the heterocycloalkyl group is a 3- to 11-membered heterocycloalkyl group substituted with , the 3- to 11-membered heterocycloalkyl group may be a 5- to 8-membered heterocycloalkyl group, wherein 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, and 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, and the 3- to 11-membered heterocycloalkyl group is preferably a piperazinyl group, a piperidinyl group, a tetrahydropyrrolyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group, or an azabicyclo[2.2.1]heptyl group.

[0061] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-4When the 6- to 10-membered aryl group is substituted with , the 6- to 10-membered aryl group may be a benzene ring or a naphthalene ring.

[0062] In one preferred embodiment, each R a and each R b is independently unsubstituted or one or more R a-5 In the case where the 5- to 10-membered heteroaryl group is a 5- to 10-membered heteroaryl group substituted with , the 5- to 10-membered heteroaryl group may be a 5- or 6-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, and the 5-membered heteroaryl group is preferably a pyrazolyl group, a thiazolyl group or an imidazolyl group.

[0063] In one preferred embodiment, the ring Cy 3 In the above formula, the 5- to 12-membered heterocycle may be a 5- or 6-membered heterocycle, the heteroatom of the 5- to 12-membered heterocycle is preferably N, S, or O, the number of heteroatoms is 1 or 2, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring.

[0064] In one preferred embodiment, Cy 3-1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0065] In one preferred embodiment, the ring Cy 4In the above formula, the 5- to 12-membered heterocycle may be a 5- to 6-membered heterocycle, the heteroatom of the 5- to 6-membered heterocycle is preferably N, S, or O, the number of heteroatoms is 1 or 2, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a piperidine ring.

[0066] In one preferred embodiment, Cy 4-1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0067] In one preferred embodiment, the ring Cy 5 In the above formula, the 5- to 12-membered heterocycle may be a 5- or 6-membered heterocycle, the heteroatom of the 5- to 12-membered heterocycle is preferably N, S, or O, the number of heteroatoms is 1 or 2, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring.

[0068] In one preferred embodiment, Cy 5-1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0069] In one preferred embodiment, Cy 6 In the above formula, the 6- to 10-membered aromatic ring may be a benzene ring or a naphthalene ring.

[0070] In one preferred embodiment, Cy 6-1wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0071] In one preferred embodiment, Cy 6-1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0072] In one preferred embodiment, the ring Cy 7 In the above, the 5- to 9-membered heteroaromatic ring may be a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring, and the 6-membered heteroaromatic ring is preferably a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring or a triazine ring, and the 5-membered heteroaromatic ring is preferably a pyrazole ring, an oxazole ring, a thiazole ring or an imidazole ring, for example, [ka] is.

[0073] In one preferred embodiment, Cy 7-1 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0074] In one preferred embodiment, Cy 7-1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group.

[0075] In one preferred embodiment, R 4wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a tert-butyl group.

[0076] In one preferred embodiment, R 4 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0077] In one preferred embodiment, R 5 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0078] In one preferred embodiment, L3 -1 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may also be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group.

[0079] In one preferred embodiment, the ring Cy 1 is a 5- to 12-membered heterocycle, the heteroatom of the 5- to 12-membered heterocycle is N, S, or O, the number of heteroatoms is 1 or 2, and the 5- to 12-membered heterocycle may be an oxetane ring, diazaspiro[3.3]heptane, tetrahydrofuran ring, piperidine ring, piperazine ring, diazaspiro[3.5]nonane, azaspiro[3.3]heptane, diazaspiro[5.5]undecane, azaspiro[3.5]nonane, or azaspiro[5.5]undecane.

[0080] In one preferred embodiment, the ring Cy 1 When is a 3- to 12-membered cycloalkane, said 3- to 12-membered cycloalkane may be a 3- to 6-membered cycloalkane, for example, cyclohexane.

[0081] In one preferred embodiment, the ring Cy 2 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, 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, and the 5-membered heteroaromatic ring is preferably a pyrazole ring, a thiazole ring or an imidazole ring.

[0082] In one preferred embodiment, L2 1-1 and L2 1-2 wherein the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0083] In one preferred embodiment, L2 1-1 and L2 1-2 wherein the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group.

[0084] In one preferred embodiment, L2 1-1 and L2 1-2 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.

[0085] In one preferred embodiment, L2 1-3 wherein the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0086] In one preferred embodiment, L2 1-3 In the C1-C6 alkyl group unsubstituted or substituted with one or more halogens, the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further 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 sec-butyl group or a tert-butyl group, and may further be a methyl group, an ethyl group or an isopropyl group, and the halogen is preferably fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine.

[0087] In one preferred embodiment, L2 1-3 In the C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group or a tert-butoxy group, and may further be a methoxy group, an ethoxy group or an isopropoxy group, and the halogen is preferably fluorine, chlorine, bromine or iodine, for example, fluorine or chlorine.

[0088] In one preferred embodiment, L2 1-3 In the above, the unsubstituted or one or more L2 1-3-1 In the 3- to 10-membered cycloalkyl group substituted by, the 3- to 10-membered cycloalkyl group may be a C3-C6 cycloalkyl group, and may further be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, and each L2 1-3-1 are independently preferably halogen or a hydroxy group.

[0089] In one preferred embodiment, L2 1-3 In the above, the unsubstituted or one or more L2 1-3-2In the 3- to 11-membered heterocycloalkyl group substituted with , the 3- to 11-membered heterocycle may be a 4- to 9-membered heterocycle, the heteroatoms of the 4- to 9-membered heterocycle are preferably one or two of N, S and O, the number of heteroatoms is 1 or 2, and the 3- to 11-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring or a tetrahydrothiophene ring, for example, a piperidine ring.

[0090] In one preferred embodiment, L2 1-3-1 and L2 1-3-2 wherein the C1-C6 alkoxy group may be a C1-C4 alkoxy group, and may further be a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a primary butoxy group, a sec-butoxy group, or a tert-butoxy group, and may further be a methoxy group, an ethoxy group, or an isopropoxy group.

[0091] In one preferred embodiment, R c is unsubstituted or one or more R c-1 When the C1-C6 alkyl group is a C1-C6 alkyl group substituted with , the C1-C6 alkyl group may be a C1-C4 alkyl group, and may further 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 sec-butyl group, or a tert-butyl group, and may further be a methyl group, an ethyl group, or an isopropyl group.

[0092] In a preferred embodiment, p is 0 or 1 in the LLM.

[0093] In a preferred embodiment, m is 1 or 2 in L2.

[0094] In a preferred embodiment, q is 1 or 2 in L2.

[0095] In a preferred embodiment, m is 1 or 2 in L3.

[0096] In a preferred embodiment, in L3, q is 1 or 2.

[0097] In the present invention, 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 may independently be a phenyl group or a naphthyl group.

[0098] In the present invention, 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 groups may independently be C1-C4 alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy groups, and may further be, for example, methoxy groups.

[0099] In the present invention, R 1-1-1 , R1-1-3 , 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 halogens may independently be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0100] In the present invention, 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 C1-C6 alkyl groups may independently be C1-C4 alkyl groups, and may further be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl, or tert-butyl groups, and may further be methyl, ethyl, or isopropyl groups.

[0101] In the present invention, 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 , R3-1-5 , 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 formula (I), the 3- to 11-membered heterocycloalkyl group may independently be a 6-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, an 8-membered heterocycloalkyl group, or a 7-membered heterocycloalkyl group, and the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or two 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, [ka] and the 5-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, for example [ka] and the 8-membered heterocycloalkyl group is preferably an azabicyclo[2.2.2]octyl group or an -azabicyclo[3.2.1]octyl group, for example [ka] and the 7-membered heterocycloalkyl group is preferably an azaspiro[3.3]heptyl group or an azabicyclo[2.2.1]heptyl group, for example [ka] is.

[0102] In the present invention, 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 formula (I), the 3- to 10-membered cycloalkyl groups may independently be 3- to 6-membered cycloalkyl groups, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0103] In the present invention, 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 formula (I), the 5- to 10-membered heteroaryl groups may independently be a 5-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered fused 5-membered heteroaryl group, and the 6-membered heteroaryl group is preferably a pyridyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidinyl group, or a triazinyl group, and the 5-membered heteroaryl group is preferably a pyrazolyl group, an oxazolyl group, a thiazolyl group, or an imidazolyl group, for example, [ka] and the 5- to 9-membered heteroaryl group is preferably a pyrazolyl group, a thiazolyl group, an imidazolyl group, a tetrahydropyrrolothiazolyl group or a tetrahydropyrrolopyrazolyl group, for example [ka] is.

[0104] In one preferred embodiment, R 1 is unsubstituted or one or more R 1-1 a 5- to 10-membered heteroaryl group or an unsubstituted or substituted with one or more R 1-2 The heteroatoms in the 5- to 10-membered heteroaryl group are selected from one or two of N, S, and O, and the number of heteroatoms is one or two. 1 is preferably unsubstituted or substituted with one or more R 1-1 a 5- to 6-membered heteroaryl group or an unsubstituted or substituted with one or more R 1-2 The heteroatoms of the 5- to 6-membered heteroaryl group are one or two selected from N, S and O, and the number of heteroatoms is one or two.

[0105] In one preferred embodiment, R 1 is unsubstituted or one or more R 1-1 a 5- to 10-membered heteroaryl group or an unsubstituted or substituted with one or more R 1-2 R is a 6- to 10-membered aryl group substituted with R, wherein the heteroatoms in 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, 2, or 3. 1 is preferably unsubstituted or substituted with one or more R 1-1 a 5- to 9-membered heteroaryl group or an unsubstituted or substituted with one or more R 1-2 R is a 6- to 10-membered aryl group substituted with R, wherein the heteroatoms in the 5- to 9-membered heteroaryl group are selected from one or two of N, S, and O, and the number of heteroatoms is 1, 2, or 3. 1is preferably unsubstituted or substituted with one or more R 1-1 The heteroatoms of the 5- to 9-membered heteroaryl group are one or two of N and O, and the number of heteroatoms is 1, 2, or 3. 1 is preferably unsubstituted or substituted with one or more R 1-1 and the 5- to 9-membered heteroaryl group is a pyridyl group, an oxazolyl group, a pyrazolyl group, or [ka] R 1 is preferably one or more R 1-1 or a pyridyl group substituted with one or more R 1-1 replaced with [ka] is.

[0106] In one preferred embodiment, each R 1-1 and R 1-2 are independently a halogen, a hydroxy group, [ka] -SO2-R a , -SO-R a , unsubstituted or one or more R 1-1-4 C1-C6 alkyl group substituted with, or unsubstituted or one or more R 1-1-7 wherein the heteroatoms in 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. 1-1 and R 1-2 are independently preferably halogen, unsubstituted or one or more R 1-1-7 a 5- to 6-membered heteroaryl group or an unsubstituted or substituted with one or more R 1-1-4wherein 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.

[0107] In one preferred embodiment, each R 1-1 is unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group or an unsubstituted or substituted with one or more R 1-1-7 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; and 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, 2, or 3.

[0108] In one preferred embodiment, each R 1-1-4 are independently halogen.

[0109] In one preferred embodiment, each R 1-1-4 are independently halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0110] In one preferred embodiment, each R 1-1-7 are independently a halogen, a hydroxy group, a C1-C6 alkoxy group unsubstituted or substituted with one or more halogens, a cyano group, a nitro group, a C1-C6 alkyl group unsubstituted or substituted with one or more halogens ... R 1-1-1-2 a 6- to 10-membered aryl group substituted with, or unsubstituted or one or more R 1-1-1-3wherein 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; and 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. 1-1-7 are independently preferably C1-C6 alkyl groups unsubstituted or substituted with one or more halogens.

[0111] In one preferred embodiment, each R 1-1-7 are independently preferably halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0112] In one preferred embodiment, each R 1-1-1 are independently halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens. 1-1-1 are independently preferably C1-C6 alkyl groups unsubstituted or substituted with one or more halogens.

[0113] In one preferred embodiment, each R 1-1-1-1 , R 1-1-1-2 and R 1-1-1-3 are independently halogen or a C1-C6 alkyl group.

[0114] In one preferred embodiment, R 2 is hydrogen.

[0115] In one preferred embodiment, R 3 is hydrogen, a hydroxy group, a halogen, a cyano group, unsubstituted or one or more R 3-1 a 3- to 10-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 3-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-7C1-C6 alkoxy group substituted with R 3-8 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two selected from N and O, and the number of heteroatoms is one, two, or three. 3 is preferably unsubstituted or substituted with one or more R 3-1 a 3- to 6-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 C3-C6 cycloalkyl group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group, unsubstituted or substituted with one or more R 3-4 a C1-C6 alkyl group substituted with R 3-8 The heteroatoms of the 3- to 6-membered heterocycloalkyl group are one or two selected from N and O, and the number of heteroatoms is one or two.

[0116] In one preferred embodiment, R 3 is hydrogen, hydroxyl group, halogen, cyano group, [ka] Unsubstituted or one or more R 3-1 a 3- to 10-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 a 3- to 8-membered cycloalkyl group, unsubstituted or substituted with one or more R 3-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group substituted with R 3-8 The heteroatoms of the 3- to 10-membered heterocycloalkyl group are one or two selected from N and O, and the number of heteroatoms is one, two, or three. 3 is preferably a halogen, [ka] Unsubstituted or one or more R 3-1a 3- to 6-membered heterocycloalkyl group, unsubstituted or substituted with one or more R 3-2 C3-C6 cycloalkyl group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group, unsubstituted or substituted with one or more R 3-4 a C1-C6 alkyl group substituted with R 3-8 The heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N and O, and the number of heteroatoms is one or two. 3 is preferably unsubstituted or substituted with one or more R 3-4 C1-C6 alkyl group or unsubstituted or substituted with one or more R 3-7 is a C1-C6 alkoxy group substituted with

[0117] R 3 is preferably unsubstituted or substituted with one or more R 3-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group or unsubstituted or substituted with one or more R 3-1 is a tetrahydropyrrolyl group substituted with

[0118] In one preferred embodiment, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently oxo, hydroxy, halogen, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N, S, and O, and the number of heteroatoms is 1 or 2. 3-1 are independently preferably a hydroxy group or a halogen. 3-2 is independently preferably a hydroxy group. 3-4 are independently preferably a hydroxy group, and each R 3-7 is independently preferably halogen.

[0119] In one preferred embodiment, each R 3-1 , R 3-2 , R 3-4 and R 3-7 are independently deuterium, oxo, hydroxy, halogen, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N, S, and O, and the number of heteroatoms is 1 or 2. 3-1 are independently preferably a hydroxy group or a halogen. 3-2 is independently preferably a hydroxy group. 3-4 are independently preferably deuterium, halogen, or a hydroxy group, and each R 3-7 are independently preferably deuterium or halogen.

[0120] In one preferred embodiment, each R 3-1 are independently deuterium, a hydroxy group, or a halogen.

[0121] In one preferred embodiment, each R 3-4 are independently deuterium, halogen, or a hydroxy group.

[0122] In one preferred embodiment, each R 3-7 are independently deuterium or a hydroxy group.

[0123] In one preferred embodiment, R 3 There are multiple R 3-4 When R is a C1-C6 alkyl group substituted with 3-4 is a hydroxy group, a deuterium and a hydroxy group, or a halogen and a hydroxy group.

[0124] In one preferred embodiment, R 3-8is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein 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. 3-8 is preferably a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein the heteroatom of the 3- to 6-membered heterocycloalkyl group is selected from one or two of N and O, and the number of heteroatoms is 1.

[0125] In one preferred embodiment, each R a and each R b are independently H or unsubstituted or one or more R a-1 Each R is a C1-C6 alkyl group substituted with a and each R b is independently preferably H.

[0126] In a preferred embodiment, L is unsubstituted or one or more L -2 a 5- to 12-membered cycloalkylene group or an unsubstituted or -3 wherein the 5- to 12-membered cycloalkylene group is a spiro ring, a fused ring, or a bridged ring, and the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spiro ring, a fused ring, or a bridged ring, and 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, and each L0 -2 are independently halogen, hydroxy, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, and each L0 -3 are independently a halogen, a hydroxy group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0127] In a preferred embodiment, L is unsubstituted or one or more L -2 a 5- to 12-membered cycloalkylene group or an unsubstituted or -3wherein the 5- to 12-membered cycloalkylene group is a spiro ring, a fused ring, or a bridged ring, and the 5- to 12-membered heterocycloalkylene group is a monocyclic ring, a spiro ring, a fused ring, or a bridged ring, and 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, and each L0 -2 are independently deuterium, halogen, hydroxyl, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, and each L0 -3 are independently deuterium, halogen, hydroxy, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0128] In a preferred embodiment, L is unsubstituted or one or more L -2 a 7- to 11-membered cycloalkylene group or an unsubstituted or -3 wherein the 7- to 11-membered cycloalkylene group is a spiro ring, the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, the number of heteroatoms is 1 or 2, and each L0 -2 are independently halogen, hydroxy, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, and each L0 -3 are independently a halogen, a hydroxy group, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens.

[0129] In a preferred embodiment, L is unsubstituted or one or more L -2 a 7- to 11-membered cycloalkylene group or an unsubstituted or -3wherein the 7- to 11-membered cycloalkylene group is a spiro ring, the 7- to 11-membered heterocycloalkylene group is a spiro ring or a fused ring, the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, the number of heteroatoms is 1 or 2, and each L0 -2 are independently deuterium, halogen, hydroxyl, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, and each L0 -3 are independently deuterium, halogen, hydroxy, or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens. 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, and the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1.

[0130] In a preferred embodiment, L 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 fused ring, the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1 or 2.

[0131] 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 fused 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 [ka] wherein the 8- to 11-membered heterocycloalkylene group is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0132] In a preferred embodiment, L is a 9- to 11-membered spiroheterocyclylene group, and the heteroatom of the 9- to 11-membered spiroheterocyclylene group is N, and the number of heteroatoms is 1. Preferably, the 9- to 11-membered spiroheterocyclylene group is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0133] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] Unsubstituted or one or more L2 1-2 replaced with [ka] or unsubstituted or one or more L2 1-3 replaced with [ka] wherein m is an integer of 1 to 4, q is an integer of 1 to 6, X is absent or O, and the ring Cy 1 is a 4- to 11-membered heterocycle or a 4- to 11-membered cycloalkane, and the ring Cy 2is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring, wherein 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; and 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.

[0134] In one preferred embodiment, preferably, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] is.

[0135] In one preferred embodiment, preferably, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] where the a' end points towards L0 and the b' end points towards LLM.

[0136] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] or unsubstituted or one or more L2 1-2 replaced with [ka] wherein m is 1 or 2, q is 1 or 2, X is absent or O, and the ring Cy 1 is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatoms of the 4- to 11-membered heterocycle are N and / or O, the number of heteroatoms is 1 or 2, the 4- to 11-membered heterocycle is a monocycle, a bridged ring, or a spirocycle, and the 4- to 11-membered cycloalkane is a monocycle, a bridged ring, or a spirocycle.

[0137] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] Unsubstituted or one or more L2 1-2 replaced with [ka] or unsubstituted or one or more L2 1-3 replaced with [ka] wherein m is 1 or 2, q is 1 or 2, X is absent or O, and the ring Cy 1 is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatoms of the 4- to 11-membered heterocycle are N and / or O, the number of heteroatoms is 1 or 2, the 4- to 11-membered heterocycle is a monocycle, a bridged ring or a spiro ring, and the 4- to 6-membered cycloalkane is a monocycle. 2is 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.

[0138] In a preferred embodiment, when the 4- to 11-membered heterocycle is a spiro ring, the 4- to 11-membered heterocycle is a 4,6-azaspiro ring, a 6,6-azaspiro ring, or a 4,4-azaspiro ring.

[0139] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] or unsubstituted or one or more L2 1-2 replaced with [ka] wherein m is 1 or 2, q is 1, X is absent or O, and the ring Cy 1 is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is 1 or 2, the 4- to 10-membered heterocycle is a 6-membered monocycle or a 4,6-azaspirocycle, R c is H.

[0140] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4does not exist independently, [ka] Unsubstituted or one or more L2 1-1 replaced with [ka] Unsubstituted or one or more L2 1-2 replaced with [ka] or unsubstituted or one or more L2 1-3 replaced with [ka] wherein m is 1 or 2, q is 1, X is absent or O, and the ring Cy 1 is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is 1 or 2, the 4- to 10-membered heterocycle is a 6-membered monocycle, a 4,4-azaspirocycle or a 4,6-azaspirocycle, and R c is H and the ring Cy 2 is a 5-membered heteroaromatic ring, 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 does not exist independently, [ka] wherein m is 1 or 2, q is 1, X is absent, and the ring Cy 1 is a 4- to 6-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is 1 or 2, the 4- to 6-membered cycloalkane is a 6-membered monocycle, and R c is H.

[0141] In one preferred embodiment, L2 -1 , L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] wherein m is 1 or 2, q is 1, X is absent, and the ring Cy 1 is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is 1 or 2, the 4- to 6-membered cycloalkane is a 6-membered monocycle, and R c is H and the ring Cy 2 is a 5-membered heteroaromatic ring, the heteroatom of said 5-membered heteroaromatic ring is N, the number of heteroatoms is 2, for example, a pyrazole ring.

[0142] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 and L2 -2 does not exist, L2 -3 teeth, [ka] and L2 -4 is unsubstituted or one or more L2 1-2 replaced with [ka] and the ring Cy 1 is a piperidinyl group or a piperazinyl group. Preferably, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 and L2 -2 does not exist, L2 -3 teeth, [ka] and L2 -4 is an unsubstituted ring Cy 1 and the ring Cy 1 is a piperidinyl group or a piperazinyl group.

[0143] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 does not exist, L2 -2 , L2 -3 and L2 -4 is, independently, [ka] or unsubstituted or one or more L2 1-2 Ring Cy substituted with 1 and the ring Cy 1 is a cyclohexyl group, a piperidinyl group, or a piperazinyl group.

[0144] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 , L2 -2 , L2 -3 and L2 -4 is, independently, [ka] or unsubstituted or one or more L2 1-2 Ring Cy substituted with 1 and the ring Cy 1 is a cyclohexyl group, a piperidinyl group, or a piperazinyl group.

[0145] In one preferred embodiment, each L2 1-2 are independently a halogen or a hydroxy group.

[0146] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or [ka] and L2 -1 teeth, [ka] and L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] or unsubstituted or one or more L2 1-2 replaced with [ka] and the ring Cy 1 is a 4- to 6-membered heterocycle, the heteroatom of said 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, and said 4- to 6-membered heterocycle is a monocycle.

[0147] In a preferred embodiment, in L2, R c is H or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens, more preferably H.

[0148] In one preferred embodiment, the ring Cy 3 is unsubstituted or one or more Cy 3-1 The heteroatom of the 5- to 6-membered heterocycle is N, S or O, and the number of the heteroatoms is 1. 3 is preferably unsubstituted or multiple Cy 3-1 and the heteroatom of said 5- to 6-membered heterocycle is N and the number is one.

[0149] In one preferred embodiment, each Cy 3-1 is independently oxo. In one preferred embodiment, the ring Cy 4 is unsubstituted or one or more Cy 4-1 wherein the heteroatoms in 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. 4 is unsubstituted or one or more Cy 4-1 The heteroatom of the 5- to 8-membered heterocycle is N, S or O, and the number of heteroatoms is 1.

[0150] In one preferred embodiment, each Cy 4-1 are independently a C1-C6 alkyl group, a hydroxy group or oxo, preferably oxo.

[0151] In a preferred embodiment, the five-membered fused six-membered compound represented by formula I is a compound represented by formula Ia, Ib, Id, Ig, Ih or Ii. [ka] is.

[0152] In a preferred embodiment, the five-membered fused six-membered compound represented by formula I is a compound represented by formula Ia, Ib, Id, Ig, Ih, Ii, Ik, Im or In. [ka] [ka] [ka] is.

[0153] In one preferred embodiment, the LLM comprises: [ka] and preferably [ka] and more preferably, [ka] ,for example, [ka] is.

[0154] In one preferred embodiment, the LLM comprises: [ka] and preferably [ka] and more preferably, [ka] ,for example, [ka] is.

[0155] In one preferred embodiment, the LLM comprises: [ka] for example, [ka] and further, for example, [ka] is.

[0156] In one preferred embodiment, R 1 teeth, [ka] and preferably [ka] is.

[0157] In one preferred embodiment, R 3 is a methoxy group, an isopropoxy group, a difluoromethoxy group, a trifluoromethoxy group, a carboxyl group, a fluorine group, [ka] and preferably a methoxy group, [ka] is.

[0158] In one preferred embodiment, [ka] teeth, [ka] For example, [ka] is.

[0159] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] wherein X is N or CH and X1 is S or O.

[0160] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0161] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0162] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0163] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0164] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0165] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0166] In one preferred embodiment, in the compound of formula I, [ka] teeth, [ka] is.

[0167] In a preferred embodiment, L0 is [ka] is.

[0168] In a preferred embodiment, L0 is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0169] In a preferred embodiment, L0 is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0170] In a preferred embodiment, in L0, [ka] teeth, [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0171] In a preferred embodiment, L2 is [ka] [ka] [ka] is.

[0172] In a preferred embodiment, L2 is [ka] [ka] [ka] where the a' end is linked to L0 and the b' end is linked to LLM.

[0173] In a preferred embodiment, L0 is [ka] (furthermore, L0 is unsubstituted or one or more L0 -3 When L2 is a 5- to 12-membered heterocycloalkylene group substituted with [ka] [ka] [ka] is.

[0174] In a preferred embodiment, L0 is [ka] (furthermore, L0 is unsubstituted or one or more L0 -3 When L2 is a 5- to 12-membered heterocycloalkylene group substituted with [ka] [ka] [ka] where the a' end of L2 is linked to L0 and the b' end of L2 is linked to LLM.

[0175] In one preferred embodiment, R 1 but [ka] If L0 is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0176] In one preferred embodiment, R 1 but [ka] If L0 is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0177] In one preferred embodiment, R 1 but [ka] If L0 is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to L2.

[0178] In one preferred embodiment, R 1 but [ka] If so, L2- is [ka] wherein the a' end of L2 is linked to L0 and the b' end of L2 is linked to LLM.

[0179] In one preferred embodiment, R 1 but [ka] If so, L2- is [ka] wherein the a' end of L2 is linked to L0 and the b' end of L2 is linked to LLM.

[0180] In one preferred embodiment, R 1 but [ka] If so, L2- is [ka] wherein the a' end of L2 is linked to L0 and the b' end of L2 is linked to LLM.

[0181] In one preferred embodiment, -L0-L2- is [ka] and preferably [ka] is.

[0182] In one preferred embodiment, -L0-L2- is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to the LLM.

[0183] In one preferred embodiment, [ka] If -L0-L2- is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to the LLM, preferably [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to the LLM.

[0184] In one preferred embodiment, [ka] If -L0-L2- is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to the LLM.

[0185] In one preferred embodiment, [ka] If -L0-L2- is [ka] wherein the a' end is linked to the ring Cy and the b' end is linked to the LLM.

[0186] In a preferred embodiment, the compound of formula I is a compound of formula Id, [ka] where R 1 is one or more R 1-1 a pyridyl group substituted with one or more R 1-1 replaced with [ka] and R 1 is one or more R 1-1 When R is a pyridyl group substituted with 1-1 independently represent one or more R 1-1-4 is a C1-C6 alkyl group substituted with R 1 is one or more R 1-1 replaced with [ka] If R 1-1 is unsubstituted or one or more R 1-1-1 wherein the heteroatoms of said 7- to 8-membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is two; Each R 1-1-4 are independently halogen, and each R 1-1-1 are independently a C1-C6 alkyl group substituted with one or more halogens; R 2 is hydrogen, R 3 is unsubstituted or one or more R 3-4 C1-C6 alkyl group or unsubstituted or substituted with one or more R 3-7 is a C1-C6 alkoxy group substituted with Each R 3-4are independently deuterium, halogen, or a hydroxy group, and each R 3-7 are independently deuterium, L0 is a 9- to 11-membered spiroheterocyclylene group, the heteroatom of the 9- to 11-membered spiroheterocyclylene group is N, and the number of heteroatoms is 1; L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or [ka] and L2 -1 teeth, [ka] and L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] or unsubstituted or one or more L2 1-2 replaced with [ka] and the ring Cy 1 is a 4- to 6-membered heterocycle, the heteroatom of the 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, the 4- to 6-membered heterocycle is a monocycle, and each L2 1-2 are independently a hydroxy group, LLM is [ka] and Ring Cy 3 is unsubstituted or multiple Cy 3-1 wherein the heteroatom of the 5- to 6-membered heterocycle is N, S, or O, and the number of heteroatoms is 1; and Cy 3-1 are independently oxo; Ring Cy4 is unsubstituted or one or more Cy 4-1 a 5- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 5- to 8-membered heterocycle is N, S, or O, and the number of heteroatoms is 1; 4-1 are independently oxo; Each R 5 are independently halogen; p is 0, 1, 2 or 3.

[0187] In one preferred embodiment, R 1 is one or more R 1-1 a pyridyl group substituted with one or more R 1-1 replaced with [ka] is.

[0188] In one preferred embodiment, R 1 is one or more R 1-1 When R is a pyridyl group substituted with 1-1 independently represent one or more R 1-1-4 is a C1-C6 alkyl group substituted with

[0189] In one preferred embodiment, R 1 is one or more R 1-1 replaced with [ka] If R 1-1 is unsubstituted or one or more R 1-1-1 wherein the heteroatoms of said 7- to 8-membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is two.

[0190] In one preferred embodiment, each R 1-1-4 are independently fluorine, chlorine or bromine, preferably fluorine.

[0191] In one preferred embodiment, R 1-1 However, independently, multiple R 1-1-4 When the group is a C1-C6 alkyl group substituted with , the number of the groups is two or three, preferably three.

[0192] In one preferred embodiment, each R 1-1-1 are independently a C1-C6 alkyl group substituted with one or more halogens.

[0193] In one preferred embodiment, R 3 is unsubstituted or one or more R 3-4 C1-C6 alkyl group or unsubstituted or substituted with one or more R 3-7 is a C1-C6 alkoxy group substituted with

[0194] In one preferred embodiment, each R 3-4 are independently deuterium, halogen, or a hydroxy group.

[0195] In one preferred embodiment, each R 3-7 are independently deuterium.

[0196] In one preferred embodiment, R 3 There are multiple R 3-4 When R is a C1-C6 alkyl group substituted with 3-4 is a hydroxy group, a deuterium and a hydroxy group, or a halogen and a hydroxy group.

[0197] In a preferred embodiment, L0 is a 9- to 11-membered spiroheterocyclylene group, the heteroatom of the 9- to 11-membered spiroheterocyclylene group is N, and the number of heteroatoms is one.

[0198] In a preferred embodiment, L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 -or [ka] and L2 -1 teeth, [ka] and L2 -2 , L2 -3 and L2 -4 does not exist independently, [ka] or unsubstituted or one or more L2 1-2 replaced with [ka] and the ring Cy 1 is a 4- to 6-membered heterocycle, the heteroatom of said 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, and said 4- to 6-membered heterocycle is a monocycle.

[0199] In one preferred embodiment, each L2 1-2 are independently a hydroxy group.

[0200] In a preferred embodiment, the compound of formula I is a compound of formula Id, [ka] where R 1 is unsubstituted or one or more R 1-1 wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or two of N and O, and the number of heteroatoms is 1, 2, or 3; Each R 1-1 is unsubstituted or one or more R 1-1-4 C1-C6 alkyl group, unsubstituted or substituted with one or more R 1-1-1 a 3- to 11-membered heterocycloalkyl group or an unsubstituted or substituted with one or more R 1-1-7wherein 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; and 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; Each R 1-1-1 , R 1-1-4 and R 1-1-7 are independently halogen or a C1-C6 alkyl group unsubstituted or substituted with one or more halogens; R 3 is unsubstituted or one or more R 3-4 C1-C6 alkyl group or unsubstituted or substituted with one or more R 3-7 C1-C6 alkoxy group or unsubstituted or substituted with one or more R 3-1 is a tetrahydropyrrolyl group substituted with Each R 3-1 are independently deuterium, halogen, or a hydroxy group, and each R 3-4 are independently deuterium, halogen, or a hydroxy group, and each R 3-7 are independently deuterium or a hydroxy group; 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.

[0201] L2 is one of the following cases: In case (1), L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 and L2 -2 does not exist, L2 -3 teeth, [ka] and L2 -4 is unsubstituted or one or more L2 1-2 Ring Cy substituted with 1 and the ring Cy 1 is a piperidinyl group or a piperazinyl group, and each L2 1-2 are independently a halogen or a hydroxy group; In case (2), L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 does not exist, L2 -2 , L2 -3 and L2 -4 is, independently, [ka] or unsubstituted or one or more L2 1-2 Ring Cy substituted with 1 and the ring Cy 1 is a cyclohexyl group, a piperidinyl group, or a piperazinyl group, and each L2 1-2 are independently a halogen or a hydroxy group; In case (3), L2 is -L2 -1 -L2 -2 -L2 -3 -L2 -4 - and L2 -1 , L2 -2 , L2 -3 and L2 -4 is, independently, [ka] or unsubstituted or one or more L2 1-2 Ring Cy substituted with 1 and the ring Cy 1 is a cyclohexyl group, a piperidinyl group, or a piperazinyl group, and each L2 1-2 are independently a halogen or a hydroxy group; LLM is [ka] is.

[0202] In one preferred embodiment, the compound of formula I is [ka] [ka] [ka] [ka] [ka] [ka] The compound is any one of the following:

[0203] In one preferred embodiment, [ka] teeth, [ka] is.

[0204] In one preferred embodiment, [ka] teeth, [ka] is.

[0205] In one preferred embodiment, [ka] teeth, [ka] is.

[0206] In one preferred embodiment, [ka] teeth, [ka] is.

[0207] In one preferred embodiment, [ka] teeth, [ka] is.

[0208] In one preferred embodiment, [ka] teeth, [ka] is.

[0209] In one preferred embodiment, [ka] teeth, [ka] is.

[0210] In one preferred embodiment, [ka] teeth, [ka] is.

[0211] In one preferred embodiment, [ka] teeth, [ka] is.

[0212] In one preferred embodiment, [ka] teeth, [ka] is.

[0213] In one preferred embodiment, [ka] teeth, [ka] is.

[0214] In one preferred embodiment, [ka] teeth, [ka] is.

[0215] In one preferred embodiment, [ka] teeth, [ka] is.

[0216] In one preferred embodiment, [ka] teeth, [ka] is.

[0217] In one preferred embodiment, [ka] teeth, [ka] is.

[0218] In one preferred embodiment, [ka] teeth, [ka] is.

[0219] In a preferred embodiment, the pharmaceutically acceptable salt of the compound shown in I-12 is [ka] is.

[0220] In one preferred embodiment, [ka] is a compound having a retention time of 2.262 min or 3.319 min under the following conditions: chromatographic column: IH 25 x 250 mm, 10 μm (Daicel), mobile phase: CO2 / (MeOH:MeCN=1:1)=50 / 50, flow rate: 120 mL / min.

[0221] In one preferred embodiment, [ka] is a compound with a retention time of 12.068 min or 14.283 min under the following conditions: chromatographic column: IC 25 x 250 mm, 10 μm (Daicel), mobile phase: HEX (0.1% DEA): EtOH (0.1% DEA): = 50:50, flow rate: 50 mL / min.

[0222] In one preferred embodiment, [ka] is a compound having a retention time of 1.759 min or 2.520 min under the following conditions: chromatographic column: IH 25 x 250 mm, 10 μm (Daicel), mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50, flow rate: 120 mL / min.

[0223] In one preferred embodiment, [ka] is a compound with a retention time of 1.299 min or 1.936 min under the following conditions: chromatographic column: AS 25 x 250 mm, 10 μm (Daicel), mobile phase: CO2 / [MeOH (0.2% NH3 (7 M in MeOH):MeCN = 1:1] = 40 / 60, flow rate: 100 mL / min.

[0224] In one preferred embodiment, [ka] is a compound having a retention time of 2.309 min or 3.384 min under the following conditions: chromatographic column: IH 25 x 250 mm, 10 μm (Daicel), mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50, flow rate: 120 mL / min.

[0225] The present invention further provides a pharmaceutical composition, which comprises a substance Z and a pharmaceutical excipient, wherein said substance Z is a compound of formula I, a pharmaceutically acceptable salt or an isotopic compound thereof.

[0226] In a preferred embodiment, the substance Z in the pharmaceutical composition is an effective amount of substance Z.

[0227] In a preferred embodiment, the pharmaceutical composition is used for treating and / or preventing a disease associated with Myd88 and / or IRAK4.

[0228] The present invention further provides an application of substance Z in the manufacture of an IRAK4 decomposing agent and a drug for treating and / or preventing Myd88 and / or IRAK4-related diseases, wherein substance Z is a compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotope thereof.

[0229] The present invention further provides a method for treating and / or preventing a Myd88 and / or IRAK4-associated disease, which comprises administering to a patient an effective amount of substance Z, wherein substance Z is a compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotopic compound thereof.

[0230] In a preferred embodiment, the IRAK4-associated disease includes one or more of an autoimmune disease, an inflammatory disease, a tumor, a cardiovascular or cerebrovascular disease, and a central nervous system disease.

[0231] In a preferred embodiment, the IRAK4-associated disease includes one or more of chronic lung diseases, autoimmune diseases, inflammatory diseases, tumors, cardiovascular / cerebrovascular diseases, and central nervous system diseases.

[0232] In a preferred embodiment, the autoimmune disease includes psoriasis and rheumatoid arthritis.

[0233] In one preferred embodiment, the autoimmune disease includes psoriasis, systemic lupus erythematosus, and rheumatoid arthritis.

[0234] In one preferred embodiment, the inflammatory disease comprises ulcerative colitis.

[0235] In one preferred embodiment, the inflammatory disease comprises inflammatory bowel disease, such as ulcerative colitis.

[0236] In a preferred embodiment, the tumor may be a hematological tumor or a solid tumor.

[0237] In a preferred embodiment, the hematological tumor includes large B-cell lymphoma and acute chronic lymphocytic leukemia; In a preferred embodiment, the solid tumor includes intestinal cancer and skin cancer caused by MYD88 gene mutation.

[0238] In a preferred embodiment, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis.

[0239] In a preferred embodiment, the central nervous system disease comprises primary central nervous system lymphoma.

[0240] The present invention further provides an application of substance Z or the above pharmaceutical composition in the manufacture of a medicament, wherein substance Z is a compound represented by formula I, a pharmaceutically acceptable salt or an isotope thereof, and the medicament is used to treat one or more of autoimmune diseases, inflammatory diseases, tumors, cardiovascular / cerebrovascular diseases and central nervous system diseases.

[0241] In a preferred embodiment, the autoimmune disease, inflammatory disease, tumor, cardiovascular / cerebrovascular disease, and central nervous system disease are as described in any one of the embodiments of the present invention.

[0242] The present invention further provides a compound of formula II or III, a salt thereof, a boc-protected compound thereof, or an isotopic compound thereof, [ka] R 1 , R 2 , R3 , Q, Y, ring Cy, L0 and L2 are as defined in any one of the above; Preferably, the compound of formula II or III is [ka] [ka] [ka] [ka] The compound is any one of the following:

[0243] The present invention further provides the use of the compound represented by formula II or III, a salt thereof, a boc-protected compound or an isotopic compound thereof in the production of the compound represented by formula I, a pharmaceutically acceptable salt thereof or an isotopic compound thereof.

[0244] Unless otherwise specified, the terms used in this invention have the following meanings.

[0245] The terms "compound" and "pharmaceutically acceptable salt" refer to compounds that, when tautomers exist, may exist in the form of a single tautomer or a mixture thereof, and preferably exist in a form in which a relatively stable tautomer is predominant.

[0246] When 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, for -ABC-, if B is absent, -ABC- becomes -AC-.

[0247] [ka] The term denotes presence or absence.

[0248] The term "oxo" refers to the replacement of a hydrogen or lone pair of electrons on a non-oxygen atom with oxygen, e.g., [ka] is substituted with oxo and then [ka] and [ka] is substituted with oxo and then [ka] is.

[0249] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0250] The term "cycloalkyl group" refers to a group having a specified number of carbon atoms (e.g., C3-C 10 ) refers to a saturated monocyclic ring group composed only of carbon atoms, having a carbon atom, where monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0251] The term "alkyl group" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-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.

[0252] The term "heterocycloalkyl group" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 11 members, further e.g., 3 to 8 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom species (one or more of N, O, and S), where the heteroatoms may or may not be linked to other groups as linking groups (e.g., a piperidinyl group is [ka] Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like, which may be monocyclic, fused, bridged, or spirocyclic, and each ring is saturated.

[0253] The term "heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom species (one or more of N, O, and S), where the heteroatoms may or may not be linked to other groups as linking groups (e.g., a piperidine ring is [ka] etc.), which may be a single ring, fused rings, bridged rings, or spiro rings, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidine ring, tetrahydropyrrole ring, tetrahydrofuran ring, morpholine ring, and piperidinyl ring.

[0254] The term "heteroaryl group" refers to a cyclic group having a specified number of ring atoms (e.g., 5-9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom species (one or more of N, O, and S), which may be monocyclic or polycyclic, and in which at least one ring is aromatic (complies with Hückel's rule). Heteroaryl groups are linked to other fragments of the molecule through rings that are aromatic or non-aromatic. Heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0255] The term "heteroaromatic ring" refers to a cyclic group having a specified number of ring atoms (e.g., 5-9 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom species (one or more of N, O, and S), which may be monocyclic or polycyclic, and at least one ring is aromatic (complies with Hückel's rule). Heteroaromatic rings are connected to other fragments in a molecule through rings that are aromatic or non-aromatic. 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.

[0256] A "-" at the end of a group indicates that the group is linked to another fragment in the molecule through this site. For example, CH3-C(=O)- refers to an acetyl group.

[0257] in structural fragments [ka] indicates that this structural fragment is linked to other fragments in the molecule via this site. For example, [ka] refers to an acetyl group.

[0258] The term "cycloalkylene group" is a divalent group that is connected to the rest of the molecule via two single bonds, the rest of the definition being the same as the term "cycloalkyl group".

[0259] The term "heterocycloalkylene group" is a divalent group that is connected to the rest of the molecule through two single bonds, the rest of the definition being the same as the term "heterocycloalkyl group".

[0260] The term "isotopic compound" refers to a compound in which the isotopic abundance of one or more atoms is different from its natural abundance. For example, one or more atoms in the compound are replaced by atoms that naturally occupy a lower mass number, one hydrogen atom in the compound is replaced by deuterium, or C is replaced by 13 It can be replaced by C.

[0261] The term "plurality" refers to two, three, four or five.

[0262] The term "boc-protected" generally refers to N being protected with a boc group.

[0263] Substituents such as a heterocycle, aromatic ring, heteroaryl group, aryl group, heterocycloalkyl group, alkoxy group, alkyl group, and cycloalkyl group described in the present invention may be referred to as a heterocyclylene, arylcyclylene, heteroarylene group, arylene group, heterocycloalkylene group, alkyleneoxy group, alkylene group, or cycloalkylene group when they are linked as linking units to different constituent parts of a compound.

[0264] Any variable (e.g., group R 1-1 ) appear multiple times in a compound definition, the definitions are independent of each other and do not influence each other. For example, three R 1-1 C6~C substituted with 10 The aryl group is C6-C 10 Three aryl groups in R 1-1 It refers to the substitution of three R1-1 The definitions are independent of each other and do not affect each other.

[0265] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic and safe, and suitable for administration to a patient) 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, potassium, calcium, aluminum, magnesium, bismuth, 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, hydrochloride, acetate, trifluoroacetate, sulfate, methanesulfonate, and the like. Specifically, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0266] A "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic and safe, and suitable for administration to a patient) acid or base and a solvent (including, but not limited to, water, methanol, ethanol, etc.), where pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloride monohydrate.

[0267] The term "pharmaceutical excipients" refers to the excipients and additives used in the production and formulation of pharmaceuticals, including all substances contained in drug formulations, excluding active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).

[0268] The term "treatment" refers to any one of: (1) alleviating one or more biological symptoms of a disease; (2) interrupting one or more points in the biological cascade that causes a disease; or (3) alleviating the progression of one or more biological symptoms of a disease.

[0269] The term "prevention" refers to reducing the risk of developing a disease.

[0270] The term "patient" refers to any animal currently undergoing or to be treated, preferably a mammal, and 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.

[0271] Without going against common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain preferred examples of the present invention.

[0272] All reagents and raw materials used in the present invention are commercially available.

[0273] The positive effects of the present invention are as follows: the compounds of the present invention have an inhibitory and / or degrading effect on IRAK4, and can almost completely degrade IRAK4 protein at relatively low drug concentrations. The compounds of the present invention can also inhibit the scaffolding function of the Myddosome complex. The compounds of the present invention are expected to have potential clinical application value and be applicable to various immune diseases associated with IRAK4, as well as various blood diseases and solid tumors caused by Myd88 gene mutations. DETAILED DESCRIPTION OF THE INVENTION

[0274] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the examples. Although the following examples do not specify specific experimental conditions, they can be selected according to conventional methods and conditions or according to product instructions.

[0275] Example 1: Synthesis of Compound I-1 Synthesis of I-1 [ka]

[0276] Step 1: Synthesis of I-1-A A mixture 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 and clarified. p-Toluenesulfonyl chloride (521.40 mg, 2.73 mmol) was added, and the mixture was heated to 40 °C and stirred for 18 h until the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give I-1-A (1 g, crude). MS(ESI)m / z:396.2[M+H] + It was.

[0277] Step 2: Synthesis of I-1-1 A mixture 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 purged with hydrogen gas three times. The mixture was then stirred at 25 °C under hydrogen gas for 18 hours, and the reaction was continued until complete. The mixture was filtered through diatomaceous earth to remove the catalyst methanol (10 mL x 2). The filter cake was washed, and the filtrate was concentrated under reduced pressure to give the brown solid product I-1-1 (1.59 g, crude). MS (ESI) m / z: 164.1 [M+H] + and was used directly in the next step.

[0278] Step 3: Synthesis of I-1-2 At 0°C, 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphane 2,4,6-trioxide (7.44 g, 11.69 mmol, 50% purity) was added dropwise to a mixed solution of I-1-1 (1.59 g, 9.74 mmol), 6-(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) with stirring. After the dropwise addition was completed, the reaction system was maintained at 15°C and stirred under nitrogen gas protection for 2 hours, and the reaction was continued until the reaction was complete. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 5). The combined organic phase was washed with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the brown solid product I-1-2 (3.08 g, crude). MS (ESI) m / z: 337.1 [M+H]. + and was used directly in the next step.

[0279] Step 4: Synthesis of I-1-3 A mixture 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 h until the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). 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, 30.05% yield). MS (ESI) m / z: 560.2 [M+H] + It was.

[0280] Step 5: Synthesis of I-1-4 A mixture 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 mixture was spun dry, and the crude product was purified by C18 column chromatography to give a yellow solid I-1-4 (200 mg, 435.29 μmol, 97.43% yield). MS (ESI) m / z: 460.2 [M+H] + It was.

[0281] Step 6: Synthesis of I-1-5 A mixture of I-1-4 (25.00 mg, 54.41 μmol), 1-Boc-4-piperidinecarboxylic acid (12.47 mg, 54.41 μmol), diisopropylethylamine (35.16 mg, 272.06 μmol, 47.39 μL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.83 mg, 65.29 μmol), and N,N-dimethylformamide (2 mL) was added to a reaction flask and stirred at room temperature for 12 h until the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative thin layer chromatography to give I-1-5 (36 mg, 53.67 μmol, 98.64% yield). MS (ESI) m / z: 671.3 [M+H] + It was.

[0282] Step 7: Synthesis of I-1-6 Trifluoroacetic acid (2 mL) was added dropwise to a mixture of I-1-5 (36.00 mg, 53.67 μmol) and dichloromethane (2 mL) while stirring at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was spin-dried to give I-1-6 (30 mg, crude trifluoroacetate salt). MS (ESI) m / z: 571.6 [M+H] + and was used directly in the next step reaction.

[0283] Step 8: Synthesis of I-1 A mixture of I-1-6 (30.00 mg, 52.58 μmol), 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindoline-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 reacted at 100 °C for 2 hours to complete the reaction. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative thin-layer chromatography to give I-1 (23 mg, 27.26 μmol, 51.85% yield). MS(ESI)m / z:827.9[M+H] + It was. 1 H NMR(500MHz,DMSO-d6)δ 11.08(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=13.0,5.0 Hz,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),2.94-2.83(m,1 H),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).

[0284] 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 as shown in the table below.

[0285] [Table 1(1)] [Table 1(2)]

[0286] Example 2: Synthesis of II-1 [ka]

[0287] Step 1: Synthesis of II-1-A1 2-(2,6-Dioxo-3-piperidinyl)-5-fluoro-isoindoline-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). Diisopropylethylamine (346.95 mg, 2.68 mmol, 467.59 μL) was weighed and added to the reaction mixture. The mixture was stirred at 100 °C for 2 h until the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography (dichloromethane:methanol=20:1) gave a yellow solid product II-1-A1 (260 mg, 587.62 μmol, 65.67% yield). MS (ESI) m / z: 443.2 [M+H] + It was.

[0288] Step 2: Synthesis of II-1-A 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 at 0°C while stirring. After the addition was complete, the mixture was stirred at 25°C for 2 hours until the reaction was complete. The reaction mixture was filtered and washed with dichloromethane (10 mL). The filter cake was dried to give the white solid product II-1-A (204 mg, 538.52 μmol, 91.65% yield). MS (ESI) m / z: 343.2 [M+H] + It was.

[0289] Step 3: Synthesis of II-1-1 A mixture of I-1-2 (1.02 g, 3.03 mmol), tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (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 gas protection for 2 h until the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (20 mL x 3) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by high-performance chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the off-white solid product II-1-1 (0.35 g, 673.70 μmol, 22.21% yield). MS(ESI)m / z:520.2[M+H] + It was.

[0290] Step 4: Synthesis of II-1-2 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 at 0°C while stirring. After the addition was complete, the mixture was stirred at 25°C for 2 hours until the reaction was complete. The reaction mixture was filtered and washed with dichloromethane (10 mL). The filter cake was dried to give the white solid product II-1-2 (280 mg, 667.62 μmol, 99.10% yield). MS (ESI) m / z: 420.2 [M+H] + It was.

[0291] Step 5: Synthesis of II-1-3 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. The reaction mixture was stirred at 25 °C for 6 h until complete reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) afforded a yellow solid II-1-3 (80 mg, 158.26 μmol, 55.31% yield). MS (ESI) m / z: 506.2 [M+H] + It was.

[0292] Step 6: Synthesis of II-1-4 A mixture 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. The reaction was continued until complete. The methanol was removed by distillation under reduced pressure, and dilute hydrochloric acid (2 M) was added to the system to adjust the pH to approximately 6-7. The solid was purified using a C18 reverse-phase chromatography column and lyophilized to give a yellow solid, II-1-4 (30 mg, 62.84 μmol, 31.76% yield). MS (ESI) m / z: 478.2 [M+H] + It was.

[0293] Step 7: Synthesis of II-1 A mixture of II-1-4 (15 mg, 31.42 μmol), II-1-A (12.91 mg, 34.07 μmol), 2-(7-azabenzotriazole)-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 gas protection for 2 h until the reaction was complete. Water (25 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (25 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by C18 column chromatography to give a yellow solid product II-1 (6 mg, 7.41 μmol, 23.58% yield). MS (ESI) m / z: 802.8 [M+H] + It was. 1 H NMR(500MHz,DMSO-d6)δ 11.08(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=8.0,1.0 Hz,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=13.0,5.5Hz, 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).

[0294] 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 as shown in the table below.

[0295] [Table 2]

[0296] Example 3: Synthesis of I-9 [ka]

[0297] Step 1: Synthesis (int-F-1) To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (5.0 g, 18.0 mmol) in anhydrous DMSO (20.0 mL) were added DIPEA (4.7 g, 36.2 mmol) and tert-butyl piperidine-4-carboxylate (4.0 g, 21.6 mmol), and the reaction mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was 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 give the yellow solid product int-F-1 (7.5 g, 94.2% yield). MS (ESI) m / z: 442.2 [M+H]+.

[0298] Step 2: Composite (int-F) To a solution of int-F-1 (5 g, 11.3 mmol) in DCM (50 mL) was added TFA (20 mL) dropwise at 0 °C. After the addition was complete, the mixture was stirred at 25 °C for 16 h. Ether was added to the reaction mixture with stirring. After the solid precipitated, it was filtered and the filter cake was washed with ether to give the yellow solid product int-F (3.7 g, 84.9% yield). MS (ESI) m / z: 386.1 [M+H]+.

[0299] Step 3: Synthesis (I-9-1) 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). CsCO (1.35 g, 4.13 mmol) and KI (685.87 mg, 4.13 mmol) were added with stirring, and the reaction mixture was stirred at 100 °C for 2 h. Water (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (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:EA = 1:1) to give a pale yellow solid I-9-1 (500 mg, 26.01% yield). MS (ESI) m / z: 465.1 [M+H].

[0300] Step 4: Synthesis (I-9-2) I-9-1 (250 mg, 537.24 μmol) and morpholine (936.09 mg, 10.74 mmol) were dissolved in 1,4-dioxane (2 mL). CuI (51.16 mg, 268.62 μmol) and KPO (456.15 mg, 2.15 mmol) were added with stirring, and the mixture was reacted at 90 °C for 6 h under nitrogen gas protection. Saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (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 to give a pale yellow solid I-9-2 (70 mg, 27.63% yield). MS (ESI) m / z: 472.2 [M+H].

[0301] Step 5: Synthesis (I-9-3) 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 the mixture was purged with hydrogen gas three times. The mixture was reacted under hydrogen gas at 25 °C for 6 h. The reaction mixture was filtered through diatomaceous earth, and the filter cake was rinsed with ethyl acetate (30 mL) three times. The filtrate was collected. The solvent was removed under reduced pressure. The resulting white solid was product I-9-3 (60 mg, 91.53% yield). MS (ESI) m / z: 442.3 [M+H]+.

[0302] Step 6: Synthesis (I-9-4) 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). DIPEA (50.72 mg, 392.45 μmol) and HATU (74.61 mg, 196.22 μmol) were added with stirring and the mixture was allowed to react at 25 °C for 2 h. Water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 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 to give the pale yellow solid product I-9-4 (50 mg, 62.18% yield). MS (ESI) m / z: 615.3 [M+H]+.

[0303] Step 7: Synthesis (I-9-5) 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 with stirring. After the addition was complete, the reaction was continued for 2 h at 25 °C. The reaction mixture was filtered, and the filter cake was washed three times with DCM (30 mL). After drying, a white solid product I-9-5 (50 mg, 79.68% yield, hydrochloride salt) was obtained. MS (ESI) m / z: 515.2 [M+H]+.

[0304] Step 8: Synthesis (I-9) To a solution of I-9-5 (40 mg, 72.59 μmol, hydrochloride salt), int-F (33.57 mg, 87.11 μmol), and DMF (1.5 mL) were added DIPEA (28.15 mg, 217.78 μmol) and HATU (41.40 mg, 108.89 μmol), and the resulting mixture was stirred at 25 °C for 1 h. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 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 preparative thin-layer chromatography (DCM:MeOH = 20:1) to give the yellow solid product I-9 (23 mg, 35.93% yield). MS (ESI) m / z: 882.7 [M+H]+. H NMR (500 MHz, DMSO-d6) δ 11.15(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).

[0305] Compound I-10 can be prepared by referring to the method of Example 3 above, and its structure and characterization data are as shown in the table below.

[0306] [Table 3]

[0307] Example 4, Synthesis of I-12F [ka]

[0308] Step 1: Synthesis (I-12F-1) 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) was added TsOH (627 mg, 3.3 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with HO (120 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give a yellow solid product I-12F-1 (4.8 g, 88% yield). MS (ESI) m / z: 326.0 [M+H] + It was.

[0309] Step 2: Synthesis (I-12F-2) To a solution of I-12F-1 (4.1 g, 15.6 mmol) in 1,4-dioxane (15 mL), tributyl(1-ethoxyvinyl)stannane (5.45 g, 15.1 mmol) and TEA (3.2 g, 31.5 mmol) were added. The mixture was stirred at 25 °C for 15 min under a nitrogen atmosphere. Pd(PPh3)2Cl2 (0.9 g, 1.3 mmol) was then added, and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with saturated aqueous potassium fluoride (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 I-12F-2 (2.9 g, 72.7% yield) as a yellow oil. MS(ESI)m / z:318.3[M+H] + It was.

[0310] Step 3: Synthesis (I-12F-3) To a solution of I-12F-2 (2.5 g, 7.9 mmol), acetone (15 mL), and water (15 mL) was added TsOH (0.15 g, 0.8 mmol), and the mixture was stirred at 50 °C for 2 h. Water (30 mL) was added for dilution 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 the white solid product I-12F-3 (1.8 g, 78.8% yield). MS (ESI) m / z: 290.1 [M+H] + It was.

[0311] Step 4: Synthesis (I-12F-4) A solution of I-12F-3 (2.0 g, 6.92 mmol) in THF (20 mL) was added with a solution of trifluoromethyltrimethylsilane (2.04 mL, 13.84 mmol) in THF (27.6 mL) at 25 °C. After stirring for 15 min, TBAF (6.92 mL, 6.92 mmol) was added, and the mixture was microwaved at room temperature for 16 h. The reaction mixture was poured into saturated NH4Cl solution and extracted with ethyl acetate (50 mL x 2). 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 high-performance silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the yellow solid product I-12F-4 (1.4 g, 22.5% yield). MS (ESI) m / z: 360.1 [M+H] + It was.

[0312] Step 5: Synthesis (I-12F-5) To a solution of I-12F-4 (0.6 g, 1.7 mmol) and MeOH (10 mL) at 25 °C, wet Pd / C (0.3 g, 10% purity) was added, and the mixture was purged with H2 three times while stirring, followed by stirring under H2 for 16 h. The resulting mixture was filtered and concentrated to give the brown solid product I-12F-5 (0.5 g, 91% yield). MS (ESI) m / z: 330.2 [M+H] + It was.

[0313] Step 6: Synthesis (I-12F-6) 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 mmol), DIPEA (784.90 mg, 6.07 mmol, 1.06 mL), and DMF (10 mL) was stirred at 25 °C for 3 h 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 eluting with PE / EA (0-45%) to give the white solid product I-12F-6 (1.4 g, 91.77% yield). MS (ESI) m / z: 503.3 [M+H] + It was.

[0314] Step 7: Synthesis (I-12F-7) 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 h. The resulting mixture was concentrated to dryness under reduced pressure to give the white solid product I-12F-7 (0.4 g, 63.13% yield, hydrochloride salt). MS (ESI) m / z: 419.3 [M+H] + It was.

[0315] Step 8: Synthesis (I-12F-8) A mixture of I-12F-7 (1 g, 2.20 mmol), I-1-A (1.30 g, 3.30 mmol), CsCO (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 gas protection for 4 h. The reaction was quenched with water (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were 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 0.1% HCOOH in water, gradient from 1% to 70% in 60 min, detector: UV 254 nm) to give the white solid product I-12F-8 (0.21 g, 14.88% yield). MS(ESI)m / z:642.5[M+H] + It was.

[0316] Step 9: Synthesis (I-12F-9) I-12F-8 (0.1 g, 155.86 μmol) was dissolved in DCM (2 mL), and TFA (1.49 g, 13.07 mmol, 1 mL) was added, and the mixture was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure to give the white solid product I-12F-9 (0.1 g, crude, TFA salt). MS (ESI) m / z: 542.3 [M+H] + It was.

[0317] Step 10: Synthesis (I-12F) 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 h. The reaction mixture was purified by reverse-phase C18 column chromatography (mobile phase: MeCN and 0.1% HCOOH in water, gradient 1% to 60% in 10 min, detector: UV 254 nm) to give the yellow solid product I-12F (0.032 g, 25.37% yield, formate salt). MS (ESI) m / z: 909.6 [M+H] + It was. 1H NMR(500MHz,DMSO-d6)δ 12.28(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=9.0Hz,1H),5.3 5-5.20(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).

[0318] 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 Example 1 and Example 4 above, and their structures and characterization data are as shown in the following table.

[0319] [Table 4(1)] [Table 4(2)] [Table 4(3)]

[0320] Example 5, Synthesis of I-22 [ka]

[0321] Step 1: Synthesis (I-22-1) At 0 °C under nitrogen gas, CD3-I (31 g, 214.2 mmol) was added to a solution of 2-fluoro-4-hydroxybenzaldehyde (25 g, 178.4 mmol) and K2CO3 (49.3 g, 356.9 mmol) in DMF (400 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was quenched with saturated NH4Cl solution (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 the white solid product I-22-1 (27 g, 95.7% yield). MS (ESI) m / z: 158.2 [M+H] + It was. 1 H NMR(400MHz,CDCl3)δ 10.21(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).

[0322] Step 2: Synthesis (I-22-2) I-22-1 (25 g, 163 mmol) was added batchwise to a solution of KNO (18 g, 179 mmol) and concentrated HSO (130 mL) at 0 °C, and after 0.5 h of addition was complete, the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with ice water, filtered, washed with HO, and the filter cake was dried under vacuum to give the yellow solid product I-22-2 (30 g, 93.2% yield). MS (ESI) m / z: 203.2 [M+H] + It was. 1 H NMR(400MHz,CDCl3)δ 10.22(s,1H),8.46(d,J=7.2Hz,1H),6.87(d,J=11.6Hz,1H).

[0323] Step 3: Synthesis (I-22-3) 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 h. After cooling to room temperature, the reaction mixture was washed with ice water to give the yellow solid product I-22-3 (30 g, 97% yield). MS (ESI) m / z: 197.2 [M+H] + It was.1 H NMR(400MHz,DMSO-d6)δ 13.36(s,1H),8.41(s,1H),8.20(s,1H),7.21(s,1H).

[0324] Step 4: Synthesis (I-22-4) A mixture of I-22-3 (16 g, 81.6 mmol), wet Pd / C (3 g, 10% purity) in THF (1 L), and DMF (100 mL) was stirred under a hydrogen atmosphere at 25 °C for 16 h. The reaction was filtered through diatomaceous earth, washed with THF (1 L), and the filtrate was distilled under reduced pressure to give the brown solid product I-22-4 (11.5 g, 84.9% yield). MS (ESI) m / z: 167.2 [M+H] + It was.

[0325] Step 5: Synthesis (I-22-5) A mixture 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 min. Then, a solution of 6-(trifluoromethyl)pyridinecarboxylic 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 h. The reaction mixture was diluted with HO (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was concentrated under reduced pressure to give the brown solid product I-22-5 (24 g, 51.1% yield). MS (ESI) m / z: 340.1 [M+H] + It was.

[0326] Step 6: Synthesis (I-22-6) A solution of I-22-5 (24 g, 70.8 mmol), I-1-A (42 g, 106.2 mmol), CsCO (69 g, 212.4 mmol), KI (11.8 g, 70.8 mmol), and DMF (120 mL) was stirred at 90 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with HO (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 high-performance silica gel column chromatography (PE / EtOAc = 1 / 1) to give the yellow solid product I-22-6 (5 g, 13% yield). MS (ESI) m / z: 563.2 [M+H] + It was.

[0327] Step 7: Synthesis (I-22-7) A solution of I-22-6 (5 g, 8.9 mmol) and HCl-dioxane (1 M, 100 mL) was stirred at 25 °C for 1 h. Ether was added to the reaction mixture while stirring. After standing, the supernatant was removed. This was repeated three times to remove residual HCl in the reaction mixture, yielding a white solid product I-22-7 (4 g, 97% yield). MS (ESI) m / z: 463.2 [M+H]. + It was.

[0328] Step 8: Synthesis (I-22) 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 min. Then, at 0 °C, a solution of I-22-7 (3.7 g, 7.5 mmol) in DMF (10 mL) was added. The resulting mixture was stirred for 2 h until the reaction was complete. The mixture was diluted with HO (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase C18 column chromatography to give the yellow solid product I-22 (2.1 g, 32% yield). MS (ESI) m / z: 830.2 [M+H] + It was. 1H NMR(400MHz,DMSO-d6)δ 11.08(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).

[0329] Example 6, Synthesis of I-23 [ka]

[0330] Step 1: Synthesis (I-23-1) Methyl 5-amino-2H-indazole-6-carboxylate (5 g, 26 mmol) was dissolved in tetrahydrofuran (50 mL), and DIPEA (27 g, 209 mmol) was slowly added dropwise, followed by T3P (propylphosphonic anhydride, 25 g, 78.6 mmol). 6-(trifluoromethyl)pyridinecarboxylic acid (7.5 g, 39 mmol) was then added to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 hours. Water was added to the reaction mixture to precipitate a solid, which was then filtered. The filter cake was dried under vacuum to give the pale yellow solid product I-23-1 (9.3 g, 98% yield). MS (ESI) m / z: 365.3 [M+H] + .

[0331] Step 2: Synthesis (I-23-2) A solution of I-23-1 (5 g, 13.72 mmol), I-1-A (10.86 g, 27.45 mmol), CsCO (13.4 g, 41.2 mmol), KI (2.28 g, 13.72 mmol), and DMF (50 mL) was stirred at 50 °C for 16 h. The mixture was diluted with HO (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 high-performance silica gel column chromatography (PE / EtOAc = 1 / 1) to give the brown solid product I-23-2 (1.0 g, 12.3% yield). MS (ESI) m / z: 588.2 [M+H] + It was.

[0332] Step 3: Synthesis (I-23-3) To a solution of I-23-2 (850 mg, 1.45 mmol) in THF (40 mL) was added (methyl-D3)magnesium iodide (14.5 mL, 14.5 mmol) dropwise at 0 °C, and the mixture was stirred at 25 °C for 16 h. The reaction solution was poured into water and 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 give a yellow solid product I-23-3 (100 mg, 11.6% yield). MS (ESI) m / z: 594.4 [M+H] + It was.

[0333] Step 4: Synthesis (I-23-4) To a solution of I-23-3 (100 mg, 0.17 mmol) in DCM (5 mL) was added TFA (2 mL) dropwise at 0 °C, and the mixture was stirred at 25 °C for 2 h. Ether was added to the reaction mixture while stirring, and after standing, the supernatant was removed. This was repeated three times to remove residual TFA from the reaction mixture, and the reaction mixture was dried in vacuo to give the yellow solid product I-23-4 (80 mg, 95.2% yield). MS (ESI) m / z: 494.3 [M+H] + It was.

[0334] Step 5: Synthesis (I-23) To a solution of int-F (80 mg, 0.21 mmol), HATU (92 mg, 0.24 mmol), and DMF (5 mL) was added DIEA (53 mg, 0.42 mmol) and I-23-4 (100 mg, 0.21 mmol) at 0 °C, and the mixture was stirred at 25 °C for 16 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (30 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 preparative HPLC to give the white solid product I-23 (24.05 mg, 13.9% yield). MS (ESI) m / z: 861.3 [M+H] + It was. 1 H NMR(400MHz,DMSO-d6)δ 12.42(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=7.6H z,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,1H),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).

[0335] Compounds I-24 to I-29, I-31 to I-38, I-48, I-51, I-53, and I-56 were prepared according to the methods of Examples 1, 3, 5, and 6, and their structures and characterization data are shown in the following table.

[0336] [Table 5(1)] [Table 5(2)] [Table 5(3)] [Table 5(4)] [Table 5(5)] [Table 5(6)] [Table 5(7)] [Table 5(8)] [Table 5(9)]

[0337] Example 7, Synthesis of I-30 [ka]

[0338] Step 1: Synthesis (I-30-1) Under nitrogen gas protection, 4-bromo-2-methoxy-5-methyl-aniline (1 g, 4.63 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (1.06 g, 5.55 mmol), DIPEA (1.20 g, 9.26 mmol, 1.61 mL), and anhydrous THF (15 mL) were added to a reaction flask. The temperature was lowered to 0 °C, and T3P (2.95 g, 9.26 mmol) was slowly added dropwise. The reaction mixture was stirred at 25 °C for 1 h. HO (60 mL) was added to the reaction mixture to precipitate the product. The product was filtered, washed with water, and dried under vacuum to give white solid product I-30-1 (1.77 g, 98.16% yield). MS (ESI) m / z: 389.2 [M+H] + It was.

[0339] Step 2: Synthesis (I-30-2) Under nitrogen gas protection, I-30-1 (1.77 g, 4.54 mmol), phenyl formate (1.1 g, 9.08 mmol), Pd(OAc) (palladium acetate, 101 mg, 0.45 mmol), P(t-Bu) .HBF (tri-tert-butylphosphine tetrafluoroborate, 516.4 mg, 1.78 mmol), EtN (triethylamine, 917.08 mg, 9.08 mmol), and acetonitrile (3 mL) were added to a reaction flask and heated to 80 °C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The mixture was diluted with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material 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, 70% yield). MS (ESI) m / z: 431.1 [M+H] + It was.

[0340] Step 3: Synthesis (I-30-3) I-30-2 (1.3 g, 3.2 mmol), potassium carbonate (1.77 g, 12.8 mmol), and methanol (4 mL) were added to a reaction flask and reacted at room temperature for 2 hours. Water was added to precipitate the product, which was then filtered. The filter cake was washed with water and dried under vacuum to obtain the crude product. The crude product was purified by reverse-phase C18 column chromatography (mobile phase: 0-60% water / acetonitrile) to obtain the white solid product I-30-3 (900 mg, 75% yield). MS (ESI) m / z: 369.1 [M+H] + It was.

[0341] Step 4: Synthesis (I-30-4) Under nitrogen gas 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 a reaction flask and heated to 80 °C for 5 h. After cooling to room temperature, the reaction mixture was filtered. HO (30 mL) was added to the filtrate and extracted with EA (25 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse-phase C18 column chromatography eluting with MeCN / HO + 1‰ HCOOH to give the desired white solid product I-30-4 (802 mg, 76% yield). MS (ESI) m / z: 447.1 [M+H] + It was.

[0342] Step 5: Synthesis (I-30-5) A mixture of I-30-4 (300 mg, 670.84 μmol), tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate (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 h. H2O (20 mL) was added to the reaction mixture, which was then extracted with EA (15 mL x 3). 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 high-performance silica gel column chromatography (DCM:MeOH = 30:1) to give the brown solid product I-30-5 (135 mg, 35.02% yield). MS (ESI) m / z: 575.3 [M+H] + It was.

[0343] Step 6: Synthesis (I-30-6) I-30-5 (135 mg, 234.95 μmol) was dissolved in DCM (3 mL), TFA (1.5 mL) was added, and the mixture was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure to give a white solid product I-30-6 (86 mg, 70.32% yield, TFA salt). MS (ESI) m / z: 475.2 [M+H] + It was.

[0344] Step 7: Synthesis (I-30) A mixture 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 h. HO (25 mL) was added to the reaction mixture, which was then extracted with EA (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give the yellow solid product I-30 (27 mg, 40.90% yield). 1 H NMR(500MHz,DMSO-d6)δ 11.08(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),2.9 3-2.84(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).

[0345] Example 8, Synthesis of I-41 [ka]

[0346] Step 1: Synthesis (I-41-1) Under nitrogen gas 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 h. After cooling to room temperature, the reaction mixture was added with HO (60 mL) and extracted with DCM (35 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by high-performance silica gel column chromatography (DCM / MeOH = 98 / 2) to give the white solid product I-41-1 (770 mg, 24.38% yield). MS (ESI) m / z: 417.5 [M+H] + It was.

[0347] Step 2: Synthesis (I-41-2) Under a hydrogen atmosphere, I-41-1 (770 mg, 1.85 mmol) was dissolved in MeOH (7 mL), and catalytically wet Pd / C (80 mg, 10% purity) was added. The mixture was allowed to react at 25 °C for 4 hours. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the filtrate was concentrated under reduced pressure to give the yellow solid product II-41-2 (500 mg, 69.97% yield). MS (ESI) m / z: 387.2 [M+H] + It was.

[0348] Step 3: Synthesis (I-41-3) A mixture of II-41-2 (50 mg, 129.37 μmol), 6-morpholinepyridine-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 h. HO (30 mL) was added to the reaction mixture, which was then extracted with EA (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to give the white solid product II-41-3 (64 mg, 85.78% yield). MS (ESI) m / z: 577.5 [M+H] + It was.

[0349] Step 4: Synthesis (I-41-4) A mixture 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 mixture 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] + It was.

[0350] Step 5: Synthesis (I-41) A mixture 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 h. HO (30 mL) was added to the reaction mixture, followed by extraction 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 give the yellow solid product I-41 (28 mg, 29.80% yield). MS (ESI) m / z: 844.6 [M+H]. + It was. 1 H NMR(500MHz,DMSO-d6)δ 11.08(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,1 H),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=12.5,5.5 Hz,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).

[0351] Compounds I-42, I-44, I-46, I-47, I-49, I-50, I-52, I-54, and I-55 were prepared according to the method of Example 8, and their structures and characterization data are shown in the table below.

[0352] [Table 6(1)] [Table 6(2)] [Table 6(3)] [Table 6(4)]

[0353] Example 9, Synthesis of I-43 [ka]

[0354] Step 1: Synthesis (I-43-1) 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 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water and stirred to precipitate a solid, which was filtered and washed with ether. The filter cake was dried under vacuum to give the white solid product I-43-1 (1.2 g, 55% yield). MS (ESI) m / z: 260.2 [M+H] + It was.

[0355] Step 2: Synthesis (I-43-2) To a solution of I-43-1 (1.1 g, 4.4 mmol) in anhydrous DMSO (10.0 mL), DIEA (1.14 g, 8.8 mmol) and tert-butyl piperidine-4-carboxylate (0.82 g, 4.4 mmol) were added and the mixture was reacted at 90 °C for 2 h. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted 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-phase C18 column chromatography to give a yellow solid product I-43-2 (200 mg, 11% yield). MS (ESI) m / z: 425.3 [M+H] + It was.

[0356] Step 3: Synthesis (I-43-3) To a solution of I-43-2 (200 mg, 0.47 mmol) and DCM (5 mL) was added TFA (1 mL) dropwise at 0 °C, and the mixture was stirred at 25 °C for 16 h. Ether was added to precipitate a solid, and the mixture was allowed to stand. The supernatant was removed, and this process was repeated three times. The yellow solid product I-43-3 (180 mg, 99% yield) was obtained by vacuum drying. MS (ESI) m / z: 369.1 [M+H] + It was.

[0357] Step 4: Synthesis (I-43) A mixture 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 h. The reaction mixture was purified by preparative HPLC to give the yellow solid product I-43 (11.2 mg, 10% yield). MS (ESI) m / z: 810.2 [M+H] + It was. 1H NMR(400MHz,DMSO-d6)δ 10.51(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=9.5Hz,1H),5.21-5.14(m,1H),4.20-4.07(m,3H),3.99(s,3 H),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).

[0358] Example 10: Synthesis of I-45 [ka]

[0359] Step 1: Synthesis (I-45-1) To a solution of KCO (18.35 g, 132.8 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (10 g, 44.25 mmol) in acetone / HO (120 / 40 mL) was added (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)allyl carbonate (10.6 g, 53.1 mmol) at 0 °C under a nitrogen atmosphere and stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (500 mL), washed with 3 N HCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product I-45-1 (13.0 g, 94% yield). Purification by high-performance silica gel column chromatography afforded a yellow solid product I-45-1 (13.0 g, 94% yield). 1 H NMR(400MHz,CDCl3)δ 6.00-5.87(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).

[0360] Step 2: Synthesis (I-45-2) To a solution of I-45-1 (12.2 g, 39.0 mmol) in DCM (240 mL) was added TFA (24 mL) at 0 °C, and the mixture was allowed to react at 25 °C for 2 h. Ether was added to precipitate the solid, and the mixture was allowed to stand. The supernatant was removed, and this reaction was repeated three times. The brown solid product I-45-2 (10 g, 100% yield) was obtained by vacuum drying. 1 H NMR(400MHz,DMSO-d6)δ 5.97-5.87(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).

[0361] Step 3: Synthesis (I-45-3) To a solution of KNO (31 g, 308 mmol) and concentrated HSO (250 mL) was added 6-chloropyridin-3-ol (22 g, 170 mmol) in a batchwise manner at 0 °C. The reaction was completed after 0.5 h, and the resulting mixture was stirred at 25 °C for 2 h. After quenching with ice water, the solid was filtered and washed with HO. The filter cake was dried under vacuum to give the yellow solid product I-45-3 (20 g, 69% yield). MS (ESI) m / z: 175.1 [M+H] + It was. 1 H NMR(400MHz,DMSO-d6)δ 11.92(s,1H),7.73(q,J=8.8Hz,2H).

[0362] Step 4: Synthesis (I-45-4) Under a nitrogen atmosphere, Fe (25.4 g, 453 mmol) was added to a solution of I-45-3 (15 g, 90 mmol) and NHCl (24 g, 453 mmol) in MeOH / HO (150 mL / 50 mL) and the mixture was reacted at 70 °C for 4 h. The mixture was cooled to room temperature, diluted with water (300 mL), and 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 give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to give the yellow solid product I-45-4 (5 g, 24% yield). MS (ESI) m / z: 145.0 [M+H] + It was.

[0363] Step 5: Synthesis (I-45-5) Under a nitrogen atmosphere, I-45-4 (7 g, 48 mmol), potassium O-ethyldithiocarbonate (10.8 g, 68 mmol), and pyridine (80 mL) were stirred at 110 °C for 16 h. The reaction mixture was returned to room temperature, diluted with ice water (100 mL), acidified with dilute hydrochloric acid (4 M) to pH 3-4 with stirring, and 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 give a yellow solid product I-45-5 (4 g, 45% yield). MS (ESI) m / z: 186.1 [M+H] + It was.

[0364] Step 6: Synthesis (I-45-6) To a solution of I-45-5 (6 g, 32 mmol) and EtOAc (60 mL) were 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 gas protection for 2 h. The reaction mixture was diluted with HO (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, 62.5% yield). MS (ESI) m / z: 200.9 [M+H] + It was. 1 H NMR(400MHz,CDCl3)δ 7.58(d,J=8.4Hz,1H),7.14(d,J=8.4Hz,1H),2.73(s,3H).

[0365] Step 7: Synthesis (I-45-7) 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 h under a nitrogen atmosphere. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to give the yellow solid product I-45-7 (5 g, 65% yield). MS (ESI) m / z: 363.1 [M+H] + It was.

[0366] Step 8: Synthesis (I-45-8) To a solution of I-45-7 (5 g, 13.7 mmol) and concentrated HSO (40 mL) was added concentrated HSO (10 mL) and HNO (10 mL) slowly dropwise with stirring at -30 to -20 °C. The addition was complete after 2 h. After stirring for 20 min, ice water was added to quench the reaction. The solid was filtered and washed with H2O. The filter cake was dried under vacuum to give the yellow solid product I-45-8 (2.2 g, 50% yield). MS (ESI) m / z: 324.1 [M+H] + It was.

[0367] Step 9: Synthesis (I-45-9) 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 h until the reaction was complete. The mixture was diluted with HO (200 mL) and extracted with EtOAc (200 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 preparative thin-layer chromatography (PE / EtOAc = 1 / 1) to give the yellow solid product I-45-9 (600 mg, 21% yield). MS (ESI) m / z: 424.0 [M+H] + It was.

[0368] Step 10: Synthesis (I-45-10) 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 gas protection for 16 h. After returning to room temperature, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 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 preparative thin-layer chromatography (PE / EtOAc = 1 / 1) to give a yellow solid product I-45-10 (350 mg, 52.6% yield). MS (ESI) m / z: 475.3 [M+H]+ It was.

[0369] Step 11: Synthesis (I-45-11) To a solution of I-45-10 (350 mg, 0.73 mmol) in MeOH (2 mL) was added wet Pd / C (35 mg, 10% purity) and stirred at 25 °C under a hydrogen atmosphere for 4 h. The reaction was filtered through diatomaceous earth, the filter cake was washed with EtOAc (30 mL), and the filtrate was concentrated under reduced pressure to give the green solid product I-45-11 (200 mg, 61.5% yield). MS (ESI) m / z: 445.2 [M+H] + It was.

[0370] Step 12: Synthesis (I-45-12) A mixture of 6-(trifluoromethyl)pyridinecarboxylic 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 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were 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, 30% yield). MS (ESI) m / z: 618.1 [M+H] + It was.

[0371] Step 13: Synthesis (I-45-13) At 0 °C, I-45-12 (50 mg, 0.08 mmol) was added to HCl-dioxane (1 M, 3 mL), and the reaction mixture was stirred at 25 °C for 1 h. Ether was added to the reaction mixture with stirring, and after standing, the supernatant was removed. This process was repeated three times to give the yellow solid product I-45-13 (35 mg, 85.3% yield). MS (ESI) m / z: 518.2 [M+H] + It was.

[0372] Step 14: Synthesis (I-45) A mixture 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 h until the reaction was complete. The reaction mixture was diluted with HO (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 give the yellow solid product I-45 (23 mg, 35% yield). MS (ESI) m / z: 885.6 [M+H] + It was. 1 H NMR(400MHz,DMSO-d6)δ 11.07(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=13.0,5.5Hz, 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).

[0373] Example 11: Synthesis of Compound II-2 [ka]

[0374] Step 1: Synthesis (int-G-1) A mixture of 2-(2,6-dioxo-3-piperidinyl)-5-fluoroisoindoline-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. The mixture was returned to room temperature, and water (60 mL) was added with stirring to precipitate a solid. The precipitate was filtered and dried to obtain the white solid product int-G-1 (1.2 g, crude). MS (ESI) m / z: 443.3 [M+H] + It was.

[0375] Step 2: Synthesis (int-G) A mixture of int-G-1 (35 mg, 79.10 μmol), TFA (1 mL), and DCM (1 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give the yellow solid product int-G (25 mg, 69.25% yield, TFA salt), which was used directly in the next step of the reaction. MS (ESI) m / z: 343.2 [M+H] + It was.

[0376] Step 3: Synthesis (II-2-1) 5-Nitro-6-(trifluoromethoxy)-2H-indazole (250 mg, 1.01 mmol) was dissolved in MeOH (3 mL), and catalyst-wet Pd / C (26.14 mg, 10% purity) was added. The mixture was purged with hydrogen gas three times while stirring, and the hydrogen gas atmosphere was maintained for 2 h. The reaction mixture was filtered through diatomaceous earth to remove the catalyst, and the filtrate was spin-dried to give brown solid product II-2-1 (211 mg, 96.05% yield). MS (ESI) m / z: 218.1 [M+H] + It was.

[0377] Step 4: Synthesis (II-2-2) A mixture 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 h until the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with EA (50 mL x 3). The combined organic layers were 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 the brown solid product II-2-2 (295 mg, 51.30% yield). MS (ESI) m / z: 391.2 [M+H] + It was.

[0378] Step 5: Synthesis (II-2-3) A mixture 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 h. Water (30 mL) was added to the reaction mixture, which was then extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to give the brown solid product II-2-3 (71 mg, 48.31% yield). MS (ESI) m / z: 574.5 [M+H] + It was.

[0379] Step 6: Synthesis (II-2-4) II-2-3 (71 mg, 123.80 μmol) was dissolved in DCM (5 mL). 4 M HCl-dioxane solution (309.51 μL) was added dropwise to the mixture at 25 °C. After the addition was complete, the reaction mixture was stirred for 2 h. Water (30 mL) was added to the reaction mixture, the pH was adjusted to neutral with saturated NaHCO₃, and the mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the white solid product II-2-4 (48 mg, 81.90% yield). MS (ESI) m / z: 474.1 [M+H] + It was.

[0380] Step 7: Synthesis (II-2-5) 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 h. Water (20 mL) was added to the reaction mixture, which was then extracted with EA (20 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 silica gel column chromatography (DCM:MeOH = 20:1) to give the white solid product II-2-5 (45 mg, 75.54% yield). MS (ESI) m / z: 588.5 [M+H] + It was.

[0381] Step 8: Synthesis (II-2-6) A mixture 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, yielding a white solid product II-2-6 (24 mg, 58.96% yield). MS (ESI) m / z: 532.1 [M+H] + It was.

[0382] Step 9: Synthesis (II-2) A mixture 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 h. Water (20 mL) was added, and the mixture was extracted with EA (20 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 preparative thin-layer chromatography to give the yellow solid product II-2 (23 mg, 58.32% yield). MS (ESI) m / z: 856.3 [M+H] + It was. 1 H NMR(500MHz,DMSO-d6)δ 11.08(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=11.0Hz) ,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).

[0383] Compounds II-4, II-7, II-10, II-12, II-13, II-16, II-17, II-20, II-21 were prepared according to the methods of Example 2 and Example 11, and their structures and characterization data are as shown in the following table.

[0384] [Table 7(1)] [Table 7(2)] [Table 7(3)] [Table 7(4)]

[0385] Example 12: Synthesis of I-57 and I-58 [ka]

[0386] I-1 (100 mg) was subjected to chiral separation by SFC (supercritical fluid chromatography) to give yellow solid I-57 (47 mg) and yellow solid I-58 (44 mg).

[0387] I-57 or I-58: Chiral HPLC: Optical purity (ee value) = 100%, RT = 2.262 min. MS (ESI) m / z: 827.8 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 11.09(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). 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)δ 11.10(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),5.24-5.13(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).

[0388] The SFC split conditions are as follows:

[0389] Instrument: SFC-150 (Waters) Chromatography column: IH 25 x 250mm, 10um (Daicel) Column temperature: 35℃ Mobile phase: CO2 / (MeOH:MeCN=1:1)=50 / 50 Flow rate: 120mL / min Back pressure: 100bar Detection wavelength: 214 nm Circulation time: 8.2min Sample solution: 100 mg of sample was dissolved in 25 mL of methanol / dichloromethane. Sample input volume: 4.0 mL

[0390] Example 13: Synthesis of I-59 and I-60 [ka]

[0391] I-4 (50 mg) was subjected to chiral separation by SFC to give yellow solid I-59 (17.4 mg) and yellow solid I-60 (15.9 mg).

[0392] 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] + . 1 H NMR(500MHz,DMSO-d6)δ 11.07(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). 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] + . 1H NMR(500MHz,DMSO-d6)δ 11.07(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).

[0393] The SFC split conditions are as follows:

[0394] Instrument: Gilson-281 Chromatography column: IC 25 x 250mm, 10um (Daicel) Mobile phase: HEX(0.1%DEA):EtOH(0.1%DEA):=50:50 Flow rate: 50mL / min Single needle run time: 30 min Sample input volume: 3 mL Sample solution: 50 mg of sample dissolved in 35 mL of methanol

[0395] Example 14: Synthesis of I-61 and I-62 [ka]

[0396] I-8 (100 mg) was subjected to chiral separation by SFC to give yellow solid I-61 (40.6 mg) and yellow solid I-62 (41.2 mg).

[0397] I-61 and I-62: KIRAL HPLC: optical purity (ee value) = 100%, RT = 1.759 min. MS(ESI)m / z:845.8[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 11.12(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). I-61 and I-62: KIRAL HPLC: optical purity (ee value) = 99.74%, RT = 2.520 min. MS(ESI)m / z:845.8[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 11.12(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).

[0398] SFC division conditions are as follows.

[0399] Instrument: SFC-150 (Waters) Chromatography column: IH 25 x 250mm, 10um (Daicel) Column temperature: 35℃ Mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50 Flow rate: 120mL / min Back pressure: 100bar Detection wavelength: 214 nm Circulation time: 6.15min Sample solution: 100 mg of sample was dissolved in 18 mL of methanol. Sample input volume: 4.0 mL

[0400] Example 15. Synthesis of I-63 and I-64 [ka]

[0401] I-5 (20 mg) was subjected to chiral separation by SFC to give yellow solid I-63 (5.7 mg) and yellow solid I-64 (3.9 mg).

[0402] I-63 or I-64: Chiral HPLC: Optical purity (ee value) = 100%, RT = 1.299 min. MS (ESI) m / z: 855.9 [M+H] + .

[0403] 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] + .

[0404] The SFC split conditions are as follows:

[0405] Instrument: SFC-150 (Waters) Chromatography column: AS 25 x 250mm, 10um (Daicel) Column temperature: 35℃ Mobile phase: CO2 / [MeOH(0.2% NH3(7M in MeOH):MeCN=1:1]=40 / 60 Flow rate: 100mL / min Back pressure: 100bar Detection wavelength: 214 nm Circulation time: 7.1min Sample solution: 20 mg of sample was dissolved in 35 mL of methanol. Sample input volume: 4.9 mL

[0406] Example 16: Synthesis of I-65 and I-66 [ka]

[0407] I-22 (100 mg) was subjected to chiral separation by SFC to give yellow solid I-65 (48.2 mg) and yellow solid I-66 (46.6 mg).

[0408] I-65 or I-66: Chiral HPLC: Optical purity (ee value) = 100%, RT = 2.309 min. MS (ESI) m / z: 830.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.09(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). 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] + . 1H NMR(400MHz,DMSO-d6)δ 11.09(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).

[0409] The SFC split conditions are as follows:

[0410] Instrument: SFC-150 (Waters) Chromatography column: IH 25 x 250mm, 10um (Daicel) Column temperature: 35℃ Mobile phase: CO2 / [MeOH:MeCN=1:1]=50 / 50 Flow rate: 120mL / min Back pressure: 100bar Detection wavelength: 214 nm Circulation time: 8.65min Sample solution: 100 mg of sample was dissolved in 35 mL of methanol. Sample input volume: 4.8 mL

[0411] Application example 1. Evaluation of compound inhibitory activity against kinase activity Based on the experimental method of fluorescent microfluidic mobility detection, IC of compounds for competitive binding of kinase IRAK4 to ATP 50 The starting detection concentration of the compound was 10 μM, diluted in a 4-fold gradient to 0.38 nM, and detected in duplicate wells. Here, commercialized staurosporine was the standard control in this experiment.

[0412] 1.1 Reagent and consumable information is as follows:

[0413] [Table 8]

[0414] 1.2 Experimental procedures 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.

[0415] 2) The substrate peptide FAM-P8 and ATP were dissolved in the above kinase buffer, and the final concentrations of the IRAK4 substrate peptide FAM-P8 and ATP were adjusted to 3 μM and 10 μM, respectively.

[0416] 3) Compound dilution: Compounds were initially diluted to 50 μM and then diluted in a 4-fold gradient with DMSO, where a solution without compound and kinase was the blank control and corresponds to the "Min" value shown below, and a solution without compound but containing kinase, adenosine 5'-triphosphate disodium salt hydrate, DMSO, and buffer was the positive control and corresponds to the "Max" value shown below.

[0417] 4) Kinase reaction and termination: 10 μL of kinase buffer was added to a 384-well plate containing 5 μL of test compound and incubated at room temperature for 10 minutes. 10 μL of a buffer containing the substrate peptide and adenosine 5'-triphosphate disodium salt hydrate was then added to the 384-well plate and incubated at 28°C for 1 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 then added per well to terminate the reaction.

[0418] 5) Data reading: The conversion data was read using the CaliperEZ Reader II instrument, and the conditions were set as follows: downstream voltage -500V, upstream voltage -2250V, reference pressure -0.5 PSI, screening pressure -1.2 PSI.

[0419] 6) Data calculation: Copy the conversion rate data from CaliperEZ Reader II and convert the conversion rate into inhibition rate data. The calculation formula is as follows:

[0420] Percent inhibition (%) = (maximum value - conversion rate) / (maximum value - minimum value) * 100% IC using XLFit Excel add-in version 5.4.0.8 50 Fitting the values, Fitting formula: Y=Bottom + (Top-Bottom) / (1+(IC 50 / X)^HillSlope) Kinase activity data are shown in Tables 1 and 2.

[0421] [Table 9]

[0422] [Table 10]

[0423] 2. Stimulation of THP-1-Released Cytokines by LPS 2.1 Experimental materials

[0424] [Table 11]

[0425] 2. Detection of induction of IRAK4 proteolysis in THP-1 cells by PROTAC 2.1. Western Blot: THP-1 cell samples were electrophoresed and stained with specific antibodies. The staining location and depth were analyzed to determine the degradation activity of compounds against IRAK4 protein in THP-1 cells. Compound concentrations included 0 μM, 0.3 μM, 1 μM, and 3 μM, and the compound treatment times included 8, 16, 24, and 48 hours. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the internal standard protein in this experiment.

[0426] 2.2. Information on cells, reagents and consumables is as follows:

[0427] [Table 12]

[0428] 2.3, Equipment [Table 13]

[0429] 2.4. Reagent preparation method Electrophoresis buffer: 50 mL of MOPS SDS Running Buffer (20x) and 50 mL of 20x TBS Tween-20 buffer diluted to 1 L with deionized water to form the electrophoresis buffer. 5% skim milk (w / v): Dilute 2.5 g of skim milk in 50 mL of 1x TBS Tween-20 buffer to make 5% skim milk.

[0430] 5% BSA (w / v): Dilute 2.5 g of BSA in 50 mL of 1x TBS Tween-20 buffer to prepare 5% BSA.

[0431] Dilute the anti-IRAK4 antibody 1:1000 in 5% BSA to make the primary antibody working solution. Dilute Goat Anti-Rabbit IgG H&L (HRP) 1:2000 with 5% BSA to make the secondary antibody working solution. Goat Anti-Mouse IgG H&L (HRP) was diluted 1:2000 with 5% BSA to prepare the secondary antibody working solution.

[0432] THP-1 cells were plated at a density of 1.5 x 10 cells per milliliter in a 6-well plate and incubated in a cell incubator at 37°C with 5% CO2 for 2 hours. Compounds were diluted with DMSO to 0.6 mM, 0.2 mM, and 0.06 mM, respectively. 10 μL of compound solution was added to the corresponding wells and cultured in the incubator for 16, 24, and 48 hours, respectively. The drug-treated THP-1 cells in the wells were harvested and lysed with 120 μL of RIPA lysis solution containing protease inhibitors, phosphatase inhibitor solution II, and phosphatase inhibitor solution III on wet ice for 30 minutes. The cell lysate was then centrifuged at high speed for 5 minutes in the cold, and the supernatant was removed. Protein concentration was measured for the cell samples according to the instructions in the Pierce™ BCA Protein Assay Kit.

[0433] The sample concentration was adjusted to uniformity with lysis buffer and NuPAGE® LDS sample buffer containing 1M DTT. The sample was heated at 95°C for 5 minutes and centrifuged at low temperature. 20 μL of the prepared protein sample and 4 μL of PageRuler Prestained Protein Ladder were added to the gel wells. The gel was run at 80 V for 0.5 hours, then the voltage was adjusted to 120 V and continued running for 1.5 hours. The gel was removed and the proteins in the gel were transferred to an IBlot™ 2 transfer membrane at 20 V. After successful membrane transfer, the band positions were cut at 65 kDa-40 kDa and 40 kDa-30 kDa, respectively. The membrane was blocked with 5% nonfat milk at room temperature for 1 hour. The membrane was washed three times with 1x TBST and then incubated overnight in IRAK4 antibody working solution at 4°C. The IRAK4 antibody working solution was discarded, and the membrane was washed three times with 1x TBST. The corresponding membrane pieces were then incubated for 1 hour at room temperature with Goat Anti-Rabbit IgG H&L (HRP) working solution and Goat Anti-Mouse IgG H&L (HRP) working solution. The antibody working solution was then discarded, and the membrane was washed three times with 1x TBST. TM Referring to the West Femto Maximum Sensitivity Substrate instruction manual, the reagents in the kit were mixed in equal volume ratios to prepare a luminescent liquid mixture, and the membrane strip was incubated for 1 minute, after which it was removed and exposed to light.

[0434] The drug concentration was 1 μM, and the Western blot results 24 hours after administration are shown in Table 3.

[0435] [Table 14]

[0436] The concentrations required for 50% IRAK4 degradation by Western blot 24 hours after administration are shown in Table 4.

[0437]

Table 15

Claims

1. A compound shown in formula I, a pharmaceutically acceptable salt or isotope thereof, 【Chemistry 1】 The Cy ring is a five-membered heterocycle or a five-membered heteroaromatic ring, and the heteroatoms of the five-membered heterocycle are selected from one or two of N, S, and O, with one or two heteroatoms; or the heteroatoms of the five-membered heteroaromatic ring are selected from one or more of N, S, and O, with one, two, or three heteroatoms. 【Chemistry 2】 teeth, 【Transformation 3】 And, Q is either C or N, E is CH or N, Y is either C or N, R １ This is unsubstituted or one or more R １－１ A 5- to 10-membered heteroaryl group substituted with, or an unsubstituted or one or more R groups. １－２ A 6- to 10-membered aryl group substituted with, wherein 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 one, two, or three. Each R １－１ and R １－２ These are, independently, halogens, hydroxyl groups, 【Chemistry 4】 -SO ２ -R ａ , -SO-R ａ , a cyano group, a nitro group, an unsubstituted or one or more R １－１－１ -substituted 3- to 11-member heterocycloalkyl group, an unsubstituted or one or more R １－１－３ -substituted C １ -C ６ alkoxy group, an unsubstituted or one or more R １－１－４ -substituted C １ -C ６ alkyl group, 【Transformation 5】 Unsubstituted or one or more R １－１－５ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R １－１－８ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. １－１－７ A 5 to 10-membered heteroaryl group substituted with, wherein 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 one, two, or three; 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 one, two, or three. 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 These independently consist of deuterium, halogen, oxo, and hydroxyl groups. 【Transformation 6】 -SO ２ -R ａ , -SO-R ａ , unsubstituted or substituted with one or more halogens C １ -C ６ Alkoxy group, cyano group, nitro group, unsubstituted or one or more R groups １－１－１－１ A 3 to 11-membered heterocycloalkyl group substituted with C, unsubstituted or substituted with one or more halogens or deuterium. １ -C ６ Alkyl alkyl groups, 3 to 10-membered cycloalkyl groups, unsubstituted or one or more R １－１－１－２ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. １－１－１－３ A 5 to 10-membered heteroaryl group substituted with, wherein 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 one, two, or three; 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 one, two, or three. Each R １－１－１－１ , R １－１－１－２ and R １－１－１－３ These are, independently, halogen, oxo, hydroxyl, and C １ -C ６ Alkoxy group or C １ -C ６ It is an alkyl group, R ２ R is hydrogen, hydroxyl group, cyano group, halogen, unsubstituted or one or more R ２－３ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ２－２ C replaced by １ -C ６ Alkoxy group, 【Transformation 7】 Unsubstituted or one or more R ２－１ A 5- to 10-membered heteroaryl group substituted with or unsubstituted or one or more R ２－４ A 4- to 10-membered heterocycloalkyl group substituted with, wherein 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 one, two, or three; the heteroatoms of the 4- to 10-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three. Each R ２－１ , R ２－２ , R ２－３ and R ２－４ These are, independently, halogens, hydroxyl groups, cyano groups, nitro groups, unsubstituted or substituted with one or more halogens. １ -C ６ alkyl group, 【Transformation 8】 Or C is unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkoxy group, R ３ These are hydrogen, deuterium, halogens, cyano groups, hydroxyl groups, nitro groups, 【Chemistry 9】 -SO ２ -R ａ 、-SO-R ａ 、 【Chemistry 10】 Unsubstituted or one or more R ３－１ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ A 3 to 10-membered cycloalkyl group substituted with 【Chemistry 11】 Unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－５ A 6- to 10-membered aryl group substituted with, unsubstituted or one or more R ３－６ A 5- to 10-membered heteroaryl group substituted with R ３－８ A hydroxyl group substituted with, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group 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 one, two, or three. 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 one, two, or three. Each R ３－１ , R ３－２ , R ３－４ , R ３－５ , R ３－６ and R ３－７ These are independently deuterium, halogen, oxo, hydroxyl group, unsubstituted or one or more R ３－１－１ 3 to 11 member heterocycloalkyl groups substituted with 【Chemistry 12】 Cyano group, unsubstituted or one or more R groups ３－１－３ substituted alkoxy group, 【Chemistry 13】 Unsubstituted or one or more R ３－１－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－１－５ Substituted with 3 to 10 member cycloalkyl groups, -SO ２ -R ａ , -SO-R ａ , 【Chemistry 14】 The group is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; 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 one, two, or three. 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 heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or more of N, S, and O, the number of heteroatoms is one, two, or three, the heteroatom of the 5- to 10-membered heteroaryl group is selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three. Each R ３－１－１ , R ３－１－３ , R ３－１－４ and R ３－１－５ These are C, which are independently unsubstituted or substituted with one or more halogens. １ -C ６ These are alkyl groups, halogens, oxo or hydroxyl groups, Each R ａ and each R ｂ is independently H, C ａ－１ -C １ alkyl group unsubstituted or substituted with one or more R ６ a 3- to 10-membered cycloalkyl group unsubstituted or substituted with one or more R ａ－２ a 3- to 11-membered heterocycloalkyl group unsubstituted or substituted with one or more R ａ－３ a 6- to 10-membered aryl group unsubstituted or substituted with one or more R ａ－４ or a 5- to 10-membered heteroaryl group unsubstituted or substituted with one or more R ａ－５ and is or R ａ and R ｂ These atoms, together with the atoms linked to them, form a 3- to 11-membered heterocyclic ring, and 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 one, two, or three. Each R ａ－１ , R ａ－２ , R ａ－３ , R ａ－４ and R ａ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The group is an alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; and 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 one, two, or three. L ０ This is unsubstituted or one or more L ０ －２ A 5- to 12-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 5- to 12-membered heterocycloalkylene group substituted with, the 5- to 12-membered cycloalkylene group is bicyclic or polycyclic, the 5- to 12-membered heterocycloalkylene group is a monocyclic, bicyclic or polycyclic compound, the heteroatoms of the 5- to 12-membered cycloalkylene group are selected from one or more of N, S and O, the number of heteroatoms is one, two or three, and each L ０ －２ These are, independently, deuterium, a hydroxyl group, a halogen, unsubstituted or substituted with one or more halogens or deuterium C １ -C ６ Alkoxy group, 【Chemistry 15】 Or C that is unsubstituted or substituted with one or more halogens or deuterium １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, deuterium, a hydroxyl group, a halogen, unsubstituted or substituted with one or more halogens or deuterium C １ -C ６ Alkoxy group, 【Chemistry 16】 Or C that is unsubstituted or substituted with one or more halogens or deuterium １ -C ６ It is an alkyl group, L ２ This is a linker unit, L ０ but 【Chemistry 17】 If L ２ At least, [Chemistry 18] Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 19】 It contains one or more of the following fragments, where a and b are independently 1 or 2, m is an integer from 1 to 4, q is an integer from 1 to 6, X is 0, L ２ １－１ C is a halogen, unsubstituted, or substituted with one or more halogens. １ -C ６ C is an alkyl group, unsubstituted, or substituted with one or more halogens. １ -C ６ Alkoxy group, 【Chemistry 20】 Hydroxyl group, oxo or 【Chemistry 21】 And, Each R ｃ These are independently H, unsubstituted or one or more R ｃ－１ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ｃ－２ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R ｃ－３ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ｃ－４ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. ｃ－５ A 5- to 10-membered heteroaryl group substituted with, Each R ｃ－１ , R ｃ－２ , R ｃ－３ , R ｃ－４ and R ｃ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The group is an alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; and 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 one, two, or three. LLM is 【Chemistry 22】 And, Ring Cy ３ is non-substitutable or one or more Cy ３－１ A 5- to 12-membered heterocycle substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ３－１ Independently, C １ -C ６ It is an alkyl group, halogen, hydroxyl group or oxo, Ring Cy ４ is non-substitutable or one or more Cy ４－１ A 5- to 12-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ４－１ Independently, C １ -C ６ It is an alkyl group, halogen, hydroxyl group or oxo, Ring Cy ５ is non-substitutable or one or more Cy ５－１ A 5- to 12-membered heterocycle substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ５－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or an oxo group. Ring Cy ６ is non-substitutable or one or more Cy ６－１ A 6- to 10-membered aromatic ring substituted with Cy ６－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or a halogen, Ring Cy ７ is non-substitutable or one or more Cy ７－１ A 5- to 9-membered heteroaromatic ring substituted with, wherein 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 one, two, or three, and Cy ７－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or a halogen, R ４ These are, independently, hydrogen, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, p is 0, 1, 2, or 3. Each R ５ It is, independently, a halogen, L ３ This is unsubstituted or one or more L ３ －１ Replaced with 【Chemistry 23】 Here, m is an integer from 1 to 4, q is an integer from 1 to 6, X does not exist or is O, and L ３ －１ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ A compound represented by formula I, which is an alkyl group, or a pharmaceutically acceptable salt or isotope thereof.

2. A compound shown in formula I, a pharmaceutically acceptable salt or isotope thereof, 【Chemistry 24】 The Cy ring is a five-membered heterocycle or a five-membered heteroaromatic ring, and the heteroatoms of the five-membered heterocycle are selected from one or two of N, S, and O, with one or two heteroatoms; or the heteroatoms of the five-membered heteroaromatic ring are selected from one or more of N, S, and O, with one, two, or three heteroatoms. 【Chemistry 25】 teeth, 【Chemistry 26】 And, Q is either C or N, E is CH or N, Y is either C or N, R １ This is unsubstituted or one or more R １－１ A 5- to 10-membered heteroaryl group substituted with, or an unsubstituted or one or more R groups. １－２ A 6- to 10-membered aryl group substituted with, wherein 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 one, two, or three. Each R １－１ and R １－２ These are, independently, halogens, hydroxyl groups, 【Chemistry 27】 -SO ２ -R ａ , -SO-R ａ , cyano group, nitro group, unsubstituted or one or more R １－１－１ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R １－１－３ C replaced by １ -C ６ Alkoxy group, unsubstituted, or one or more R groups １－１－４ C replaced by １ -C ６ alkyl group, 【Chemistry 28】 Unsubstituted or one or more R １－１－５ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R １－１－８ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. １－１－７ A 5 to 10-membered heteroaryl group substituted with, wherein 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 one, two, or three; 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 one, two, or three. 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 These independently include halogen, oxo, and hydroxyl groups. 【Chemistry 29】 -SO ２ -R ａ , -SO-R ａ , unsubstituted or substituted with one or more halogens C １ -C ６ Alkoxy group, cyano group, nitro group, unsubstituted or one or more R groups １－１－１－１ A 3 to 11-membered heterocycloalkyl group substituted with C, unsubstituted or substituted with one or more halogens. １ -C ６ Alkyl alkyl groups, 3 to 10-membered cycloalkyl groups, unsubstituted or one or more R １－１－１－２ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. １－１－１－３ A 5 to 10-membered heteroaryl group substituted with, wherein 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 one, two, or three; 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 one, two, or three. Each R １－１－１－１ , R １－１－１－２ and R １－１－１－３ These are, independently, halogen, oxo, hydroxyl, and C １ -C ６ Alkoxy group or C １ -C ６ It is an alkyl group, R ２ R is hydrogen, hydroxyl group, cyano group, halogen, unsubstituted or one or more R ２－３ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ２－２ C replaced by １ -C ６ Alkoxy group, 【Transformation 30】 Unsubstituted or one or more R ２－１ A 5- to 10-membered heteroaryl group substituted with or unsubstituted or one or more R ２－４ A 4- to 10-membered heterocycloalkyl group substituted with, wherein 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 one, two, or three; the heteroatoms of the 4- to 10-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three. Each R ２－１ , R ２－２ , R ２－３ and R ２－４ These are, independently, halogens, hydroxyl groups, cyano groups, nitro groups, unsubstituted or substituted with one or more halogens. １ -C ６ alkyl group, 【Chemistry 31】 Or C is unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkoxy group, R ３ These are hydrogen, deuterium, halogens, cyano groups, hydroxyl groups, nitro groups, 【Chemistry 32】 -SO ２ -R ａ 、-SO-R ａ 、 【Transformation 33】 Unsubstituted or one or more R ３－１ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ A 3 to 10-membered cycloalkyl group substituted with 【Transformation 34】 Unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－５ A 6- to 10-membered aryl group substituted with, unsubstituted or one or more R ３－６ A 5- to 10-membered heteroaryl group substituted with R ３－８ A hydroxyl group substituted with, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group 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 one, two, or three. 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 one, two, or three. Each R ３－１ , R ３－２ , R ３－４ , R ３－５ , R ３－６ and R ３－７ These are independently deuterium, halogen, oxo, hydroxyl group, unsubstituted or one or more R ３－１－１ 3 to 11 member heterocycloalkyl groups substituted with 【Chemistry 35】 Cyano group, unsubstituted or one or more R groups ３－１－３ substituted alkoxy group, 【Transformation 36】 Unsubstituted or one or more R ３－１－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－１－５ Substituted with 3 to 10 member cycloalkyl groups, -SO ２ -R ａ , -SO-R ａ , 【Chemistry 37】 The group is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; 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 one, two, or three. R ３－８ This 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, wherein 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 one, two, or three; and 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 one, two, or three. Each R ３－１－１ , R ３－１－３ , R ３－１－４ and R ３－１－５ These are C, which are independently unsubstituted or substituted with one or more halogens. １ -C ６ These are alkyl groups, halogens, oxo or hydroxyl groups, Each R ａ and each R ｂ These are independently H, unsubstituted or one or more R ａ－１ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ａ－２ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R ａ－３ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ａ－４ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. ａ－５ A 5- to 10-membered heteroaryl group substituted with, or R ａ and R ｂ These atoms, together with the atoms linked to them, form a 3- to 11-membered heterocyclic ring, and 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 one, two, or three. Each R ａ－１ , R ａ－２ , R ａ－３ , R ａ－４ and R ａ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The group is an alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; and 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 one, two, or three. L ０ This is unsubstituted or one or more L ０ －２ A 5- to 12-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 5- to 12-membered heterocycloalkylene group substituted with, the 5- to 12-membered cycloalkylene group is bicyclic or polycyclic, the 5- to 12-membered heterocycloalkylene group is a monocyclic, bicyclic or polycyclic compound, the heteroatoms of the 5- to 12-membered cycloalkylene group are selected from one or more of N, S and O, the number of heteroatoms is one, two or three, and each L ０ －２ These are, independently, a hydroxyl group, a halogen, unsubstituted or substituted with one or more halogens, C １ -C ６ Alkoxy group, 【Transformation 38】 Or C is unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, a hydroxyl group, a halogen, unsubstituted or substituted with one or more halogens, C １ -C ６ Alkoxy group, 【Chemistry 39】 Or C is unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, L ２ This is a linker unit, L ０ but 【Chemistry 40】 If L ２ At least, 【Chemistry 41】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 42】 It contains one or more of the following fragments, where a and b are independently 1 or 2, m is an integer from 1 to 4, q is an integer from 1 to 6, X is 0, L ２ １－１ C is a halogen, unsubstituted, or substituted with one or more halogens. １ -C ６ C is an alkyl group, unsubstituted, or substituted with one or more halogens. １ -C ６ Alkoxy group, 【Chemistry 43】 Hydroxyl group, oxo or 【Chemistry 44】 And, Each R ｃ These are independently H, unsubstituted or one or more R ｃ－１ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ｃ－２ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R ｃ－３ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ｃ－４ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. ｃ－５ A 5- to 10-membered heteroaryl group substituted with, Each R ｃ－１ , R ｃ－２ , R ｃ－３ , R ｃ－４ and R ｃ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The group is an alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; and 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 one, two, or three. LLM is 【Chemistry 45】 And, Ring Cy ３ is non-substitutable or one or more Cy ３－１ A 5- to 12-membered heterocycle substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ３－１ Independently, C １ -C ６ It is an alkyl group, halogen, hydroxyl group or oxo, Ring Cy ４ is non-substitutable or one or more Cy ４－１ A 5- to 12-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycloalkyl group are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ４－１ Independently, C １ -C ６ It is an alkyl group, halogen, hydroxyl group or oxo, Ring Cy ５ is non-substitutable or one or more Cy ５－１ A 5- to 12-membered heterocycle substituted with, wherein the heteroatoms of the 5- to 12-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and Cy ５－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or an oxo group. Ring Cy ６ is non-substitutable or one or more Cy ６－１ A 6- to 10-membered aromatic ring substituted with Cy ６－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or a halogen, Ring Cy ７ is non-substitutable or one or more Cy ７－１ A 5- to 9-membered heteroaromatic ring substituted with, wherein 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 one, two, or three, and Cy ７－１ Independently, C １ -C ６ It is an alkyl group, a hydroxyl group, or a halogen, R ４ These are, independently, hydrogen, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, p is 0, 1, 2, or 3. Each R ５ It is, independently, a halogen, L ３ This is unsubstituted or one or more L ３ －１ Replaced with 【Chemistry 46】 Here, m is an integer from 1 to 4, q is an integer from 1 to 6, X does not exist or is O, and L ３ －１ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ A compound represented by formula I, which is an alkyl group, or a pharmaceutically acceptable salt or isotope thereof.

3. LLM is a group that binds to a ligase, and 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, CBLL 1, 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, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, U BR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOI P / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP (pan), ITCH / AIP4, KAP1, MARCH8, Mind Bomb 1 / 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, L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 47】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 48】 Unsubstituted or one or more L ２ １－２ Replaced with 【Chemistry 49】 Or non-substituted or one or more L ２ １－３ Replaced with [Transformation 50] The ring Cy is formed when m is an integer from 1 to 4, q is an integer from 1 to 6, X does not exist or is O, and １ These are 4- to 12-membered heterocycles or 3- to 12-membered cycloalkanes, and the ring Cy ２ The 5- to 10-membered heteroaromatic ring or the 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 one, two, or three; 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 one, two, or three. L ２ １－１ and L ２ １－２ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ C is an alkyl group, unsubstituted, or substituted with one or more halogens. １ -C ６ Alkoxy group, 【Chemistry 51】 Hydroxyl group, oxo or 【Chemistry 52】 And, L ２ １－３ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ C is an alkyl group, unsubstituted, or substituted with one or more halogens. １ -C ６ Alkoxy group, cyano group, 【Chemistry 53】 Unsubstituted or one or more L ２ １－３－１ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more L ２ １－３－２ 3 to 11 member heterocycloalkyl groups substituted with 【Chemistry 54】 -SO ２ -R ａ 、-SO-R ａ 、 【Transformation 55】 Alternatively, it is a hydroxyl group, and 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 one, two, or three. Each L ２ １－３－１ and L ２ １－３－２ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ C is an alkyl group, unsubstituted, or substituted with one or more halogens. １ -C ６ Alkoxy group, hydroxyl group, oxo or 【Transformation 56】 And, Each R ｃ These are independently H, unsubstituted or one or more R ｃ－１ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ｃ－２ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R ｃ－３ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ｃ－４ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. ｃ－５ A 5- to 10-membered heteroaryl group substituted with, Each R ｃ－１ , R ｃ－２ , R ｃ－３ , R ｃ－４ and R ｃ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The group is an alkoxy group, a 3- to 10-membered cycloalkyl group, a 3- to 11-membered heterocycloalkyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein 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 one, two, or three; and 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 one, two, or three. Each R ａ and each R ｂ These are independently H, unsubstituted or one or more R ａ－１ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ａ－２ A 3 to 10-membered cycloalkyl group substituted with, unsubstituted or one or more R ａ－３ A 3 to 11-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ａ－４ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. ａ－５ A 5- to 10-membered heteroaryl group substituted with, Each R ａ－１ , R ａ－２ , R ａ－３ , R ａ－４ and R ａ－５ These are, independently, halogen, cyano group, hydroxyl group, nitro group, and C １ -C ６ Alkyl alkyl group, C １ -C ６ The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope compound thereof, characterized in that the compound is an alkoxy group, a 3 to 10-membered cycloalkyl group, a 3 to 11-membered heterocycloalkyl group, a 6 to 10-membered aryl group, or a 5 to 10-membered heteroaryl group, wherein 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 one, two, or three, and 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 one, two, or three.

4. When the ring Cy is a five-membered heterocycle, the heteroatom of the five-membered heterocycle is O, and there is one such heteroatom. Preferably, the five-membered heterocycle is a tetrahydrofuran ring. and / or, if the ring Cy is a five-membered heteroaromatic ring, the heteroatoms of the five-membered heteroaromatic ring are selected from one or two of N, S, and O, the number of heteroatoms is one or two, and the five-membered heteroaromatic ring is preferably a pyrrole ring, a pyrazole ring, a thiazole, an oxazole ring, or an imidazole ring. and / or, R １ is unsubstituted or one or more R １－１ In the case of a 5 to 10-membered heteroaryl group substituted with, the heteroatoms of the 5 to 10-membered heteroaryl group are selected from one or two of N, O, and S, the number of heteroatoms is one, two, or three, and the 5 to 10-membered heteroaryl group is an oxazolyl group, pyrazolyl group, thiazolyl group, imidazolyl group, pyridyl group, pyridadinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, or pyrazolopyrimidinyl group, for example, a pyridyl group, an oxazolyl group, a pyrazolyl group or 【Chemistry 57】 Even if that is the case, and / or, R １ is unsubstituted or one or more R １－２ In the case of a 6 to 10-membered aryl group substituted with, the 6 to 10-membered aryl group is preferably a phenyl group or a naphthyl group. and / or each R １－１ and R １－２ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－１ In the case of a 3 to 11-membered heterocycloalkyl group substituted with, the 3 to 11-membered heterocycloalkyl group is a 4 to 8-membered heterocycloalkyl group, and 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 one or two, preferably the heteroatoms of the 3 to 11-membered heterocycloalkyl group are N, S, or O, and the number of heteroatoms is one or two, and each R １－１－１ These are, independently, preferably, halogens, hydroxyl groups, oxo, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ The alkyl group is preferably a piperadinyl group, piperadinylene group, piperidinyl group, tetrahydropyrrolyl group, oxetanyl group, azabicyclo[2.2.2]octyl group, azabicyclo[3.2.1]octyl group, azaspiro[3.3]heptyl group, or azabicyclo[2.2.1]heptyl group, for example, 【Chemistry 58】 And, and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－３ C replaced by １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, and each R １－１－３ These are, independently, preferably, a halogen, a hydroxyl group, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ It is an alkyl group, and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－４ C replaced by １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ Alkyl groups, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or tert-butyl group, and each R １－１－４ These are, independently, preferably, a halogen, a hydroxyl group, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ It is an alkyl group, and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－５ In the case of a 3 to 10-membered cycloalkyl group substituted with, the 3 to 10-membered cycloalkyl group is a 3 to 6-membered cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and each R １－１－５ These are, independently, preferably, a halogen, a hydroxyl group, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ It is an alkyl group, and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－７ In the case of a 5 to 10-membered heteroaryl group substituted with, the heteroatoms of the 5 to 10-membered heteroaryl group are N, and the number of heteroatoms is one, two, or three, and each R １－１－７ These are, independently, preferably, a halogen, a hydroxyl group, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ The alkyl group is a 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group may be a pyridyl group, pyridylene group, pyridadinyl group, pyrazinyl group, pyrimidinyl group, or triazinyl group, for example, a pyridyl group or a pyridylene group. and / or each R １－１ and R １－２ However, independently, non-substitutable or one or more R １－１－８ In the case of a 6 to 10-membered aryl group substituted with, the 6 to 10-membered aryl group is a phenyl group or a naphthyl group, and each R １－１－８ These are, independently, preferably, a halogen, a hydroxyl group, unsubstituted or substituted with one or more halogens. １ -C ６ C with an alkoxy group, or unsubstituted or substituted with one or more halogens １ -C ６ It is an alkyl group, and / or each R １－１－１ and R １－１－７ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ Alkyl groups, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or tert-butyl group, and / or each R １－１－４ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or, R ２ If the halogen is a halogen, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, R ２ is unsubstituted or one or more R ２－１ In the case of a 5 to 10-membered heteroaryl group substituted with , the heteroatom of the 5 to 10-membered heteroaryl group is N, the number of heteroatoms is one, two, or three, and the 5 to 10-membered heteroaryl group is preferably a pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, or triazinyl group, for example, a pyridyl group. and / or, R ２ is unsubstituted or one or more R ２－２ C replaced by １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ Alkoxy groups, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, or tert-butoxy group, and / or, R ２ is unsubstituted or one or more R ２－３ C replaced by １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ Alkyl groups, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or tert-butyl group, and / or, R ２ is unsubstituted or one or more R ２－４ In the case of a 4 to 10-membered heterocycloalkyl group substituted with, the 4 to 10-membered heterocycloalkyl group is a 5 to 8-membered heterocycloalkyl group, and the heteroatoms of the 4 to 10-membered heterocycloalkyl group are selected from one or two of N, S, and O, and the number of heteroatoms is one or two, preferably the heteroatoms of the 4 to 10-membered heterocycloalkyl group are N, S, or O, and the number of heteroatoms is one or two, and the 4 to 10-membered heterocycloalkyl group is preferably a piperadinyl group, a piperidinyl group, a tetrahydropyrrolyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group, or an azabicyclo[2.2.1]heptyl group, for example, 【Chemistry 59】 And, and / or each R ２－１ , R ２－２ , R ２－３ and R ２－４ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each R ２－１ , R ２－２ , R ２－３ and R ２－４ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ The alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each R ２－１ , R ２－２ , R ２－３ and R ２－４ However, independently, C １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group is, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, for example, a methoxy group, and the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or, R ３ If the halogen is a halogen, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or, R ３ is unsubstituted or one or more R ３－１ In the case of a 3 to 11-membered heterocycloalkyl group substituted with, the 3 to 11-membered heterocycloalkyl group is a 3 to 8-membered heterocycloalkyl group, the heteroatoms of the 3 to 11-membered heterocycloalkyl group are preferably N and / or O, the number of heteroatoms is one or two, and the 3 to 11-membered heterocycloalkyl group is preferably a piperidinyl group, a tetrahydropyrrolyl group, a tetrahydropyrrolylene group, a 2-azaspiro[3.3]heptyl group, a 2-oxaspiro[3.3]heptyl group, a morpholinyl group, a tetrahydropyranyl group, an oxetanyl group, an azabicyclo[2.2.1]heptyl group, or a diazabicyclo[2.2.1]heptyl group, and each R ３－１ R is independently, preferably, a halogen, an oxo, or a hydroxyl group, for example, a hydroxyl group, and the R is unsubstituted or one or more Rs. ３－１ The 3 to 8-membered heterocycloalkyl group substituted with is preferably, 【Transformation 60】 And, and / or, R ３ is unsubstituted or one or more R ３－２ In the case of a 3 to 10 member cycloalkyl group substituted with C ３ -C ６ It is a cycloalkyl group, which may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, and each R ３－２ R is independently, preferably, a halogen or a hydroxyl group, and is unsubstituted or one or more R groups. ３－２ The 3 to 10-membered cycloalkyl group substituted with is preferably, 【Chemistry 61】 And, and / or, R ３ is unsubstituted or one or more R ３－４ C replaced by １ -C ６ If it is an alkyl group, then C １ -C ６ The alkyl group is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, primary pentyl group, sec-pentyl group, tert-pentyl group, or neopentyl group, and may also be a methyl group, ethyl group, propyl group, isopropyl group, or isopentyl group, each R ３－４ These are, independently and preferably, deuterium, halogen, hydroxyl group, and -SO ２ -R ａ or 【Transformation 62】 And R ａ C １ -C ６ It is an alkyl group (preferably each R ３－４ These are, independently and preferably, halogens, hydroxyl groups, and -SO4. ２ -R ａ or 【Transformation 63】 And R ａ C １ -C ６ (It is an alkyl group), R ｂ is hydrogen, and the unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl groups are 【Chemistry 64】 Even if that is the case, and / or, R ３ is unsubstituted or one or more R ３－７ C replaced by １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group or tert-butoxy group, and may also be a methoxy group, ethoxy group or isopropoxy group, each R ３－７ These are, independently and preferably, deuterium or halogen (preferably, each R ３－７ (which are independently, preferably halogens), the unsubstituted or one or more R ３－７ C replaced by １ -C ６ The alkoxy group is preferably a methoxy group. 【Transformation 65】 It is an isopropoxy group or a trifluoromethoxy group, and / or, R ３ R ３－８ If it is a hydroxyl group substituted with, ３－８ is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein the heteroatom of the 3- to 6-membered heterocycloalkyl group is oxygen, and the number of heteroatoms is 1, and the R ３－８ The hydroxyl group substituted with is preferably, 【Chemical 66】 And, and / or, R ３ but 【Transformation 67】 If R ａ H is, and / or each R ３－１ , R ３－２ , R ３－４ , R ３－５ , R ３－６ and R ３－７ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each R ３－１ , R ３－２ , R ３－４ , R ３－５ , R ３－６ and R ３－７ However, independently, non-substitutable or one or more R ３－１－１ In the case of a 3 to 11-membered heterocycloalkyl group substituted with, the 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 preferably N and / or O, the number of heteroatoms is one or two, and the unsubstituted or one or more R ３－１－１ The substituted 3 to 11-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, an oxetanyl group, or a spiroheptyl group containing one oxygen and / or one nitrogen, for example, 【Transformation 68】 And, and / or each R ３－１－１ , R ３－１－３ , R ３－１－４ and R ３－１－５ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an 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 primary butyl group, a sec-butyl group, or a tert-butyl group, and may further be a methyl group or an ethyl group. and / or each R ３－１－１ , R ３－１－３ , R ３－１－４ and R ３－１－５ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or, L ０ is unsubstituted or one or more L ０ －２ In the case of a 5- to 12-membered cycloalkylene group substituted with, the 5- to 12-membered cycloalkylene group is spirocyclylene, crosslinked cyclylene, or condensed cyclylene. 【Transformation 69】 It may also be the case that a, b, c, and d are independently 0, 1, or 2, for example, 【Transformation 70】 And furthermore, for example, 【Chemistry 71】 Here, the a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, L ０ is unsubstituted or one or more L ０ －３ In the case of a 5- to 12-membered heterocycloalkylene group substituted with, the 5- to 12-membered heterocycloalkylene group is a monocyclic, spirocyclylene, crosslinked cyclylene, or condensed cyclylene, and further 【Chemistry 72】 It may also be that 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, 【Transformation 73】 And furthermore, for example, 【Chemistry 74】 Here, the a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or each L ０ －２ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ The alkyl group may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group, or tert-butyl group, and may further be a methyl group, ethyl group, or isopropyl group, and the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －２ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －２ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the case of an alkoxy group, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －２ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group, or tert-butoxy group, and may further be a methoxy group, ethoxy group, or isopropoxy group. and / or each L ０ －３ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ The alkyl group may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group, or tert-butyl group, and may further be a methyl group, ethyl group, or isopropyl group, and the halogen may be fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －３ However, if it is a halogen independently, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －３ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the case of an alkoxy group, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or each L ０ －３ However, independently, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the case of an alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group, or tert-butoxy group, and may further be a methoxy group, ethoxy group, or isopropoxy group. and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－１ C replaced by １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－２ In the case of a 3 to 10-membered cycloalkyl group substituted with, the 3 to 10-membered cycloalkyl group is a 3 to 6-membered cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－３ In the case of a 3 to 11-membered heterocycloalkyl group substituted with, the 3 to 11-membered heterocycloalkyl group is a 5 to 8-membered heterocycloalkyl group, and 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 one or two, preferably the heteroatoms of the 3 to 11-membered heterocycloalkyl group are N, S, or O, and the number of heteroatoms is one or two, and the 3 to 11-membered heterocycloalkyl group is preferably a piperadinyl group, piperidinyl group, tetrahydropyrrolyl group, azabicyclo[2.2.2]octyl group, azabicyclo[3.2.1]octyl group, azaspiro[3.3]heptyl group, or azabicyclo[2.2.1]heptyl group, for example, 【Chemistry 75】 And, and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－３ In the case of a 3 to 11-membered heterocycloalkyl group substituted with, the 3 to 11-membered heterocycloalkyl group is a 5 to 8-membered heterocycloalkyl group, and 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 one or two, preferably the heteroatoms of the 3 to 11-membered heterocycloalkyl group are N, S, or O, and the number of heteroatoms is one or two, and the 3 to 11-membered heterocycloalkyl group is preferably a piperadinyl group, a piperidinyl group, a tetrahydropyrrolyl group, an azabicyclo[2.2.2]octyl group, an azabicyclo[3.2.1]octyl group, an azaspiro[3.3]heptyl group, or an azabicyclo[2.2.1]heptyl group. and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－４ In the case of a 6 to 10-membered aryl group substituted with, the 6 to 10-membered aryl group is a benzene ring or a naphthalene ring, and / or each R ａ and each R ｂ However, independently, non-substitutable or one or more R ａ－５ In the case of a 5- to 10-membered heteroaryl group substituted with, the 5- to 10-membered heteroaryl group is a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 6-membered heteroaryl group is preferably a pyridyl group, pyridadinyl group, pyrazinyl group, pyrimidinyl group or triazinyl group, and the 5-membered heteroaryl group is preferably a pyrazolyl group, thiazolyl group or imidazolyl group. and / or, the ring Cy ３ In this, the 5- to 12-membered heterocycle is a 5- to 6-membered heterocycle, the heteroatoms of the 5- to 12-membered heterocycle are preferably N, S, or O, the number of heteroatoms is one or two, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring. and / or, Cy ３－１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, the ring Cy ４ In this, the 5- to 12-membered heterocycle is a 5- to 6-membered heterocycle, the heteroatoms of the 5- to 6-membered heterocycle are preferably N, S, or O, the number of heteroatoms is one or two, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a piperidine ring. and / or, Cy ４－１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, the ring Cy ５ In this, the 5- to 12-membered heterocycle is a 5- to 6-membered heterocycle, the heteroatoms of the 5- to 12-membered heterocycle are preferably N, S, or O, the number of heteroatoms is one or two, and the 5- to 12-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a tetrahydropyrrole ring. and / or, Cy ５－１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, Cy ６ In this, the 6 to 10 membered aromatic ring is a benzene ring or a naphthalene ring. and / or, Cy ６－１ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, Cy ６－１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, the ring Cy ７ In this, 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, pyridazine ring, pyrazine ring, pyrimidine ring, or triazine ring, and the 5-membered heteroaromatic ring is preferably a pyrazole ring, oxazole ring, thiazole ring, or imidazole ring, for example, 【Transformation 76】 And, and / or, Cy ７－１ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, Cy ７－１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may also be a methyl group. and / or, R ４ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It may be an alkyl group, and further may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and further may be a tert-butyl group. and / or, R ４ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, R ５ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, L ３ －１ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, and may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group, or tert-butyl group, for example, a methyl group. and / or, the ring Cy １ If the compound is a 5- to 12-membered heterocycle, the heteroatoms of the 5- to 12-membered heterocycle are N, S, or O, and the number of heteroatoms is one or two. The 5- to 12-membered heterocycle may also be an oxetane ring, a diazaspiro[3.3]heptane, a tetrahydrofuran ring, a piperidine ring, a piperazine ring, a diazaspiro[3.5]nonane, azaspiro[3.3]heptane, azaspiro[5.5]undecane, azaspiro[3.5]nonane, or azaspiro[5.5]undecane. and / or, the ring Cy １ If the cycloalkane is a 3 to 12-membered cycloalkane, then the 3 to 12-membered cycloalkane is a 3 to 6-membered cycloalkane, for example, cyclohexane. and / or, the ring Cy ２ When 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, the number of heteroatoms is one or two, the 5- to 10-membered heteroaromatic ring is preferably a 5-membered or 6-membered heteroaromatic ring, the 6-membered heteroaromatic ring is preferably a pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, or triazine ring, and the 5-membered heteroaromatic ring is preferably a pyrazole ring, thiazole ring, or imidazole ring. and / or, L ２ １－１ and L ２ １－２ In the case of C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, L ２ １－１ and L ２ １－２ In the case of C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group, or tert-butoxy group, and may further be a methoxy group, ethoxy group, or isopropoxy group. and / or, L ２ １－１ and L ２ １－２ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. and / or, L ２ １－３ In this, the halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, L ２ １－３ In this case, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the alkyl group, the C １ -C ６ Alkyl alkyl groups are C １ -C ４ The alkyl group may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group, or tert-butyl group, and may further be a methyl group, ethyl group, or isopropyl group, and the halogen is preferably fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, L ２ １－３ In this case, C is unsubstituted or substituted with one or more halogens. １ -C ６ In the alkoxy group, the C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group, or tert-butoxy group, and may further be a methoxy group, ethoxy group, or isopropoxy group, and the halogen is preferably fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, L ２ １－３ In this case, the unsubstituted or one or more L ２ １－３－１ In a 3 to 10-membered cycloalkyl group substituted with C, the 3 to 10-membered cycloalkyl group is C ３ -C ６ It is a cycloalkyl group, which may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, each L ２ １－３－１ These are, independently, preferably a halogen or a hydroxyl group. and / or, L ２ １－３ In this case, the unsubstituted or one or more L ２ １－３－２ In a 3 to 11-membered heterocycloalkyl group substituted with , the 3 to 11-membered heterocycle is a 4 to 9-membered heterocycle, the heteroatoms of the 4 to 9-membered heterocycle are preferably one or two of N, S, and O, the number of heteroatoms is one or two, and the 3 to 11-membered heterocycle may be a tetrahydropyrrole ring, a piperidine ring, a tetrahydrofuran ring, or a tetrahydrothiophene ring, for example, a piperidine ring. and / or, L ２ １－３－１ and L ２ １－３－２ In the case of C １ -C ６ The alkoxy group is C １ -C ４ The alkoxy group may be a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, primary butoxy group, sec-butoxy group, or tert-butoxy group, and may further be a methoxy group, ethoxy group, or isopropoxy group. and / or, R ｃ is unsubstituted or one or more R ｃ－１ C replaced by １ -C ６ If it is an alkyl group, then C １ -C ６ Alkyl alkyl groups are C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. And / or, in LLM, p is 0 or 1, and / or, L ２ In this case, m is 1 or 2, and / or, L ２ In this case, q is either 1 or 2. and / or, L ３ In this case, m is 1 or 2, and / or, L ３ In this case, q is either 1 or 2. and / or, 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 this, the 6 to 10 membered aryl group is independently a phenyl group or a naphthyl group. and / or, 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, said C １ -C ６ alkoxy group is independently a C １ -C ４ alkoxy group, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, and further for example, a methoxy group, and / or, 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 this, the halogen may independently be fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. and / or, 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 case of C １ -C ６ Alkyl alkyl groups are independently C １ -C ４ It is an alkyl group, which may be a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, primary butyl group, sec-butyl group or tert-butyl group, and may further be a methyl group, ethyl group or isopropyl group. and / or, 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 which, the said 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 heteroatom of the said 3- to 11-membered heterocycloalkyl group is selected from one or two of N and O; the number of heteroatoms is one or two; the said 6-membered heterocycloalkyl group is preferably a piperazinyl group, a morpholinyl group or a piperidinyl group, for example, 【Chemical Formula 77】 The five-membered heterocycloalkyl group is preferably a tetrahydropyrrolyl group, for example, 【Transformation 78】 The 8-membered heterocycloalkyl group is preferably an azabicyclo[2.2.2]octyl group or an -azabicyclo[3.2.1]octyl group, for example, 【Chemistry 79】 The seven-membered heterocycloalkyl group is preferably an azaspiro[3.3]heptyl group or an azabicyclo[2.2.1]heptyl group, for example, 【Chemistry 80】 And, and / or, 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 this, the 3 to 10 membered cycloalkyl group is independently a 3 to 6 membered cycloalkyl group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. and / or, 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 this, the 5 to 10-membered heteroaryl group is independently a 5-membered heteroaryl group, a 6-membered heteroaryl group, and a 5-membered condensed 5-membered heteroaryl group, wherein the 6-membered heteroaryl group is preferably a pyridyl group, a pyridadinyl group, a pyrazinyl group, a pyrimidinyl group, or a triazinyl group, and the 5-membered heteroaryl group is preferably a pyrazolyl group, an oxazolyl group, a thiazolyl group, or an imidazolyl group, for example, 【Chemistry 81】 The 5- to 9-membered heteroaryl group is preferably a pyrazolyl group, a thiazolyl group, an imidazolyl group, a tetrahydropyrrolothiazolyl group, or a tetrahydropyrrolopyrazolyl group, for example, 【Chemistry 82】 The compound represented by formula I according to claim 3, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound represented by formula I, as described in claim 3.

5. R １ This is unsubstituted or one or more R １－１ A 5- to 10-membered heteroaryl group substituted with or unsubstituted or one or more R １－２ A 6- to 10-membered aryl group substituted with, 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 one, two, or three, R １ Preferably, the R is unsubstituted or one or more R １－１ A 5- to 9-membered heteroaryl group substituted with or unsubstituted or one or more R １－２ A 6- to 10-membered aryl group substituted with, the heteroatoms of the 5- to 9-membered heteroaryl group are selected from one or two of N, S, and O, and the number of heteroatoms is one, two, or three, R １ Preferably, the R is unsubstituted or one or more R １－１ A 5- to 9-membered heteroaryl group substituted with, wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or two of N and O, and the number of heteroatoms is one, two, or three. and / or each R １－１ and R １－２ These are, independently, halogens, hydroxyl groups, 【Chemistry 83】 -SO ２ -R ａ , -SO-R ａ , unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R １－１－７ A 5- to 10-membered heteroaryl group substituted with, or an unsubstituted or one or more R groups. １－１－１ A 3 to 11-membered heterocycloalkyl group substituted with, 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 one or two, preferably each R １－１ and R １－２ These are, independently, halogens, hydroxyl groups, 【Chemical 84】 -SO ２ -R ａ , -SO-R ａ , unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Alkyl alkyl group, or unsubstituted or one or more R １－１－７ A 5 to 10-membered heteroaryl group substituted with, 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 one or two, and each R １－１ and R １－２ These are independently, preferably, halogen, unsubstituted, or one or more R １－１－７ A 5- to 6-membered heteroaryl group substituted with or unsubstituted or one or more R １－１－４ C replaced by １ -C ６ The alkyl group is such that 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 one or two. and / or each R １－１－４ This is independently a halogen, and the halogen is preferably fluorine. and / or each R １－１－７ These are, independently, halogens, hydroxyl groups, unsubstituted or substituted with one or more halogens. １ -C ６ C15 is a carbon atom that has been substituted with an alkoxy group, a cyano group, a nitro group, is unsubstituted, or has been substituted with one or more halogens. １ -C ６ Alkyl alkyl group, unsubstituted or one or more R １－１－１－２ A 6- to 10-membered aryl group substituted with, or an unsubstituted or one or more R groups. １－１－１－３ A 5 to 10-membered heteroaryl group substituted with, 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 one, two, or three, and 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 one, two, or three, and each R １－１－７ These are, independently, preferably, unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, and / or each R １－１－１－１ , R １－１－１－２ and R １－１－１－３ These are, independently, halogen or C １ -C ６ It is an alkyl group, and / or, R ２ It is hydrogen, and / or, R ３ These are hydrogen, hydroxyl groups, halogens, cyano groups, 【Chemical 85】 Unsubstituted or one or more R ３－１ A 3 to 10-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ A 3- to 8-membered cycloalkyl group substituted with, unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group or R ３－８ A hydroxyl group substituted with, the heteroatoms of the 3 to 10-membered heterocycloalkyl group are selected from one or two of N and O, the number of heteroatoms is one, two or three, and R ３ Preferably, halogen, 【Chemical 86】 Unsubstituted or one or more R ３－１ A 3- to 6-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ C replaced by ３ -C ６ Cycloalkyl groups, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group, unsubstituted, or one or more R groups ３－４ C replaced by １ -C ６ Alkyl alkyl group, or R ３－８ A hydroxyl group substituted with, the heteroatoms of the 3 to 6 member heterocycloalkyl group are selected from one or two of N and O, the number of heteroatoms is one or two, preferably R ３ R is hydrogen, hydroxyl group, halogen, cyano group, unsubstituted or one or more R ３－１ A 3 to 10-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ A 3- to 8-membered cycloalkyl group substituted with, unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group or R ３－８ A hydroxyl group substituted with, the heteroatoms of the 3 to 10-membered heterocycloalkyl group are selected from one or two of N and O, the number of heteroatoms is one, two or three, and R ３ Preferably, the R is unsubstituted or one or more R ３－１ A 3- to 6-membered heterocycloalkyl group substituted with, unsubstituted or one or more R ３－２ C replaced by ３ -C ６ Cycloalkyl groups, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group, unsubstituted, or one or more R groups ３－４ C replaced by １ -C ６ Alkyl alkyl group, or R ３－８ A hydroxyl group substituted with, the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N and O, and the number of heteroatoms is one or two. and / or each R ３－１ , R ３－２ , R ３－４ and R ３－７ C is independently composed of deuterium, oxo, hydroxyl groups, halogens, 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups, or unsubstituted or substituted with one or more halogens. １ -C ６ The alkyl group is an alkyl group, and the heteroatoms of the 3 to 6-membered heterocycloalkyl group are selected from one or two of N, S, and O, and the number of heteroatoms is one or two, preferably each R ３－１ , R ３－２ , R ３－４ and R ３－７ C is independently an oxo, a hydroxyl group, a halogen, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ The alkyl group is such that the heteroatoms of the 3 to 6-membered heterocycloalkyl group are selected from one or two of N, S, and O, and the number of heteroatoms is one or two, and each R ３－１ Each R is independently preferably a hydroxyl group or a halogen, and each R ３－２ Each R is independently, preferably a hydroxyl group, and each R ３－４ Each R is independently preferably a deuterium, halogen, or hydroxyl group, more preferably a hydroxyl group, and each R ３－７ These 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, wherein 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 one, two, or three, R ３－８ Preferably, the heteroatom is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycloalkyl group, wherein the heteroatom of the 3- to 6-membered heterocycloalkyl group is selected from one or two of N and O, and the number of heteroatoms is one. and / or each R ａ and each R ｂ These are, independently, H or unsubstituted or one or more R ａ－１ C replaced by １ -C ６ Each R is an alkyl group. ａ and each R ｂ Independently, preferably, is H. and / or, L ０ This is unsubstituted or one or more L ０ －２ A 5- to 12-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 5 to 12-membered heterocycloalkylene group substituted with, wherein the 5 to 12-membered cycloalkylene group is a spiro ring, a fused ring, or a bridging ring, and the 5 to 12-membered heterocycloalkylene group is a monoring, a spiro ring, a fused ring, or a bridging ring, and the heteroatoms of the 5 to 12-membered heterocycloalkylene group are N, S, or O, and the number of heteroatoms is one, two, or three, and each L ０ －２ These are, independently, deuterium, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, deuterium, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, Preferably, L ０ This is unsubstituted or one or more L ０ －２ A 5- to 12-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 5 to 12-membered heterocycloalkylene group substituted with, wherein the 5 to 12-membered cycloalkylene group is a spiro ring, a fused ring, or a bridging ring, and the 5 to 12-membered heterocycloalkylene group is a monoring, a spiro ring, a fused ring, or a bridging ring, and the heteroatoms of the 5 to 12-membered heterocycloalkylene group are N, S, or O, and the number of heteroatoms is one, two, or three, and each L ０ －２ These are, independently, halogens, hydroxyl groups, or unsubstituted or substituted C with one or more halogens. １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, halogens, hydroxyl groups, or unsubstituted or substituted C with one or more halogens. １ -C ６ It is an alkyl group, preferably L ０ This is unsubstituted or one or more L ０ －２ A 7 to 11-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 7 to 11-membered heterocycloalkylene group substituted with, the 7 to 11-membered cycloalkylene group is a spiro ring, the 7 to 11-membered heterocycloalkylene group is a spiro ring, the heteroatom of the 7 to 11-membered heterocycloalkylene group is N, the number of heteroatoms is one or two, each L ０ －２ These are, independently, halogens, hydroxyl groups, or unsubstituted or substituted C with one or more halogens. １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, halogens, hydroxyl groups, or unsubstituted or substituted C with one or more halogens. １ -C ６ It is an alkyl group, more preferably L ０ This 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, the heteroatom of the 7- to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is 1. and / or, L ２ In R ｃ C is either H or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, more preferably H, and / or, the ring Cy ３ is non-substitutable or one or more Cy ３－１ A 5- to 6-membered heterocycle substituted with, wherein the heteroatom of the 5- to 6-membered heterocycle is N, S, or O, and there is one such heterocycle, and the ring Cy ３ Preferably, unsubstituted or multiple Cy ３－１ It is a 5- to 6-membered heterocycle substituted with, and the heteroatom of the 5- to 6-membered heterocycle is N, and there is one such heteroatom. and / or each Cy ３－１ It is independently oxo, and / or, the ring Cy ４ is non-substitutable or one or more Cy ４－１ A 5- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 5- to 8-membered heterocycle are selected from one or more of N, S, and O, and the number of heteroatoms is one, two, or three, and the ring Cy ４ Preferably, unsubstituted or one or more Cy ４－１ A 5- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 5- to 8-membered heterocycle is N, S, or O, and the number of heteroatoms is 1. and / or each Cy ４－１ Independently, C １ -C ６ A compound represented by formula I according to claim 1, characterized in that it is an alkyl group, a hydroxyl group, or an oxo group, preferably an oxo group, a pharmaceutically acceptable salt or isotope thereof.

6. L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Transformation 87】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemical 88】 Unsubstituted or one or more L ２ １－２ Replaced with 【Chemical 89】 Or non-substituted or one or more L ２ １－３ Replaced with 【Chemistry 90】 The ring Cy is formed when m is an integer from 1 to 4, q is an integer from 1 to 6, X does not exist or is O, and １ The ring Cy ２ The is a 5- to 10-membered heteroaromatic ring or a 6- to 10-membered aromatic ring, and 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 one, two, or three, and 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 one, two, or three, preferably L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 91】 Preferably, L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 92】 And here, the a' end is L ０ The compound represented by formula I according to claim 3, characterized in that the b' terminus is toward the LLM, and the b' terminus is toward the LLM, a pharmaceutically acceptable salt or isotope thereof.

7. R １ This is unsubstituted or one or more R １－１ A 5- to 10-membered heteroaryl group substituted with or unsubstituted or one or more R １－２ A 6- to 10-membered aryl group substituted with, 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 one or two, R １ Preferably, the R is unsubstituted or one or more R １－１ A 5- to 6-membered heteroaryl group substituted with or unsubstituted or one or more R １－２ A 6- to 10-membered aryl group substituted with, wherein 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 one or two. and / or each R １－１ and R １－２ These are, independently, halogen, unsubstituted, or one or more R １－１－７ A 5- to 6-membered heteroaryl group substituted with or unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Alkyl alkyl group, or unsubstituted or one or more R １－１－１ A 5 to 10-membered heterocycloalkyl group substituted with, wherein 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 one or two, and each R １－１ These are independently, preferably unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Algebraic group, unsubstituted, or one or more R's １－１－１ A 5 to 10-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 5 to 10-membered heterocycloalkyl group are selected from one or two of N and O, and the number of heteroatoms is one or two. and / or, L ０ This is unsubstituted or one or more L ０ －２ A 7 to 11-membered cycloalkylene group substituted with or unsubstituted or one or more L ０ －３ A 7 to 11-membered heterocycloalkylene group substituted with, the 7 to 11-membered cycloalkylene group is a spiro ring, the 7 to 11-membered heterocycloalkylene group is a spiro ring or a fused ring, the heteroatom of the 7 to 11-membered heterocycloalkylene group is N, the number of heteroatoms is one or two, and each L ０ －２ These are, independently, deuterium, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, and each L ０ －３ These are, independently, deuterium, halogen, hydroxyl group, or unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, preferably L ０ The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, wherein 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 fused ring, the heteroatom of the 7 to 11-membered heterocycloalkylene group is N, and the number of heteroatoms is one or two.

8. R １ is one or more R １－１ A pyridyl group substituted with or one or more R １－１ Replaced with 【Chemistry 93】 And, and / or each R １－１ These are independently, unsubstituted, or one or more R's. １－１－４ C replaced by １ -C ６ It is an alkyl group, or each R １－１ These are independently, unsubstituted, or one or more R's. １－１－１ A 7- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 7- to 8-membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is 2. and / or, R ３ This is unsubstituted or one or more R ３－４ C replaced by １ -C ６ Algebraic group, unsubstituted, or one or more R's ３－７ C replaced by １ -C ６ It is an alkoxy group, and / or, R ３ multiple R ３－４ C replaced by １ -C ６ If it is an alkyl group, then at least one R ３－４ These are a hydroxyl group, deuterium and a hydroxyl group, or a halogen and a hydroxyl group. and / or, L ０ is a 9 to 11-membered spiroheterocyclylene group, where the heteroatom of the 9 to 11-membered spiroheterocyclylene group is N, the number of heteroatoms is 1, and preferably the 9 to 11-membered spiroheterocyclylene group is 【Chemical 94】 Here, the a' end is connected to the ring Cy, and the b' end is L ２ A compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt or isotope thereof, which is linked to a compound represented by

9. L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemical 95】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 96】 Unsubstituted or one or more L ２ １－２ Replaced with 【Chemistry 97】 Or non-substituted or one or more L ２ １－３ Replaced with 【Chem.98】 The ring Cy １ is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane, wherein the heteroatoms of the 4- to 11-membered heterocycle are N and / or O, the number of heteroatoms is one or two, the 4- to 11-membered heterocycle is a monocycle, a bridging ring or a spirocycle, and the 4- to 6-membered cycloalkane is a monocycle, and the ring Cy ２ is a 5- to 6-membered heteroaromatic ring, the heteroatoms of the 5- to 6-membered heteroaromatic ring are N and / or O, the number of heteroatoms is one or two, preferably L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chem.99】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 100】 Or non-substituted or one or more L ２ １－２ Replaced with 【Chemistry 101】 The ring Cy １ is a 4- to 11-membered heterocycle or a 4- to 6-membered cycloalkane, wherein the heteroatoms of the 4- to 11-membered heterocycle are N and / or O, the number of heteroatoms is one or two, the 4- to 11-membered heterocycle is a monocycle, a bridging ring or a spirocycle, and the 4- to 11-membered cycloalkane is a monocycle, a bridging ring or a spirocycle. And / or, if the 4 to 11-membered heterocycle is a monocycle, then the 4 to 11-membered heterocycle is a 3 to 6-membered heterocycle, the heteroatoms of the 4 to 11-membered heterocycle are N or O, the number of heteroatoms is one or two, and / or, if the 4 to 11-membered heterocycle is a spirocycle, then the 4 to 11-membered heterocycle is a 4,6-azaspiror, a 6,6-azaspiror, or a 4,4-azaspiror. Preferably, L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemical Engineering 102】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 103】 Unsubstituted or one or more L ２ １－２ Replaced with 【Chemical 104】 Or non-substituted or one or more L ２ １－３ Replaced with 【Chemistry 105】 The ring Cy １ is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, wherein the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is one or two, and the 4- to 10-membered heterocycle is a 6-membered monocycle, a 4,4-azaspiro ring, or a 4,6-azaspiro ring, R ｃ is H, and the ring Cy ２ is a five-membered heteroaromatic ring, the heteroatom of the five-membered heteroaromatic ring is N, the number of heteroatoms is 2, and the five-membered heteroaromatic ring is preferably a pyrazole ring, L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It is, independently, preferably, not present. 【Chemistry 106】 Unsubstituted or one or more L ２ １－１ Replaced with 【Chemistry 107】 Or non-substituted or one or more L ２ １－２ Replaced with 【Chemistry 108】 The ring Cy １ is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is one or two, the 4- to 10-membered heterocycle is a 6-membered monocycle or a 4,6-azaspiro ring, R ｃ H is, More preferably, L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 109】 And m is 1 or 2, q is 1, X does not exist, and the ring Cy １ is a 4- to 10-membered heterocycle or a 4- to 6-membered cycloalkane, wherein the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is one or two, and the 4- to 6-membered cycloalkane is a 6-membered monocycle, R ｃ is H, and the ring Cy ２ It is a five-membered heteroaromatic ring, and the heteroatom of the aforementioned five-membered heteroaromatic ring is N, and the number of heteroatoms is two, for example, a pyrazole ring and L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ It is, independently, preferably, not present. 【Chemical 110】 And m is 1 or 2, q is 1, X does not exist, and the ring Cy １ is a 4- to 6-membered heterocycle or a 4- to 6-membered cycloalkane, the heteroatom of the 4- to 10-membered heterocycle is N, the number of heteroatoms is one or two, the 4- to 6-membered cycloalkane is a 6-membered monocycle, R ｃ H is, more, L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - or 【Chemistry 111】 And L ２ －１ teeth, 【Chemistry 112】 And L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 113】 Or non-substituted or one or more L ２ １－２ Replaced with 【Chemistry 114】 And the ring Cy １ The compound represented by formula I according to claim 3, characterized in that it is a 4- to 6-membered heterocycle, the heteroatom of the 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, and the 4- to 6-membered heterocycle is a monocycle, a pharmaceutically acceptable salt or isotope thereof.

10. The five-membered condensed six-membered compound shown in formula I is a compound shown in formulas I-a, I-b, I-d, I-g, I-h, I-i, I-k, I-m, I-n, I-o, I-p, I-q, or I-r. 【Chemical 115】 【Chemistry 116】 The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound represented by formula I, as described in claim 1.

11. LLM is 【Chemistry 117】 Preferably, 【Chemistry 118】 And, moreover, 【Chemical 119】 For example, 【Chemical 120】 And, and / or, R １ teeth, 【Chemistry 121】 Preferably, 【Chemistry 122】 And, and / or, R ３ These include methoxy groups, isopropoxy groups, difluoromethoxy groups, trifluoromethoxy groups, carboxyl groups, fluorine, 【Chemical 123】 Preferably, a methoxy group, 【Chemistry 124】 And, and / or, 【Chemistry 125】 teeth, 【Chemistry 126】 For example, 【Chemistry 127】 And, and / or, L ０ teeth, 【Chemistry 128】 Preferably, L ０ teeth, 【Chemistry 129】 Here, the a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, preferably L ０ teeth, 【Chemistry 130】 Here, the a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, L ２ teeth, 【Chemistry 131】 【Chemistry 132】 Preferably, L ２ teeth, 【Chemistry 133】 【Chemistry 134】 【Chemistry 135】 And here, the a' end is L ０ It is connected to the b' end, and the b' end is connected to the LLM. and / or, L ０ but 【Transformation 136】 (Furthermore, L ０ is unsubstituted or one or more L ０ －３ If it is a 5- to 12-membered heterocycloalkylene group substituted with L ２ teeth, 【Chemistry 137】 【Chemistry 138】 【Chemistry 139】 Preferably, L ０ but [Chemistry 140] (Furthermore, L ０ is unsubstituted or one or more L ０ －３ If it is a 5- to 12-membered heterocycloalkylene group substituted with L ２ teeth, 【Chemistry 141】 【Chemistry 142】 【Chemistry 143】 And here, L ２ The a' end is L ０ It is connected to L ２ The b' end is ligated to the LLM, and / or, in the compound shown in formula I, 【Chemistry 144】 teeth, 【Chemistry 145】 And X is N or CH, and X １ is either S or O, More preferably, in the compound shown in formula I, 【Chemistry 146】 teeth, 【Chemistry 147】 【Chemistry 148】 The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound represented by formula I, as described in claim 1.

12. R １ but 【Chemistry 149】 If L ０ teeth, [Chemical 150] The a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, R １ but 【Chemistry 151】 If L ０ teeth, 【Chemistry 152】 The a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, R １ but 【Chemistry 153】 If L ０ teeth, 【Chemistry 154】 The a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, R １ but 【Chemistry 155】 If L ２ -teeth, 【Chemistry 156】 And the a' end is L ０ It is connected to the b' end, and the b' end is connected to the LLM. and / or, R １ but 【Chemistry 157】 If L ２ -teeth, 【Chemistry 158】 And the a' end is L ０ It is connected to the b' end, and the b' end is connected to the LLM. and / or, R １ but 【Chemistry 159】 If L ２ -teeth, [Chemical 160] And the a' end is L ０ A compound represented by formula I according to claim 1, characterized in that it is linked to a , and its b' terminus is linked to an LLM, a pharmaceutically acceptable salt or isotope thereof.

13. -L ０ -L ２ -teeth, 【Chemistry 161】 The a' end is connected to the ring Cy, and the b' end is connected to LLM. or -L ０ -L ２ -teeth, 【Chemistry 162】 The a' end is connected to the ring Cy, and the b' end is connected to LLM. Preferably, 【Chemistry 163】 The compound represented by formula I according to claim 1, characterized in that the a' terminus is linked to a ring Cy and the b' terminus is linked to LLM, a pharmaceutically acceptable salt or isotope thereof. 【Request Item 14】 【Chemistry 164】 If that is the case, -L ０ -L ２ -teeth, 【Chemistry 165】 The a' end is connected to the ring Cy, and the b' end is connected to the LLM, preferably, 【Chemistry 166】 The a' end is connected to the ring Cy, and the b' end is connected to LLM. and / or, 【Chemistry 167】 If that is the case, -L ０ -L ２ -teeth, 【Chemical 168】 The a' end is connected to the ring Cy, and the b' end is connected to LLM. and / or, 【Chemistry 169】 If that is the case, -L ０ -L ２ -teeth, 【Chemistry 170】 The compound represented by formula I according to claim 1, characterized in that the a' terminus is linked to a ring Cy and the b' terminus is linked to LLM, a pharmaceutically acceptable salt or isotope thereof.

15. The compound shown in formula I is the compound shown in formula I-d, 【Chemistry 171】 Here, R １ is one or more R １－１ A pyridyl group substituted with or one or more R １－１ Replaced with 【Chemistry 172】 And, R １ One or more R １－１ If the pyridyl group is substituted with, each R １－１ These are, independently, one or more R １－１－４ C replaced by １ -C ６ It is an alkyl group, R １ One or more R １－１ Replaced with 【Chemistry 173】 If so, each R １－１ This is unsubstituted or one or more R １－１－１ A 7- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 7- to 8-membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is 2. Each R １－１－４ Each R is independently a halogen, and １－１－１ C is independently substituted with one or more halogens. １ -C ６ It is an alkyl group, R ２ It is hydrogen, R ３ This is unsubstituted or one or more R ３－４ C replaced by １ -C ６ Algebraic group, unsubstituted, or one or more R's ３－７ C replaced by １ -C ６ It is an alkoxy group, Each R ３－４ R is independently deuterium, halogen, or hydroxyl group, and each R ３－７ It is independently deuterium, L ０ This is a 9- to 11-membered spiroheterocyclylene group, where the heteroatom of the 9- to 11-membered spiroheterocyclylene group is N, and the number of heteroatoms is 1. L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - or 【Chemistry 174】 And L ２ －１ teeth, 【Chemistry 175】 And L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 176】 Or non-substituted or one or more L ２ １－２ Replaced with 【Chemistry 177】 And the ring Cy １ It is a 4- to 6-membered heterocycle, the heteroatom of the 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, and the 4- to 6-membered heterocycle is a monocycle, each L ２ １－２ It is independently a hydroxyl group, LLM is 【Chemistry 178】 And, Ring Cy ３ is non-substitutable or multiple Cy ３－１ A 5- to 6-membered heterocycle substituted with, wherein the heteroatoms of the 5- to 6-membered heterocycle are N, S, or O, and the number of heteroatoms is 1, Cy ３－１ It is independently oxo, Ring Cy ４ is non-substitutable or one or more Cy ４－１ A 5- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatom of the 5- to 8-membered heterocycle is N, S, or O, and the number of heteroatoms is 1, Cy ４－１ It is independently oxo, Each R ５ It is, independently, a halogen, The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, characterized in that p is 0, 1, 2, or 3.

16. R １ is one or more R １－１ A pyridyl group substituted with or one or more R １－１ Replaced with 【Chemistry 179】 And, and / or, R １ One or more R １－１ If the pyridyl group is substituted with, each R １－１ These are, independently, one or more R １－１－４ C replaced by １ -C ６ It is an alkyl group, and / or, R １ One or more R １－１ Replaced with 【Transformation 180】 If so, each R １－１ This is unsubstituted or one or more R １－１－１ A 7- to 8-membered heterocycloalkyl group substituted with, wherein the heteroatoms of the 7- to 8-membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is 2. and / or each R １－１－４ These are independently fluorine, chlorine, or bromine, preferably fluorine. and / or, R １－１ However, independently, multiple R １－１－４ C replaced by １ -C ６ In the case of alkyl groups, the plurality is two or three, preferably three. and / or each R １－１－１ C is independently substituted with one or more halogens. １ -C ６ It is an alkyl group, and / or, R ３ This is unsubstituted or one or more R ３－４ C replaced by １ -C ６ Algebraic group, unsubstituted, or one or more R's ３－７ C replaced by １ -C ６ It is an alkoxy group, and / or each R ３－４ These are independently deuterium, halogen, or hydroxyl group. and / or each R ３－７ It is independently deuterium, and / or, R ３ multiple R ３－４ C replaced by １ -C ６ If it is an alkyl group, then at least one R ３－４ These are a hydroxyl group, deuterium and a hydroxyl group, or a halogen and a hydroxyl group. and / or, L ０ This is a 9- to 11-membered spiroheterocyclylene group, where the heteroatom of the 9- to 11-membered spiroheterocyclylene group is N, and the number of heteroatoms is 1. and / or, L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - or 【Chemistry 181】 And L ２ －１ teeth, 【Chemistry 182】 And L ２ －２ , L ２ －３ and L ２ －４ It does not exist independently. 【Chemistry 183】 Or non-substituted or one or more L ２ １－２ Replaced with 【Chemistry 184】 And the ring Cy １ It is a 4- to 6-membered heterocycle, the heteroatom of the 4- to 6-membered heterocycle is N, the number of heteroatoms is 1, and the 4- to 6-membered heterocycle is a monocycle. and / or each L ２ １－２ The compound represented by formula I according to claim 1, characterized in that is independently a hydroxyl group, a pharmaceutically acceptable salt or isotope thereof.

17. R １ This is unsubstituted or one or more R １－１ A 5- to 9-membered heteroaryl group substituted with a pyridyl group, an oxazolyl group, a pyrazolyl group, or 【Chemistry 185】 And, and / or each R １－１ This is unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R １－１－１ A 3 to 11-membered heterocycloalkyl group substituted with or unsubstituted or one or more R １－１－７ A 5- to 10-membered heteroaryl group substituted with, 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 one or two; and 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 one, two, or three. and / or each R １－１－４ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ It is an alkyl group, and / or each R １－１－７ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ It is an alkyl group, and / or each R １－１－１ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ Each R is an alkyl group. １－１－１ These are, independently, preferably, unsubstituted or substituted with one or more halogens. １ -C ６ It is an alkyl group, and / or, R ３ This is unsubstituted or one or more R ３－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R ３－７ C replaced by １ -C ６ Alkoxy group or unsubstituted or one or more R ３－１ A tetrahydropyrrolyl group substituted with, and / or each R ３－１ These are independently deuterium, a hydroxyl group, or a halogen. and / or each R ３－４ These are independently deuterium, halogen, or hydroxyl group. and / or each R ３－７ These are independently deuterium or a hydroxyl group. and / or, L ０ is an 8- to 11-membered cycloalkylene group or an 8- to 11-membered heterocycloalkylene group, wherein 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, the number of heteroatoms is 1, preferably the 8- to 11-membered cycloalkylene group is 【Chemistry 186】 The 8 to 11 member heterocycloalkylene group is, 【Chemistry 187】 The a' end is connected to the ring Cy, and the b' end is L ２ It is connected to, and / or, L ２ This is one of the following cases: In case (1), L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ and L ２ －２ It does not exist, L ２ －３ teeth, 【Chemical 188】 And L ２ －４ This is unsubstituted or one or more L ２ １－２ Replaced with 【Chemical 189】 And the ring Cy １ is a piperidinyl group or piperadinyl group, preferably L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ and L ２ －２ It does not exist, L ２ －３ teeth, 【Chemistry 190】 And L ２ －４ is an unsubstituted ring Cy １ And the ring Cy １ This is a piperidinyl group or a piperazinyl group, In case (2), L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ It does not exist, L ２ －２ , L ２ －３ and L ２ －４ Independently, 【Chemistry 191】 Or non-substituted or one or more L ２ １－２ The ring Cy substituted with １ And the ring Cy １ This is a cyclohexyl group, a piperidinyl group, or a piperazinyl group. In case (3), L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ Independently, 【Chemistry 192】 Or non-substituted or one or more L ２ １－２ The ring Cy substituted with １ And the ring Cy １ This is a cyclohexyl group, a piperidinyl group, or a piperazinyl group. and / or each L ２ １－２ These are independently a halogen or a hydroxyl group, And / or LLM is, 【Chemistry 193】 for example, 【Chemistry 194】 And furthermore, for example, 【Chemistry 195】 The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound represented by formula I, as described in claim 1.

18. The compound shown in formula I is the compound shown in formula I-d, 【Chemistry 196】 Here, R １ This is unsubstituted or one or more R １－１ A 5- to 9-membered heteroaryl group substituted with, wherein the heteroatoms of the 5- to 9-membered heteroaryl group are one or two of N and O, and the number of heteroatoms is one, two, or three. Each R １－１ This is unsubstituted or one or more R １－１－４ C replaced by １ -C ６ Alkyl alkyl group, unsubstituted or one or more R １－１－１ A 3 to 11-membered heterocycloalkyl group substituted with or unsubstituted or one or more R １－１－７ A 5- to 10-membered heteroaryl group substituted with, 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 one or two; and 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 one or two. Each R １－１－１ , R １－１－４ and R １－１－７ C is independently halogenated, unsubstituted, or substituted with one or more halogens. １ -C ６ It is an alkyl group, R ３ This is unsubstituted or one or more R ３－４ C replaced by １ -C ６ Algebraic group, unsubstituted, or one or more R's ３－７ C replaced by １ -C ６ Alkoxy group or unsubstituted or one or more R ３－１ A tetrahydropyrrolyl group substituted with, Each R ３－１ R is independently deuterium, halogen, or hydroxyl group, and each R ３－４ R is independently deuterium, halogen, or hydroxyl group, and each R ３－７ These are independently deuterium or a hydroxyl group. L ０ This 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 one. L ２ This is one of the following cases: In case (1), L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ and L ２ －２ It does not exist, L ２ －３ teeth, 【Chemistry 197】 And L ２ －４ This is unsubstituted or one or more L ２ １－２ The ring Cy1 is substituted with a piperidinyl group or a piperadinyl group, and each L ２ １－２ These are independently a halogen or a hydroxyl group, In case (2), L ２ is, -L ２ －１ -L ２ －２ -L ２ －３ -L ２ －４ - and L ２ －１ It does not exist, L ２ －２ , L ２ －３ and L ２ －４ Independently, 【Chemistry 198】 Or non-substituted or one or more L ２ １－２ The ring Cy1 is substituted with a cyclohexyl group, a piperidinyl group, or a piperadinyl group, and each L ２ １－２ These are independently a halogen or a hydroxyl group, In case (3), L ２ is, -L ２－１ -L ２－２ -L ２－３ -L ２－４ - and L ２ －１ , L ２ －２ , L ２ －３ and L ２ －４ Independently, 【Chemistry 199】 Or non-substituted or one or more L ２ １－２ The ring Cy1 is substituted with a cyclohexyl group, a piperidinyl group, or a piperadinyl group, and each L ２ １－２ These are independently a halogen or a hydroxyl group, LLM is 【Chemistry 200】 The compound represented by formula I according to claim 1, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound represented by formula I, as described in claim 1.

19. A compound, a pharmaceutically acceptable salt thereof, or an isotopic compound, wherein the compound is 【Chemical Engineering 201】 【Chemical Engineering 202】 【Chemical 203】 【Chemical 204】 【Chemical 205】 【Chemical 206】 【Chemical 207】 A compound characterized by being one of the following compounds, a pharmaceutically acceptable salt or isotope thereof. 【Request Item 20】 【Chemistry 208】 teeth, 【Chemical Engineering 209】 is, or, 【Chemical 210】 The chromatograph column is IH 25 x 250 mm, 10 μm (Daicel), and the mobile phase is CO2. ２ The compound has a retention time of 2.262 min or 3.319 min under the conditions of (MeOH:MeCN = 1:1) = 50 / 50 and a flow rate of 120 mL / min. and / or, 【Chemistry 211】 teeth, 【Chemical Engineering 212】 is, or, 【Chemistry 213】 This refers to a compound whose retention time is 12.068 min or 14.283 min under the following conditions: chromatographic column: IC 25 x 250 mm, 10 μm (Daicel), mobile phase: HEX (0.1% DEA):EtOH (0.1% DEA):= 50:50, flow rate: 50 mL / min. and / or, 【Chemical 214】 teeth, 【Chemical 215】 is, or, 【Chemical 216】 The chromatograph column is AS 25 x 250 mm, 10 μm (Daicel), and the mobile phase is CO2. ２ / [MeOH (0.2% NH ３ The compound has a retention time of 1.299 min or 1.936 min under the conditions of (7M in MeOH):MeCN = 1:1 = 40 / 60 and flow rate: 100 mL / min. and / or, 【Chemical 217】 teeth, 【Chemistry 218】 is, or, 【Chemical 219】 The chromatograph column is IH 25 x 250 mm, 10 μm (Daicel), and the mobile phase is CO2. ２ The compound has a retention time of 1.759 min or 2.520 min under the conditions of [MeOH:MeCN = 1:1] = 50 / 50 and a flow rate of 120 mL / min. and / or, 【Chemical 220】 teeth, 【Chemistry 221】 is, or, 【Chemistry 222】 The chromatograph column is IH 25 x 250 mm, 10 μm (Daicel), and the mobile phase is CO2. ２ The compound has a retention time of 2.309 min or 3.384 min under the conditions of [MeOH:MeCN = 1:1] = 50 / 50 and a flow rate of 120 mL / min. and / or, 【Chemistry 223】 teeth, 【Chemistry 224】 And, and / or, 【Chemical 225】 teeth, 【Chemistry 226】 And, and / or, 【Chemistry 227】 teeth, 【Chemistry 228】 And, and / or, 【Chemistry 229】 teeth, 【Chemistry 230】 And, and / or, 【Chemistry 231】 teeth, 【Chemistry 232】 And, and / or, 【Chemical 233】 teeth, 【Chemistry 234】 And, and / or, 【Chemical 235】 teeth, 【Chemistry 236】 And, and / or, 【Chemistry 237】 teeth, 【Chemical 238】 And, and / or, 【Chemistry 239】 teeth, 【Chemistry 240】 And, and / or, 【Chemistry 241】 teeth, 【Chemistry 242】 And, and / or, 【Chemistry 243】 teeth, 【Chemistry 244】 And, and / or, a pharmaceutically acceptable salt of the compound shown in I-12 is, 【Chemistry 245】 The compound according to claim 19, a pharmaceutically acceptable salt or isotope thereof, characterized in that it is the compound according to claim 19.

21. A pharmaceutical composition comprising substance Z and a pharmaceutical additive, wherein substance Z is a compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt thereof, or an isotope compound thereof.

22. An application of substance Z in the manufacture of an IRAK4 degrading agent and a drug for treating and / or preventing Myd88 and / or IRAK4-related diseases, wherein substance Z is a compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt thereof, or an isotope thereof. Preferably, the IRAK4-related disease includes one or more of the following: chronic lung disease, autoimmune disease, inflammatory disease, tumor, cardiovascular / cerebrovascular disease, and central nervous system disease. More preferably, the autoimmune diseases are psoriasis, systemic lupus erythematosus, and rheumatoid arthritis. More preferably, the inflammatory disease is an inflammatory bowel disease, such as ulcerative colitis. More preferably, the tumors are hematological malignancies and solid tumors, the hematological malignancies may be large B-cell lymphoma or acute chronic lymphocytic leukemia, and the solid tumors may be intestinal cancer or skin cancer caused by MYD88 gene mutations. More preferably, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis. More preferably, the central nervous system disease is a primary central nervous system lymphoma.

23. An application of substance Z in the manufacture of a drug, wherein substance Z is a compound represented by formula I as described in claim 1, a pharmaceutically acceptable salt or isotope thereof, and the drug is used to treat one or more of the following: autoimmune diseases, inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases, and central nervous system diseases. Preferably, the autoimmune diseases are psoriasis, systemic lupus erythematosus, and rheumatoid arthritis. Preferably, the inflammatory disease is an inflammatory bowel disease, such as ulcerative colitis. Preferably, the tumors are hematological malignancies and solid tumors, the hematological malignancies may be large B-cell lymphoma or acute chronic lymphocytic leukemia, and the solid tumors may be intestinal cancer or skin cancer caused by MYD88 gene mutations. Preferably, the cardiovascular and cerebrovascular diseases include stroke and atherosclerosis. Preferably, the central nervous system disease is a primary lymphoma of the central nervous system.

24. A compound represented by formula II or III, its salt, or isotope, 【Chemistry 246】 R １ , R ２ , R ３ , Q, Y, ring Cy, L ０ and L ２ This is as described in claim 1, Preferably, the compound represented by formula II or III is 【Chemistry 247】 【Chemistry 248】 【Chemistry 249】 [Chemical 250] A compound represented by formula II or III, which is one of the compounds shown, its salt, or its isotope.

25. Application of the compound represented by formula II or III as described in claim 24, a salt thereof, a boc-protected compound thereof, or an isotope compound, in the production of the compound represented by formula I as described in any one of claims 1 to 18, a pharmaceutically acceptable salt thereof, or an isotope compound, or in the production of the compound represented by claim 19 or 20, a pharmaceutically acceptable salt thereof, or an isotope compound.

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