IRAK4-targeted protein degradation agent as well as preparation method and application thereof

Abstract

The invention discloses a protein degradation agent targeting IRAK4 as well as a preparation method and application of the protein degradation agent. The inventor of the invention creatively discovers that a compound recruits ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of MDM2 and is used in the aspects of preparation of a targeted protein degradation agent and the like. The inventor prepares a novel degradation agent compound targeting IRAK4 by utilizing the discovery, and experiments find that the prepared compound can effectively induce degradation of IRAK4, is used for treating IRAK4-mediated diseases (such as inflammatory diseases), and has a very good application prospect in the field of medicines.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a protein degrader targeting IRAK4, its preparation method, and its application. Background Technology

[0002] IRAK4 (interleukin-1 receptor-associated kinase 4) is a member of the IRAK kinase family and plays a crucial role in protein phosphorylation and cell signal transduction. It receives signals from upstream Toll-like receptor (TLR) families and interleukin-1 receptor families, activating downstream NF-κB and JNK signaling pathways. This plays a vital role in the development of autoimmune diseases (such as atopic dermatitis, hidradenitis suppurativa, and rheumatoid arthritis) and tumors. The IRAK4 protein folds into a unique "pocket-like" structure that binds to ATP. IRAK4 binds to ATP through this structure, thereby achieving protein phosphorylation. Therefore, most IRAK4 inhibitors are developed to competitively bind to this "pocket" region to inhibit phosphorylation, targeting the structural and functional characteristics of IRAK4. Further research has revealed that IRAK4's function extends beyond protein phosphorylation; its complex with MyD88 can also directly exert its function. Studies have shown that IRAK4 requires phosphorylation for activation of the JNK pathway, but not for activation of the NF-κB pathway. This suggests that in addition to its protein kinase function, IRAK4 also functions as a scaffold structural protein in signaling pathways. Therefore, traditional small molecule kinase inhibitors targeting IRAK4 cannot block all of its functions.

[0003] Targeted protein degradation is a novel and groundbreaking drug development strategy that utilizes inherent intracellular protein degradation pathways to directly degrade pathogenic target proteins. This novel drug form includes various types, such as PROTACs, molecular gels, LYTACs, ATACs, AbTACs, ATTECs, AUTACs, and AUTOTACs. PROTACs (Proteolysis Targeting Chimeras) are bifunctional molecules composed of a target protein ligand, a linker, and an E3 ubiquitin ligase recruitment element. Upon entering the cell, the target protein ligand in a PROTAC specifically binds to the target protein, while the E3 ligase recruitment element at the other end binds to the E3 ligase, forming a target protein-PROTAC-E3 ternary complex. The E3 ubiquitin ligase mediates ubiquitination of the target protein by the ubiquitin-conjugating enzyme E2. The polyubiquitinated target protein is then transported to the proteasome for degradation, thereby reducing the target protein level. In this process, the target protein ligand does not need to occupy the binding site for an extended period. Therefore, PROTACs can cycle multiple times within the cell to exert their effects. Based on the unique mechanism of action of PROTAC, PROTAC drugs have significant advantages in drug development for overcoming drug resistance and untreatable targets. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, this invention provides a protein degrader targeting IRAK4, its preparation method, and its applications. The compound is a targeted protein degrader using compound of formula I as an MDM2 recruitment element. In vivo, it can bring the target protein and E3 ubiquitin ligase closer, thereby tagging the target protein with ubiquitin, and then degrading it via the ubiquitin-proteasome pathway. Experiments show that the degrader can effectively degrade IRAK4, producing corresponding therapeutic effects, such as inhibiting inflammation.

[0005] In a first aspect of the invention, a compound (a targeted protein degrader, such as PROTAC) or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof is provided, said compound having the following structure:

[0006]

[0007] in,

[0008] ML is the recruitment element part of the MDM2 protein;

[0009] L is a linking group;

[0010] q is an integer from 1 to 15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15);

[0011] V1, V2, and Y are independently selected from: C, N, or -N + -O - ;

[0012] R P1 It is one or more independent substituents on the ring, selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: D, halogen, cyano, nitro, azide, -OR 101 -C(O)R 101 -C(S)R 101 -C(O)OR 101 -C(S)SR 101 -OC(O)R 101-OC(S)R 101 -OC(S)SR 101 -C(O)NR 102 R 103 -OC(O)NR 102 R 103 -NR 102 C(O)OR 103 -NR 102 SO2R 103 -SO2NR 102 R 103 -OSO2NR 102 R 103 -NR 102 C(O)R 103 -NR 102 R 103 -SR 101 -SOR 101 -SO2R 101 -OSO2R 101 -SO3H, -PO3H, -OP(O)(OR 101 -P(O)(OR) 102 (OR) 103 -P(O)NR 102 R 103 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0013] R P2 Selected from -(C0-C6 alkylene)-(C3-C 11 Cycloalkyl), -(C0-C6 alkylene)-(3-11 membered heterocyclic group), wherein the C0-C6 alkylene, C3-C 11 The hydrogen atoms in cycloalkyl and 3-11 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: hydrogen, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);;

[0014] R P3 The ring may be absent or may contain one or more independent substituents selected from: H, halogen, cyano, nitro, -CF3, -OCF3, C. 1-10 Alkyl, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -SC 0-10 Alkyl, -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C3-C 10 The hydrogen atoms in cycloalkyl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic);

[0015] Each R 101 R 102 and R 103 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);

[0016] The MDM2 protein recruitment element has the following structure:

[0017]

[0018] in, Represents a single or double bond, and points a and b are shown. Not both are double bonds;

[0019] R1 to R4, R7 to R 11 Independently selected from: H, =O, =C(H)-R A =NN(R) B R C ), hydroxyl, amino, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups,

[0020] Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);

[0021] R Band R C Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0022] R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OS(O)2-, -OC(O)N(R) a )-、-C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)O-、-N(R a )C(O)N(R b )-、-N(R a -, -S(O)2-, -S(O)2N(R) a )-、-N(R a -S(O)2-, -S(O)-, -S(O)N(R) a )-、-N(R a )S(O)-、-OP(O)(OR b )O-、-P(O)(OR b -O-, -P(O)-, -OP(O)N(R) a )-、-P(O)N(R a )-、-P(O)(N(R a R b ))-、-OP(O)(OR b )2N(R a )-、-P(O)(OR b )2N(R a )-、-N(R a )P(O)(OR b )O-、-N(R a )P(O)-; where, R a and R b Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0023] R E Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl groups, monosaccharide residues, amino acid residues, and nitric oxide (NO) donor residues;

[0024] Q represents a single bond or C1-C. 20 Alkylene, wherein 0-6 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) c )-、-N(R c )C(O)-、-N(R c )C(O)O-、-N(R c )C(O)N(R d )-、-N(R c -, -S(O)2-, -S(O)2N(R)c )-、-N(R c -S(O)2-, -S(O)-, -S(O)N(R) c )-、-N(R c )S(O)-、-OP(O)(OR d )O-、-P(O)(OR d -O-, -P(O)-, -OP(O)N(R) c )-、-P(O)N(R c )-、-P(O)(N(R c R d ))-、-OP(O)(OR d )2N(R f )-、-P(O)(OR d )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c P(O)-、 Where m1 is selected from integers between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and R c and R d Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); each -Cy- is independently a optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclic;

[0025] R5 and R6 are independently selected from: H, hydroxyl, amino, halogen, cyano, nitro, azide, -CF3, -OCF3, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0026] The above C0-C6 alkylene groups, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residues, amino acid residues;

[0027] Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be selected from one or more of the following schemes:

[0028] (1) R1 and R2 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0029] (2) R2 and R3 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0030] (3) R1 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0031] (4) R4 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0032] (5) R4 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0033] (6) R5 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0034] (7) R5 and R7 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0035] (8) R8 and R9 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles;

[0036] The H on the aliphatic ring, aromatic ring, or heterocycle is optionally substituted with one or more groups selected from the following: =O, ... Halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues, wherein the 0-4 methylene units in the C0-C6 alkylene group are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)O-, -OC(O)O-, -C(O)N(R) c )-、-N(R e )C(O)-、-N(R e )C(O)O-、-N(R e )C(O)N(R f )-、-N(R e -, -S(O)2-, -S(O)2N(R) e )-、-N(R e -S(O)2-, -S(O)-, -S(O)N(R) e )-、-N(R e )S(O)-、-OP(O)(OR f )O-、-P(O)(OR f -O-, -P(O)-, -OP(O)N(R) f )-、-P(O)N(R f )-、-P(O)(N(R e Rf ))-、-OP(O)(OR e )2N(R f )-、-P(O)(OR f )2N(R e )-、-N(R e )P(O)(OR f )O-、-N(R e P(O)-、 Where n1 is selected from integers between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and R e and R f Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C3-C 10 cycloalkyl, C6-C 10 The hydrogen atom on the aryl or 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 Alkyl); wherein, R x and R y Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0037] Each R' and R" is independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C0-C6 alkylene, C1-C 10Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl).

[0038] Specifically, each -Cy- can be independently selected from the following:

[0039] Specifically, the monosaccharide residues mentioned above can be selected from: glucosyl, galactosyl, xylose, and mannose.

[0040] Specifically, the aforementioned nitric oxide (NO) donor residues can be selected from: -ONO2, Among them, R H and R K Independently selected from: H, C1-C 10 Alkyl, C1-C 10 alkenyl, -(C0-C6 alkylene)-(C6-C10 Aryl), -(C0-C6 alkylene)-(4-6 membered heterocyclic) (e.g. ), or R H and R K Together with the nitrogen atom it is attached to, they form 4-6 membered heterocyclic groups (e.g. ).

[0041] In some embodiments of the present invention, R 10 For H.

[0042] In some embodiments of the present invention, R 11 For H.

[0043] In some embodiments of the present invention, R x For H.

[0044] In some embodiments of the present invention, R y It can be H or phenyl.

[0045] In some embodiments of the invention, R8 and R9, together with the carbon atoms they are attached to, form an aliphatic ring; more specifically, the MDM2 protein recruitment element has the following structure:

[0046]

[0047] Among them, R8' and R9' have the definitions of R8 and R9 mentioned above, respectively.

[0048] In some embodiments of the present invention, R8' is = 0.

[0049] In some embodiments of the present invention, R9' is selected from: H, =O, Among them, R 31 Selected from: H, halogens, C1-C6 alkyl groups, -O(C 0-6 Alkyl), -O(C) 2-12 alkenyl), -N(C) 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 alkyl)CO(phenyl); R 32 and R 33 Independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or R 32 and R 33 Together with the nitrogen atom it is attached to, it forms a 4-8 membered heterocyclic group. In some embodiments of the invention, R 31 For H.

[0050] In some embodiments of the present invention, R9' is... R9 is selected from:

[0051]

[0052] In some embodiments of the present invention, R9' together with the carbon atom it is attached to forms a 3-6 membered saturated heterocycle (e.g., ), wherein the H on the heterocycle is optionally substituted with a group selected from the following: H, -CO(C 0-6 alkyl), -CO(C) 2-6 (Alkenyl). More specifically, R9' forms together with the carbon atom it is attached to:

[0053] In some embodiments of the present invention, R9' is selected from:

[0054] In some embodiments of the present invention, R9' is H, =O, in particular

[0055] In some embodiments of the present invention, the MDM2 protein recruitment element has the following structure:

[0056]

[0057] In one embodiment of the invention, R4 and R5 together with their attached carbon atoms form an aliphatic ring, and R5 and R6 together with their attached carbon atoms form a heterocycle; more specifically, the MDM2 protein recruitment element has the following structure:

[0058]

[0059] in,

[0060] R 21 Selected from: H, =O, -O(C) 0-10 Alkyl), -OC(O)(C 0-10 alkyl groups and -O-monosaccharide residues;

[0061] R 22 Selected from: H, -O(C) 0-10 Alkyl), -OC(O)(C 0-10 alkyl), -O-monosaccharide residues; or, R 22 R7, together with the carbon atom it is attached to, forms an optionally substituted aliphatic ring, aromatic ring, or heterocyclic ring.

[0062] In one embodiment of the present invention, the MDM2 protein recruitment element has the following structure:

[0063]

[0064] in,

[0065] R 23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein, the C 0-10 The hydrogen atom on the alkyl group may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl).

[0066] In some embodiments of the present invention, R 23 and R 24 Independently selected from: H, C1-C3 alkyl, phenyl, wherein the H on the phenyl group may optionally be substituted by one or more groups selected from: halogen, hydroxyl, amino, C1-C3 alkoxy; in one embodiment of the invention, R 23 R is methyl; in one embodiment of the invention, R 24R is methyl; in one embodiment of the invention, R 23 For H, R 24 R is phenyl; in one embodiment of the invention, R 23 For H, R 24 It is 3,4-dimethoxyphenyl.

[0067] In another embodiment of the invention, R4 and R6 form a heterocycle together with the carbon atoms they are attached to, and R1 and R5 form a heterocycle together with the carbon atoms they are attached to; more specifically, the MDM2 protein recruitment element has the following structure:

[0068]

[0069] In another embodiment of the invention, R5 and R6 together with the carbon atoms they are attached to form a heterocycle; more specifically, the MDM2 protein recruitment element has the following structure:

[0070]

[0071] In another embodiment of the invention, R4 and R5 together with their attached carbon atoms form an aliphatic ring, and R4 and R6 together with their attached carbon atoms form a heterocycle; more specifically, the MDM2 protein recruitment element has the following structure:

[0072]

[0073] In another embodiment of the invention, R1 and R2 together with the carbon atoms they are attached to form a 3-10 membered heterocycle; more specifically, the MDM2 protein recruitment element has the following structure:

[0074]

[0075]

[0076] in,

[0077] X is either O or S;

[0078] R 25 Selected from: H, =O, Cl-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl), Wherein, the C 0-10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl).

[0079] In some embodiments of the present invention, in formula III-6, R 25Selected from: H, C1-C6 alkyl, -N(H)(C 0-6 Alkyl), -N(H)CO(C) 0-6 Alkyl), -N(H)(C 2-6 alkenyl) (e.g. ), -N(H)(C 3-6 cycloalkyl) (e.g. ), -N(H)(C 0-6 alkylene-4-6-membered nitrogen-containing heterocyclic groups (e.g.) ), 4-8 member nitrogen-containing heterocyclic groups (e.g. ), More specifically, R 25 Selected from: H, methyl, ethyl, amino, In some embodiments of the present invention, R 25 for

[0080] In some embodiments of the present invention, in formulas III-7 and III-8, R 25 for R 25a and R 25b Independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl (e.g. ); or, R 25a and R 25b Together with the nitrogen atom to which it is attached, it forms an optionally substituted 3-6 membered saturated heterocyclic group (e.g. ).

[0081] In some embodiments of the present invention, in formulas III-9, III-10, and III-11, R 25 It is one or more independent substituents on the ring, selected from: H, C1-C6 alkyl, -O(C 0-6 alkyl), -S(C 0-6 alkyl), -O(C) 2-6 alkenyl) (e.g. ), wherein the H on the alkyl group is optionally substituted with a group selected from the following groups: H, halogen, hydroxyl, azide, amino; or, both R groups are substituted with H. 25 Together with the atoms it is attached to, they form carbon rings or heterocycles (e.g. More specifically, R 25 Selected from: In some embodiments of the present invention, R 25 for

[0082] In another embodiment of the invention, R8' and R9' together with the carbon atoms they are attached to form a 3-10 membered heterocycle; more specifically, the MDM2 protein recruitment element has the following structure:

[0083]

[0084] in,

[0085] R 26 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), -(C0-C6 alkenyl)-(C6-C 10 aryl), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); wherein, the C 0-10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl).

[0086] In some embodiments of the present invention, in formulas III-14 and III-15, R 26 Selected from: H, halogen, cyano, nitro, azide, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -COO(C 0-3 alkyl),

[0087] In some embodiments of the present invention, in III-16 to III-18, III-20, R 26 Selected from: H, halogens, C1-C3 alkyl groups, C3-C6 cycloalkyl groups, The H on the phenyl or heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(C 0-3 Alkyl)(C 0-3 alkyl).

[0088] In one embodiment of the invention, location a is shown It is a double bond, as shown at point b. It is a single key.

[0089] In one embodiment of the invention, location a is shown It is a single bond, as shown at point b. It is a double bond.

[0090] In one embodiment of the invention, location a is shown It is a single bond, as shown at point b. It is a single key.

[0091] In some embodiments of the present invention, the compound has the following structure:

[0092]

[0093] In some embodiments of the present invention, the MDM2 protein recruitment element has the following structure:

[0094]

[0095] In some embodiments of the present invention, R2 is selected from: H, halogens, O, ... Where R J Selected from: H, C1-C6 alkyl, phenyl, C1-C6 alkyl-substituted phenyl (e.g., 4-tert-butylphenyl). In one embodiment of the invention, R2 is H.

[0096] In some embodiments of the present invention, R3 is selected from: H, halogens, O, ... Where R J Selected from: H, C1-C6 alkyl, phenyl, C1-C6 alkyl-substituted phenyl (e.g., 4-tert-butylphenyl). In one embodiment of the invention, R3 is H.

[0097] In some embodiments of the present invention, the MDM2 protein recruitment element has the following structure:

[0098]

[0099]

[0100]

[0101] in,

[0102] R 12 Selected from: H, Where Q1 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10 Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E1 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);

[0103] R 13 Selected from: H, Where Q2 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E2 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl);

[0104] R 14 and R 15 Independently selected from: H, C1-C 10 Alkyl and monosaccharide residues.

[0105] In some embodiments of the present invention, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), C(S)(C 0-6 Alkyl), C(S)S(C 0-6 Alkyl), C(O)N(C 0-6 Alkyl)(C 0-6 Alkyl), SO2 (C) 0-6 Alkyl), SO2N(C) 0-6 Alkyl)(C 0-6 Alkyl), P(O)O(C 0-6 Alkyl)(C 0-6 alkyl groups, monosaccharide residues, Among them, R 16 Selected from: halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); more specifically, R 12 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), SO2 (C) 0-6 alkyl), In some embodiments of the present invention, R 12 For H.

[0106] In some embodiments of the present invention, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), C(S)(C 0-6 Alkyl), C(S)S(C 0-6 Alkyl), C(O)N(C 0-6 Alkyl)(C 0-6 Alkyl), SO2 (C) 0-6 Alkyl), SO2N(C) 0-6 Alkyl)(C 0-6 Alkyl), P(O)O(C 0-6 Alkyl)(C 0-6 alkyl groups, monosaccharide residues, Among them, R 17 Selected from: halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); more specifically, R 13 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C(O)(C 0-6 Alkyl), SO2 (C) 0-6 alkyl), In some embodiments of the present invention, R 13 For H.

[0107] In some embodiments of the present invention, R 16 Selected from: H, halogen, cyano, nitro, azide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0108] In some embodiments of the present invention, R 17 Selected from: H, halogen, cyano, nitro, azide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy.

[0109] In some embodiments of the present invention, R 14 For H.

[0110] In some embodiments of the present invention, R 15 For H.

[0111] In other embodiments of the present invention, R 15 These are monosaccharide residues, such as glucosyl, galactosyl, xylose, and mannose.

[0112] In some embodiments of the present invention, the MDM2 protein recruitment element includes, but is not limited to, the following:

[0113]

[0114]

[0115]

[0116]

[0117] In one embodiment of the present invention, the stereoisomer of the MDM2 protein recruitment element has the following structure:

[0118] For example

[0119] In one embodiment of the present invention, the stereoisomer of the MDM2 protein recruitment element has the following structure:

[0120] For example

[0121] In addition to the compounds shown in this invention, other structural analogs have been verified or are under investigation in the prior art, such as those in patent documents CN105473566A, CN104039796A, CN101139350A, CN101723951A, CN102002051A, CN102295649A, CN102850369A, CN104003998A, CN105524076A, CN106749305A, and CN10686. 6695A, CN106883267A, CN108299458A, CN108864132A, CN110627833A, CN113698415A, CN114478566A, CN116 621855A, CN114702506A, CN113004241A, CN110950883A, CN110229168A, CN111635395A, CN106749305AShen QK, Chen ZA, Zhang HJ, Li JL, Liu CF, Gong GH, Quan ZS. Design and synthesis of noveloridonin analogues as potent anticancer agents. J Enzyme Inhib MedChem. 2018 Dec; 33(1):324-333.; Dai Yi, Zhong Fei. Research progress on structural modification and bioactivity of noveloridonin [J]. Organic Chemistry, 2017, 37(7):1701-1713. etc., which are incorporated herein by reference in their entirety.

[0122] In some embodiments of the present invention, the ML portion is selected from the following structures:

[0123]

[0124]

[0125]

[0126] Among them, R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 'Respectively R1, R2, R3, R7, R 21 R 22 R 23 R24 R 25 R 27 R 31 R 32 The divalent group obtained after a linkage reaction (e.g., loss of a leaving group);

[0127] ①, ②, ③, ④, ⑤, ⑥, ⑦, ⑧, ⑨, and ⑩ are available connection sites. When they are not used as connection sites, the corresponding R1', R2', R3', R7', and R... 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 'Respectively R1, R2, R3, R7, R 21 R 22 R 23 R 24 R 25 R 27 R 31 R 32 .

[0128] In some embodiments of the present invention, ① is a connection site.

[0129] In some embodiments of the present invention, ② is a connection site.

[0130] In some embodiments of the present invention, ③ is a connection site.

[0131] In some embodiments of the present invention, ④ is a connection site.

[0132] In some embodiments of the present invention, ⑦ is a connection site.

[0133] In some embodiments of the present invention, R1' is O or OC(O).

[0134] In some embodiments of the present invention, R7' is O or OC(O).

[0135] In some embodiments of the present invention, R 21 'For O or OC(O).

[0136] In some embodiments of the present invention, R 22 'For O or OC(O).

[0137] In some embodiments of the present invention, R2' is a single bond.

[0138] In some embodiments of the present invention, R3' is a single bond.

[0139] In some embodiments of the present invention, R 23 ' is a single bond, O, or OC(O).

[0140] In some embodiments of the present invention, R 24 ' is a single bond, O, or OC(O).

[0141] In some embodiments of the present invention, R 25 ' is a single bond, O, or OC(O).

[0142] In some embodiments of the present invention, R 26 ' is a single bond, O, or OC(O).

[0143] Furthermore, in some embodiments of the present invention, the ML portion is selected from the following structures:

[0144]

[0145]

[0146]

[0147] In some embodiments of the invention, the MDM2 protein recruitment element has the structure shown in formulas V-1 to V-29 of the first aspect, particularly

[0148] Furthermore, in some embodiments of the present invention, the ML portion is selected from the following structures:

[0149]

[0150]

[0151]

[0152] In some preferred embodiments of the present invention, only ① as a connection site, the ML portion has the following structure:

[0153]

[0154]

[0155] in particular In some embodiments of the present invention, only ② serves as the connection site, and the ML portion has the following structure:

[0156] in particular In some preferred embodiments of the present invention, only ③ serves as the connection site, and the ML portion has the following structure:

[0157]

[0158]

[0159] In some preferred embodiments of the present invention, only ④ serves as the connection site, and the ML portion has the following structure:

[0160]

[0161]

[0162] In some embodiments of the present invention, only ⑦ serves as the connection site, and the ML portion has the following structure:

[0163]

[0164] in particular In some embodiments of the present invention, the compound has the following structure:

[0165]

[0166]

[0167] In some embodiments of the present invention, the compound has the following structure:

[0168]

[0169]

[0170] Specifically, L has the following structure: in,

[0171] L1 is a divalent group attached to ML, which can be selected from: single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -N(R L2 )C(O)-(C0-C6 alkylene)-、-OP(O)(OR L1 -O-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -CON(R) L1 -(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-;

[0172] L3 is a divalent group attached to the ring, which can be selected from: single bond, -(C0-C6 alkylene)-(C2 ... 10 (-(C0-C6 alkylene)-(C2-C6 ... 10 (-(C0-C6 alkylene)-(C6-C6) 10 aryl)-(C2-C 10 (-(C0-C6 alkylene)-, -(C6-C6)-(C6-C6) 10 aryl)-(C2-C 10 -(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-C(O)-, -(C0-C6 alkylene)-C(S)-, -(C0-C6 alkylene)-N(R) L3 )-、-(C0-C6 alkylene)-CON(R L3 )-、-(C0-C6 alkylene)-N(R L3 CO-, -(C0-C6 alkylene)-SO2-, -(C0-C6 alkylene)-SO-, -(C0-C6 alkylene)-(4-10 heterocyclic)-;

[0173] L2 is a C1-C50 hydrocarbon chain (e.g., a C1-C20 alkyl chain) that is saturated or unsaturated with a single bond or divalent valence, consisting of 0-6 methylene units independently substituted with the following: -CY-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 )C(O)O-、-N(R L2 )C(O)N(R L2 )-、-N(R L2 -, -S(O)2-, -S(O)2N(R) L2 )-、-N(R L2 -S(O)2-, -S(O)-, -S(O)N(R) L2 )-、-N(R L2 )S(O)-、-P(O)(OR L2 -O-, -P(O)-, -P(O)N(R) L2 )-、-P(O)(N(R L2 )2)-、-OP(O)(OR L2 )2N(R L2 )-、-P(O)(OR L2 )2N(R L2)-、-N(R L2 )P(O)(OR L2 )O-、-N(R L2 P(O)-, -Si(R) L2 )2-、-C(=N-CN)-、 Amino acid residues, nucleotide residues, oligonucleotide residues, oligopeptide residues, wherein m2 is selected from an integer selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and each -CY- is independently a divalent ring selected from the optionally substituted groups: arylene, cycloalkylene, heterocyclic; the H in the hydrocarbon chain may optionally be substituted by one or more groups selected from the group: halogen, cyano, nitro, azido, -OR L0 -C(O)R L0 -C(S)R L0 -C(O)OR L0 -C(S)SR L0 -OC(O)R L0 -OC(S)R L0 -OC(S)SR L0 -C(O)N(R) L0 )2、-OC(O)N(R L0 )2、-N(R L0 )C(O)OR L0 -N(R) L0 SO2R L0 -SO2N(R) L0 )2、-OSO2N(R L0 )2、-N(R L0 )C(O)R L0 -N(R) L0 )2、-SR L0 -SOR L0 -SO2R L0 -OSO2R L0 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0174] R L0 RL1 R L2 and R L3 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), wherein the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in the aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, mercapto, carboxyl, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic).

[0175] Specifically, each -CY- is independently selected from the following optionally substituted divalent rings: phenylene, bicyclic arylene, tricyclic arylene, monocyclic cycloalkylene, bicyclic cycloalkylene, tricyclic cycloalkylene, monocyclic heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, monocyclic heteroalkylene, bicyclic heteroalkylene, tricyclic heteroalkylene, tricyclic heteroalkylene.

[0176] In some embodiments of the present invention, -CY- is a substituted or unsubstituted phenylene. In some embodiments of the present invention, -CY- is a substituted or unsubstituted 3-12 membered cyclohexene alkylene. In some embodiments of the present invention, -CY- is a substituted or unsubstituted 4-12 membered saturated heterocyclic alkylene.

[0177] In some embodiments of the invention, each -CY- is independently selected from the following:

[0178]

[0179]

[0180] Among them, R L4 R L5 Independently selected from: H, OH, halogens, C 1-8 Alkyl, O(C) 1-8 Alkyl), S(C) 1-8 Alkyl), NH(C) 1-8 Alkyl), N(C) 1-8 Alkyl)2, C 3-11 Cyclic hydrocarbon group, C 3-11 Heterocyclic hydrocarbon groups, O(C) 1-8 cyclic hydrocarbon group), S(C) 1-8 cyclic hydrocarbon group), NH(C) 1-8 cyclic hydrocarbon group), N(C) 1-8 Cyclohydrogen group)(C 1-8 Alkyl groups), OH, NH2, SH, SO2 (C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)2, C 1-8 Alkyne group, CH=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2、C(=O)(C 1-8 Alkyl groups), CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH (C 1-8 Alkyl), SO2N(C) 1-8 Alkyl)2, S(=O)N(C 1-8 Alkyl)2、C(=O)NH(C 1-8 Alkyl), C(=O)N(C 1-8 Alkyl)2, N(C) 1-8 alkyl)C(=O)NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)C(=O)N(C 1-8 Alkyl)2, NHC(=O)NH(C 1-8 Alkyl), NHC(=O)N(C 1-8 Alkyl)2, NHC(=O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NHSO2N(C 1-8 Alkyl)2 or NHSO2NH2; or, R L4 R L5 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups.

[0181] More specifically, R L4 R L5 Independently selected from: -CH3, -OH、 Or, R L4 R L5 Together with the atoms they are attached to, they form ternary to hexacyclic alkyl groups (such as... ) or four- to six-membered heterocyclic alkylene compounds (such as ).

[0182] In some embodiments of the present invention, R L1 For H.

[0183] In some embodiments of the present invention, R L3 For H.

[0184] In some embodiments of the present invention, R L4 For H.

[0185] In some embodiments of the present invention, R L4 It is OH.

[0186] In some embodiments of the present invention, R L5 For H.

[0187] In some embodiments of the present invention, R L5 It is OH.

[0188] In one embodiment of the invention, L2 is a C1-C20 straight-chain alkylene group, wherein 0-6 methylene units in the alkylene group are independently substituted by the following groups: -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 and R L5Independently selected from: H, OH, C1-C6 alkoxy groups.

[0189] More specifically, L2 can be selected from: C1-C20 straight-chain alkylene groups, -(CH2CH2O). m2 -CH2-, -(CH2CH2O) m2 -CH2CH2-, -CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2CH2-、-(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-NH-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-C(O)NH-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-NHC(O)-(C1-C 10 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-C(O)NH-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-NHC(O)-(C1-C6 alkylene)-,

[0190] Where m2 is selected from integers between 1 and 10, g is 0 or 1, h is selected from integers between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), i is selected from integers between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and G is any suitable trivalent group.

[0191] In some specific embodiments of the present invention, L2 is a C1-C20 straight-chain alkylene group, for example:

[0192] In some specific embodiments of the present invention, L2 is a C1-C6 straight-chain alkylene group, wherein at least one methylene unit in the alkylene group is independently substituted by the following groups: For example

[0193] In some specific embodiments of the present invention, L2 is selected from: Where h is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), i is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and j is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). For example,

[0194] In another embodiment of the invention, L2 is a C1-C20 straight-chain alkylene group, wherein 1-3 methylene units are independently substituted by the following groups: -CY-, Optionally, L2 also contains groups selected from: -O-, -C(O)-, -N(R)-. L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 Independently selected from: OH, C1-C6 alkoxy groups.

[0195] In some embodiments of the present invention, -CY- is selected from:

[0196] In some specific embodiments of the present invention, L2 is selected from:

[0197] In some embodiments of the present invention, L1 is -C(O)-.

[0198] In one embodiment of the present invention, L1 is a single bond.

[0199] In some embodiments of the present invention, L2 is C1-C 10 Straight-chain alkylene groups, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, especially -CH2CH2CH2-.

[0200] In some embodiments of the present invention, L3 is...

[0201] In some embodiments of the present invention, L3 is...

[0202] In some embodiments of the present invention, q is 1, that is, the compound has the following structure:

[0203] Specifically, V1, V2, and Y are independently selected from either C or N.

[0204] Specifically, Some have the following structure:

[0205] in particular, Among them, R P11 R P12 R P13 Having the above R P1 The definition stated above.

[0206] Specifically, R P11 R P12 R P13 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C)0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic).

[0207] Specifically, R P11 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 The hydrogen atoms in cycloalkyl or 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: D, halogen, C1-C. 10 alkyl.

[0208] In some embodiments of the present invention, R P11 Selected from:

[0209] Specifically, R P12 Selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), -OCO(C 0-10 Alkyl), -COO(C 0-10Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl).

[0210] In some embodiments of the present invention, R P12 Selected from:

[0211] Specifically, each R P13 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -N(C) 0-10 Alkyl)(C 0-10 Alkyl), -O(C) 0-10 alkyl).

[0212] In some embodiments of the present invention, R P13 For H.

[0213] In some embodiments of the present invention, R P2 -(C0-C6 alkylene)-R P21 , where R P21 Selected from:

[0214]

[0215]

[0216] in,

[0217] R P22 R P24 Independently selected from: H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 heterocyclic), -CO(C 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C.10 alkyl;

[0218] R P23 It is one or more independent substituents on the ring, selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); optionally, any two R P23 Together with the carbon atoms it is attached to, they form C3-C 10 Cycloalkyl or 3-10 membered heterocyclic group, wherein the C3-C 10 The hydrogen atoms in cycloalkyl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl).

[0219] Specifically, R P22 R P24 Independently selected from: H, C1-C 10 Alkyl, -CO(C) 0-10 Alkyl), wherein the C1-C 10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 alkyl.

[0220] In some embodiments of the present invention, R P22 Selected from: H,

[0221] In some embodiments of the present invention, R P24 Selected from: H,

[0222] In some specific embodiments of the present invention, R P21 for Specifically Among them, R P23a R P23b R P23c R P23d R P23e Having the above R P23 The definition stated above.

[0223] Specifically, R P23a R P23b R P23c R P23d R P23e Independently selected from: H, halogens, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C0-10 Alkyl), -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C 10 Haloalkyl, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, -O(C) 0-10 alkyl).

[0224] In some embodiments of the present invention, R P23a R P23b R P23c R P23d R P23e Independently selected from: H, halogen, -OH, -NH2,

[0225] In some embodiments of the present invention, R P23a It can be H or F.

[0226] In some embodiments of the present invention, R P23b It can be H or F.

[0227] In some embodiments of the present invention, R P23c For H or

[0228] In some embodiments of the present invention, R P23d For H or

[0229] In some embodiments of the present invention, R P23e For H.

[0230] Specifically, R P23a R P23b R P23c R P23d R P23e Any two groups together with the carbon atoms they are attached to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the H in the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, C1-C... 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl).

[0231] In some embodiments of the present invention, R P23a With R P23b 、or R P23b With R P23c 、or R P23c With R P23d 、or R P23d With R P23e The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed together with the carbon atom it is attached to is selected from:

[0232] In some embodiments of the present invention, R P21 Selected from:

[0233] Specifically, R P3 Selected from: H, halogens, 3-10 membered heterocyclic groups, wherein the H in the 3-10 membered heterocyclic group may optionally be substituted by one or more groups selected from: halogens, C1-C 10 alkyl.

[0234] In some embodiments of the present invention, R P3 Selected from: H, halogen,

[0235] Specifically, Some have the following structure: Among them, R P4 R P5 Independently selected from: H, C1-C 10 alkyl.

[0236] In some embodiments of the present invention, R P4 It can be H or -CH3.

[0237] In some embodiments of the present invention, R P5 It can be H or -CH3.

[0238] Specifically, Some have the following structure:

[0239] Specifically, Some stereoisomers have the following structures:

[0240] In some embodiments of the present invention, the compound has the following structure:

[0241]

[0242] In some embodiments of the present invention, the compound has the following structure:

[0243]

[0244]

[0245] In some embodiments of the present invention, the compound has the following structure:

[0246]

[0247]

[0248] In some embodiments of the present invention, the compound has the following structure:

[0249]

[0250]

[0251] In some embodiments of the present invention, the compound has the following structure:

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In a second aspect of the invention, a method for preparing the compound of the first aspect is provided, comprising the step of coupling a small molecule ligand moiety with L and ML.

[0266] In some embodiments of the present invention, the preparation method includes the following steps: first preparing... Then it is linked to the ML reaction; or,

[0267] First, prepare ML-L′-R G Then it is linked to a small molecule ligand; or,

[0268] Prepare ML-L″-R separately G 'and Then the two are coupled;

[0269] Where L', L”, and L”' are arbitrarily chosen suitable linking groups, and R G R G '、R G " " represents any suitable reactive group.

[0270] In some embodiments of the present invention, R G It is -OH.

[0271] In some embodiments of the present invention, the preparation method further includes preparing... The steps.

[0272] In some embodiments of the present invention, the small molecule ligand may be, for example, the IRAK4 inhibitor described in patent documents CN106458912A, WO2016053772A1, etc.

[0273] In a third aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0274] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of the following: fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, and preservatives.

[0275] Specifically, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0276] Specifically, the pharmaceutical composition can be prepared into pharmaceutical preparations in the following forms: injections, syrups, elixirs, suspensions, powders, granules, tablets, capsules, lozenges, creams, ointments, lotions, gels, emulsions, etc.

[0277] When preparing the injection, any commonly used carrier in the art can be used, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of dehydrated sorbitol of polyethylene. In addition, commonly used solvents and buffers can be added.

[0278] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the formulation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a capsule, tablet, or any dosage form; alternatively, the unit dosage form can also be a packaged formulation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0279] Specifically, in the pharmaceutical composition, the compound or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound may be used alone or in combination with other types of active ingredients.

[0280] Specifically, the amount of the active ingredient in the unit dose formulation may be varied or adjusted from 0.1 mg to 1000 mg (e.g., 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg), depending on the specific application and potency of the active ingredient. If desired, the composition may also contain other suitable therapeutic agents.

[0281] In a fourth aspect of the invention, the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of IRAK4-related diseases is provided.

[0282] Specifically, the diseases mentioned are those for which inhibition / degradation of IRAK4 can be beneficial for prevention and / or treatment, such as, but not limited to, tumors, autoimmune diseases, inflammatory diseases, diseases related to pathogen infection, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, metabolic diseases, fibrotic diseases, etc.

[0283] Specifically, the tumor is selected from: melanoma, colon cancer, colorectal cancer, gastric cancer, pancreatic ductal adenocarcinoma (PDAC), and hematologic malignancies.

[0284] Specifically, the malignant tumors of the hematologic system are selected from: leukemia, lymphoma, and myelodysplastic syndrome.

[0285] Specifically, leukemia can be classified as chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML).

[0286] Specifically, lymphomas can include non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), MDS lymphoma, etc. Macroglobulinemia.

[0287] Specifically, the autoimmune diseases mentioned are selected from: connective tissue diseases, lupus vulgaris, systemic lupus erythematosus (SLE), rheumatoid arthritis, rheumatic diseases, and bacterial sepsis.

[0288] Specifically, the inflammatory diseases are selected from: inflammatory bowel disease (such as ulcerative colitis, Crohn's disease), colitis, necrotizing enterocolitis, arthritis (such as osteoarthritis (OA)), acute pancreatitis (AP), endometritis, hidradenitis suppurativa (HS), atopic dermatitis (AD), pelvic inflammatory disease, microscopic polyangiitis (MPA), lung injury, alcoholic hepatitis, psoriasis, sepsis, septic shock, chronic kidney disease, hormone-resistant nephrotic syndrome (SRNS), hemophagocytic lymphohistiocytosis (HLH), acute lung injury, acute respiratory distress syndrome, and atopic dermatitis.

[0289] Specifically, the pathogens are selected from: viruses, bacteria, and mycoplasma.

[0290] Specifically, the pathogen is a virus, such as, but not limited to, influenza viruses (e.g., influenza A virus, influenza B virus, influenza C virus, etc.) and novel coronaviruses (e.g., COVID-19).

[0291] Specifically, the diseases associated with the pathogen infection are selected from: influenza and pneumonia caused by the novel coronavirus.

[0292] Specifically, the neurodegenerative diseases mentioned are selected from: Alzheimer's disease (AD) and epilepsy.

[0293] Specifically, the cardiovascular and cerebrovascular diseases mentioned are selected from: atherosclerosis, hypertension (such as gestational hypertension), ischemic stroke, cerebral ischemia, and cardiac injury.

[0294] Specifically, the metabolic diseases mentioned are selected from: diabetic nephropathy and alcoholic fatty liver.

[0295] Specifically, the fibrotic diseases mentioned are selected from: liver fibrosis and myocardial fibrosis.

[0296] In a fifth aspect of the invention, a method for degrading IRAK4 protein is provided, comprising the steps of using the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, or the pharmaceutical composition described in the third aspect of the invention.

[0297] Specifically, the method is performed in vivo or in vitro.

[0298] In a sixth aspect of the invention, a method for preventing and / or treating IRAK4-related diseases is provided, comprising administering to a subject in need a compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, or a pharmaceutical composition described in the third aspect of the invention.

[0299] Specifically, the disease is as described in the fourth aspect of the present invention.

[0300] Specifically, the subjects were mammals, particularly humans.

[0301] Specifically, the administration can be carried out via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0302] The inventors of this invention have creatively discovered that a compound recruits MDM2 through interaction with NCL. Further experiments revealed that this compound can serve as a novel recruitment element for MDM2, and can be used in the preparation of targeted protein degraders. Utilizing this discovery, the inventors prepared a novel protein degrader compound targeting IRAK4, and experiments showed that the prepared targeted protein degrader can effectively induce the degradation of IRAK4, making it promising for the treatment of IRAK4-mediated diseases and possessing excellent application prospects in the pharmaceutical field. Attached Figure Description

[0303] Figure 1 The results of the experiment described in Example 1 are shown, which demonstrate that NCL can bind to MDM2.

[0304] Figure 2 The results of the experiment described in Example 2 are shown, which indicate that compound Ori recruits MDM2 in dependence on its interaction with NCL; iSN04 can only bind to NCL, but cannot recruit MDM2 in dependence on NCL.

[0305] Figure 3 The results of the experiment described in Example 2 are shown, which indicate that Ori can capture NCL and MDM2; iSN04 can capture NCL but cannot capture MDM2.

[0306] Figure 4 The results of the experiment described in Example 2 are shown, which demonstrate that Ori can capture NCL and MDM2, and that silencing NCL can block Ori from recruiting MDM2.

[0307] Figure 5 The results of the experiment described in Example 2 are shown, which indicate that Ori does not affect the interaction between NCL and MDM2, while iSN04 blocks the binding of NCL and MDM2.

[0308] Figure 6 The diagram shows a possible mode of action of a PROTAC formed by a compound of formula I (such as Ori) as a recruiting element of MDM2, and a possible mode of action of a PROTAC targeting IRAK4 prepared by a compound of formula I (such as Ori) as a recruiting element of MDM2.

[0309] Figure 7 The results of the experiment described in Example 4 are shown, which demonstrate that the PROTAC prepared in this invention can induce the formation of a quaternary complex.

[0310] Figure 8 The results of the experiment described in Example 5 are shown, which demonstrate that the PROTAC prepared in this invention can degrade IRAK4.

[0311] Figure 9 The results of the experiment described in Example 6 are shown, which indicate that the PROTAC prepared in this invention can promote the ubiquitination of IRAK4 and the degradation of IRAK4 by the proteasome.

[0312] Figure 10 The results of the experiment described in Example 7 are shown, which indicate that the PROTAC prepared in this invention relies on MDM2 and NCL to mediate the degradation of IRAK4.

[0313] Figure 11 The results of the experiment described in Example 8 are shown, which demonstrate that the PROTAC prepared in this invention can inhibit the function of T cells.

[0314] Figure 12 The results of the experiment described in Example 9 are shown, which demonstrate that the PROTAC prepared in this invention can inhibit the function of monocytes.

[0315] Figure 13 The results of the experiment described in Example 10 are shown, which indicate that the PROTAC prepared in this invention can inhibit the function of synovial fibroblasts.

[0316] Figure 14 The results of the experiment described in Example 11 are shown, which demonstrate that the PROTAC prepared in this invention can inhibit the function of keratinocytes.

[0317] Figure 15 The results of the experiment described in Example 12 are shown, demonstrating that the PROTAC prepared according to this invention can alleviate arthritis in CIA mice. Arthritis scoring criteria: 0 points: no joint swelling; 1 point: mild swelling of a single toe joint or ankle joint; 2 points: moderate swelling of multiple toe joints or ankle joints; 3 points: significant swelling of the entire foot or ankle joint; 4 points: severe swelling accompanied by joint deformity or limited mobility. Scores are accumulated across all four limbs, with a total score of 0-16 points.

[0318] Figure 16 The results of the experiment described in Example 13 are shown, demonstrating that the PROTAC prepared according to this invention can alleviate psoriasis-like symptoms in mice. Erythema score (E) criteria: 0 points: smooth skin without erythema; 1 point: mild erythema in the treated area with indistinct borders; 2 points: erythema enlarges, deepens in color, and has clear borders; 3 points: significant erythema, bright red or dark red in color, covering most of the treated area; 4 points: extremely obvious erythema, accompanied by skin thickening, ulceration, or deterioration of the overall condition (e.g., weight loss). Desquamation Score (D) Standard: 0 points: Smooth skin surface with no visible scales or only very slight dryness; 1 point: A small amount of fine scales appear in local areas, distributed in dots or patches, accounting for less than 20% of the area covered by the medication; 2 points: The scale coverage area expands (accounting for 20%-50% of the area covered by the medication), the thickness increases, and multiple layers accumulate; 3 points: Scales cover extensively (accounting for 50%-80% of the area covered by the medication), forming silvery-white or grayish-white patches, accompanied by significant thickening of the stratum corneum; 4 points: Scales cover more than 80% of the area covered by the medication, presenting a dense, thick peeling state, possibly accompanied by skin damage or bleeding points. Thickening Score (I) Criteria: 0 points: Smooth skin surface, no thickening or slight congestion (thickness ≤ 0.2 mm); 1 point: Slight local skin elevation, thickness increase ≥ 0.3 mm but < 0.4 mm, slightly rough to the touch; 2 points: Moderate thickening, presenting as cord-like or sheet-like elevations (thickness 0.4-0.6 mm), with visible increase in skin folds; 3 points: Significant thickening (thickness 0.7-1.0 mm), accompanied by the formation of red plaques, firm to the touch; 4 points: Highly thickened skin (≥ 1.1 mm), forming hard plaques with local ulceration or bleeding points. PASI Total Score = E + D + I (total score range 0-12 points). Detailed Implementation

[0319] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0320] The term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as an "aliphatic ring") that is fully saturated or contains one or more unsaturated units, connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0321] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted with a cycloalkyl group, it is referred to as "cycloalkylalkyl," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted with an aryl group, it is referred to as "aralkylalkyl," such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted with a heterocyclic group, it is referred to as "heterocyclicalkyl." In this invention, CO alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C) 10 Alkyl groups include H and C. 1-10 Alkyl (or C1-C) 10 alkyl).

[0322] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. It can be straight-chain or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups described herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In this invention, CO alkylene refers to a single bond, i.e., C... 0-10 Alkylene (or C0-C) 10 Alkylenes include single bonds and C bonds. 1-10 Alkylene (or C1-C) 10 (alkylene).

[0323] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0324] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxyl group is replaced by an alkyl group, such as alkoxy groups containing 1-10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0325] The term "alkylamine" refers to a substituent formed when one or two hydrogen atoms of an amino group (-NH2) are replaced by an alkyl group, such as an alkylamine group containing 1-10 carbon atoms, for example...

[0326] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0327] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0328] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group (also referred to herein as "aromatic ring"), such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, C6-C as described in this invention. 12 The aryl group refers to an aryl group containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indene, etc.

[0329] The term "heterocyclic group" refers to a 3- to 18-membered non-aromatic ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused, spirocyclic, or bridged ring systems. Heterocyclic groups (also referred to herein as "heterocycles") can be partially saturated (heteroaryl, also referred to herein as "heteroaromatic rings") or fully saturated (heterocyclic alkyl). Suitable heteroaryl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, S, and P atoms. These heteroaryl groups include, for example, coumarin (including 8-coumarin), quinolinyl (including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indolyl, isoyndolyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl, cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanopyridinyl. Suitable heterocyclic alkyl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. These heterocyclic alkyl groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiohexacyclohexyl, piperazine, aziridine, oxothiobutyl, thiohexacyclobutyl, homopiperidinyl, oxopropane, thiopropane, acrylonitrile, oxazinyl, diaziridine, etc. Heptyl, triacetyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl. In this invention, for optionally substituted heterocyclic groups, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon or nitrogen atom, and it can be, for example...

[0330] In this invention, "D" refers to deuterium; "replaced by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0331] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are variations in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0332] In the compounds of this invention, any atom not specifically designated as deuterium is present at its natural isotopic abundance. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position should be understood as having hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position should be understood as having deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium doping).

[0333] The term “isotope enrichment coefficient” used in this article refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0334] In other embodiments, the compounds of the present invention have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0335] The term "isotope" refers to a substance whose chemical structure differs from that of a specific compound of the present invention only in terms of its isotopic composition.

[0336] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0337] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0338] The term "base addition salt" refers to a salt formed with a metal or amine, such as hydroxides of alkali metals and alkaline earth metals, or with an organic amine. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0339] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom; in this case, all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0340] The term "solvent" refers to the physical bond between the compound of this invention and one or more solvent molecules. This physical bond includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvents include solution phases and separable solvates. Representative solvates include ethanolides, methanolides, etc.

[0341] The term "prodrug" refers to a Formula I compound that is suitable for administration to patients without excessive toxicity, irritation, or allergic reactions, and is effective for its intended purpose. Prodrugs include acetals, esters, and zwitterionic forms. Prodrugs are converted in the body, such as through hydrolysis in the blood, to yield the parent compound.

[0342] The terms “patient” or “subject”, etc., may be used interchangeably herein to refer to any animal or its cells, whether in vitro or in situ, treated according to the methods described herein. Specifically, the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, or humans, especially humans.

[0343] The term "treatment" refers to the prevention, cure, reversal, reduction, mitigation, minimization, suppression, cessation, and / or cessation of one or more clinical symptoms of a disease after its onset.

[0344] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0345] The term "IRAK4-related disease," also known as IRAK4-mediated disease, mainly refers to diseases associated with abnormal IRAK4 activity, particularly those diseases for which prevention and / or treatment can be benefited by inhibiting / degrading IRAK4.

[0346] The term "tumor" refers to an abnormal mass of tissue that grows beyond and out of harmony with the growth of normal tissue. Tumors can be "benign" or "malignant," depending on characteristics such as the degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. "Benign tumors" are typically well-differentiated, characterized by slower growth than malignant tumors, and remain confined to their site of origin. Furthermore, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. In some cases, certain "benign" tumors may later develop into malignant tumors, possibly due to additional genetic alterations in a subset of the tumor's proliferative cells, and these tumors are called "precancerous tumors." "Malignant tumors" are typically poorly differentiated (anaplastic) and characterized by rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant tumors often have the ability to metastasize to distant sites.

[0347] The term “cancer” refers to a malignant tumor (Stedman’s Medical Dictionary, 25th ed.; Hensyled.; Williams & Wilkins: Philadelphia, 1990).

[0348] The term "autoimmune disease" refers to diseases caused by the body's immune response to its own antigens, resulting in damage to its own tissues.

[0349] The term "inflammation" refers to the body's defensive response to stimuli, manifested as redness, swelling, heat, pain, and functional impairment. It can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by immune responses (e.g., various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to a disease characterized by inflammation.

[0350] The term "diseases related to pathogen infection" primarily refers to diseases caused by pathogen infection, including symptoms of bodily damage and infection response resulting from pathogen invasion. Pathogens can be microorganisms (such as viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.), parasites (protozoa, worms, etc.), or other vectors. In particular, pathogens are viruses, for example, but not limited to, adenoviridae (such as adenovirus), herpesviruses (such as HSV1 (oral herpes), HSV2 (genital herpes), VZV (varicella-zoster virus), EBV (Ebola virus), CMV (cytomegalovirus)), poxviridae (such as smallpox virus, vaccinia virus), and lactoferrin. Viral families (e.g., human papillomavirus (HPV)), parvovirus families (e.g., B19 virus), hepatotropic DNA virus families (e.g., hepatitis B virus), polyomavirus families (e.g., polyomavirus), reoviridae families (e.g., reovirus, rotavirus), picoronaviridae families (e.g., enterovirus, foot-and-mouth disease virus), calicivirus families (e.g., norovirus, hepatitis E virus), cloacalviridae families (e.g., rubella virus), arenaviridae families (e.g., lymphocytic choriomeningitis virus), retroviridae families (HIV). -1, HIV-2, HTLV-1), Flaviviridae (such as dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, yellow fever virus, hepatitis C virus, West Nile virus, etc.), Orthomyxoviridae (such as influenza viruses (such as influenza A virus, influenza B virus, influenza C virus, etc.)), Paramyxoviridae (such as human parainfluenza virus type 1 (HPIV), HPV type 2, HPV type 3, HPV type 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, etc.). Newcastle disease virus, etc.), Bunyaviridae (e.g., California encephalitis virus, Hantavirus), Rhabdoviridae (e.g., rabies virus), Filoviridae (e.g., Ebola virus, Marburg virus), Coronaviridae (e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, etc.), Astroviridae (e.g., astrovirus), Bornaviridae (e.g., Bornavirus).

[0351] The term "neurodegenerative disease" refers to a condition caused by the loss of neurons and / or their myelin sheaths, which worsens over time and results in functional impairment.

[0352] The term "cardiovascular disease" refers to a class of diseases involving the heart or blood vessels.

[0353] The term "metabolic disease" refers to a disease caused by the accumulation or deficiency of certain metabolic substances, such as sugars, fats, proteins, purines, calcium, and copper, when the body's biochemical processes are disrupted.

[0354] The term "fibrosis" refers to a pathological process caused by inflammation, resulting in necrosis of organ parenchymal cells and an abnormal increase and excessive deposition of extracellular matrix within the tissue. In severe cases, it can lead to tissue structural damage and organ sclerosis.

[0355] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0356] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0357] The compound Ori described in the following examples is a compound of formula I and has the following structure:

[0358]

[0359] Example 1: NCL can be combined with MDM2

[0360] Co-immunoprecipitation (Co-IP) is a classic method for studying protein-protein interactions based on the specific interaction between antibodies and antigens.

[0361] 1. Hep3B liver cancer cells were lysed using IP lysis buffer (Thermo Scientific, catalog number 87788) and incubated overnight at 4°C with NCL antibody. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature for 2 hours by rotation. The NCL and its interacting protein complex bound to the magnetic beads were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C and held for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Western blot was then performed to detect whether NCL bound MDM2. The immunoblotting procedure is as follows: Protein samples are separated by SDS-PAGE electrophoresis. The separated proteins are transferred to a PVDF membrane and blocked with TBST buffer containing 5% skim milk for 1 hour at room temperature. Then, the membrane is incubated overnight at 4°C with primary antibody MDM2 (purchased from ProteinTech, catalog number 27883-1-AP) or primary antibody NCL (purchased from Cell Signaling Technology, catalog number 14574S). After washing with TBST, the membrane is incubated with HRP-labeled secondary antibody (purchased from Ibotek, catalog number AS014) at room temperature for 1 hour. The protein bands are visualized using an enhanced chemiluminescence detection kit (purchased from Ibotek, catalog number RM00021P). Figure 1 The results from A indicate that NCL can bind to MDM2.

[0362] 2. Mix 2 μg / mL recombinant human NCL (rhNCL, purchased from ACROBiosystems, NUL-H5253) and 2 μg / mL recombinant human MDM2 (rhMDM2, purchased from R&D Systems, E3-202-050) and incubate at 4°C for 7 hours. Then add the NCL antibody and incubate overnight at 4°C. Add Protein A / G magnetic beads (purchased from Thermo Scientific, catalog number 88802) and incubate at room temperature by rotation for 1.5 hours. Wash the magnetic beads three times with TBST buffer, add SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015), and heat to 100°C for 10 minutes. Adsorb the magnetic beads using a magnetic rack and collect the supernatant into a new tube. Then perform an immunoblotting assay to detect whether NCL binds to MDM2. Figure 1 The results of B indicate that NCL can bind to MDM2.

[0363] Example 2: Compound Ori recruits MDM2 in a NCL-dependent manner.

[0364] 1. We prepared the C-14 hydroxyl-biotinylated compound Ori (Bio-Ori-1). The specific preparation steps are as follows:

[0365]

[0366] Under nitrogen protection, compound 1 (100 mg, 0.29 mmol) and compound 2 (70 mg, 0.29 mmol) were added to a solution of dimethylformamide (DMF, 2 mL) with EDCI (166 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol). The mixture was stirred at room temperature for 16 hours, and the reaction progress was monitored by LCMS. After the reaction was complete, the impure product was purified by Prep-HPLC (Waters 2767 / Qda, Column: SunFire Sunfire C18, 19*250 mm, 10 μm; Mobile Phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 mL / min; gradient: 34%–44%; retention time: 7.6–8.3 min of 17 min). The pure fractions were combined and lyophilized under reduced pressure to give 34 mg of white solid compound Bio-Ori-1, with a yield of 20.17%.

[0367] LCMS: m / z = 591.6 [M+H] + ,t R =8.447min.Purity:100%(254nm).

[0368] 1H NMR(400MHz,DMSO-d6)δ6.38(2s,2H),6.00(s,1H),5.92-5.79(m,3H),5.61(s,1H),4.40(s,1H),4.34-4.26(m,1H) ,4.17-4.02(m,2H),3.83(d,J=10.2Hz,1H),3.53-3.49(m,1H),3.33(s,1H),3.10-3.05(m,1H),2.96(d,J=9.6Hz,1H ),2.84-2.79(m,1H),2.59-2.56(m,1H),2.50-2.43(m,1H),2.18-2.12(m,2H),2.09-2.00(m,7.6Hz,1H),1.86-1.8 1(m,1H),1.77-1.64(m,1H),1.64-1.39(m,7H),1.35-1.17(m,4H),1.12(d,J=6.8Hz,1H),1.00(s,3H),0.99(s,3H).

[0369] 13 C NMR(101MHz,DMSO-d6)δ207.68,172.06,163.19,151.33,119.83,96.20,74.51,73.63,72.04,62.97,62.26,61.49,59.66 ,59.54,55.80,54.31,41.87,40.93,39.37,38.83,34.25,33.81,33.20,30.75,29.81,28.43,28.40,24.56,22.14,20.19.

[0370] 2. We also prepared the C-1 hydroxyl-biotinylated compound Ori (Bio-Ori-2), and the specific preparation steps are as follows: (1)

[0372]

[0373] A mixture of compound 1 (1 g, 0.27 mmol), 2,2-dimethoxypropane (0.572 g, 5.49 mmol), p-TsOH (3 mg, 0.0137 mmol), and acetone (6 mL) was stirred and refluxed under N2 for 1 hour. The mixture was concentrated to dryness. The residue was diluted with dichloromethane (20 mL), washed with sodium bicarbonate aqueous solution (15 mL x 2), water (10 mL), and brine (15 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate in dichloromethane: 0–10%) to give compound 2 (1.0 g, 90.9%) as a white solid.

[0374] LCMS: m / z = 387.2 [M-OH] + ,Rt=1.894min.Purity:92.4%(214nm). (2)

[0376]

[0377] Under N2, EDCI (1.56 g, 8.16 mmol) and DMAP (1 g, 8.16 mmol) were added to a DMF (10 mL) solution of compound 2 (1.1 g, 2.72 mmol) and compound 3 (1 g, 4.08 mmol). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was purified by preparative HPLC (Welch Xtimate C18 200 × 30 mm × 5 μm water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to give compound 4 (317 mg, 17.84%) as a white solid.

[0378] LCMS: m / z = 613.3 [M-OH] + ,Rt=1.610min.Purity:96.31%(214nm). (3)

[0380]

[0381] A solution of compound 4 (317 mg, 0.5 mmol) in hydrochloric acid (2%, 2 mL) and THF (2 mL) was stirred at room temperature under N2 for 2 hours. LC-MS showed the reaction was complete. The pH was adjusted to 6 with sodium hydroxide (1 M.aq). The reaction solution was purified by preparative HPLC (Welch Ultimate C18 150 × 30 mm × 5 μm, water (0.1% FA)-MeCN, 5-95%, 60 mL / min) to give Bio-Ori-2 (47 mg, 15.83%) as a white solid.

[0382] LCMS: m / z = 573.6 [M-OH] + ,Rt=8.691min.Purity:100%(214nm).

[0383] 1 H NMR (400MHz, DMSO-d6) δ6.94(s,1H),6.43(s,1H),6.37(s,1H),6.14(s,1H),6.07(d,J=10.4Hz,1H),5.98(s ,1H),5.58(s,1H),4.79(s,1H),4.62-4.58(m,1H),4.35–4.26(m,1H),4.23–4.08(m,2H),4.01(d,J=10.4Hz, 1H),3.56–3.52(m,1H),3.13–3.04(m,1H),2.95(d,J=9.6Hz,1H),2.85–2.80(m,1H),2.58(d,J=12.4Hz,1H) ,2.43–2.31(m,1H),2.23(t,J=7.2Hz,2H),2.03–1.89(m,2H),1.64–1.24(m,13H),1.01(s,3H),1.05(s,3H).

[0384] 13 C NMR(101MHz,DMSO-d6)δ208.93,172.31,163.17,152.10,119.99,97.31,75.07,73.44,72.90,62.89,61.62,61.57,59.73 ,59.65,55.89,51.81,43.06,40.62,40.34,39.36,37.90,34.23,33.66,32.78,30.08,28.51,25.27,24.76,21.96,18.04.

[0385] 3. The procedure of the pull-down experiment is to fix a known substance (bait) on a carrier and use it to capture binding proteins (prey) and protein complexes that interact with the binding proteins from a complex mixture.

[0386] After mixing 6 μg / mL recombinant human NCL (rhNCL) and 6 μg / mL recombinant human MDM2 (rhMDM2), the mixture was incubated at 4°C for 7 hours. Then, 400 nM of Bio-Ori-1, Bio-Ori-2, biotin-labeled CRO (Bio-CRO: CCTCCTCCTCCTTCTCCTCCTCCTCC, negative control) or iSN04 (Bio-iSN04: AGATTAGGGTGAGGGTGA) was added, and the mixture was incubated at 4°C for 6 hours. Streptavidin agarose gel beads (purchased from Cytiva, catalog number 17511301) were added, and the mixture was incubated overnight at 4°C. The gel beads were washed four times with TBST buffer, and SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added. The mixture was heated to 100°C and held for 10 minutes. After centrifugation, the supernatant was collected. Then, an immunoblotting assay was performed to detect the downsinking product. Figure 2 The results of A and 2B indicate that Ori can bind to NCL but not to MDM2; however, in the presence of NCL, Ori can recruit MDM2 in reliance on NCL. Figure 2 The results of C indicate that CRO cannot bind to NCL or recruit MDM2. Figure 2 The results of D indicate that iSN04 can only bind to NCL, but cannot recruit MDM2 by relying on NCL.

[0387] 4. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and then incubated with different concentrations (0 μM, 200 nM, 500 nM, 1 μM, 5 μM, 10 μM, 20 μM) of Bio-Ori-1, Bio-Ori-2, Bio-CRO or Bio-iSN04 at 4 °C for 6 hours. Then, streptavidin agarose gel beads (Cytiva, catalog number 17511301) were added and incubated overnight at 4 °C. After repeatedly washing the Bio-Ori-1, Bio-Ori-2, Bio-CRO, or Bio-iSN04 bound to the gel beads and the proteins they captured with IP lysis buffer (Thermo Scientific, catalog number 87788), SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. The supernatant, the pull-down product, was collected after centrifugation. The pull-down product was then detected using Western blotting. Figure 3 The results of A and 3B indicate that Ori can capture NCL and MDM2; Figure 3 The results of C indicate that CRO cannot capture NCL and MDM2; Figure 3 The results from D indicate that iSN04 can capture NCL, but not MDM2.

[0388] 5. Hep3B liver cancer cells were incubated with DMSO (Vehicle) or 1 μM Bio-Ori-1 for 12 hours. After cell lysis, the supernatant was incubated overnight at 4°C with streptavidin agarose gel beads (purchased from Cytiva, catalog number 17511301). The Bio-Ori-1 bound to the gel beads and the captured proteins were washed multiple times with IP lysis buffer (purchased from Thermo Scientific, catalog number 87788). SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. After centrifugation, the supernatant, i.e., the pull-down product, was collected. The pull-down product was detected using Western blotting. The results are as follows: Figure 4 As shown in A, Ori can capture NCL and MDM2.

[0389] 6. Hep3B liver cancer cells were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT). After 48 hours, the cells were incubated with 1 μM Bio-Ori-1 for 12 hours to lyse the cells. The supernatant was then incubated overnight at 4°C with streptavidin agarose gel beads. The Bio-Ori-1 bound to the gel beads and the captured proteins were washed multiple times with IP lysis buffer (Thermo Scientific, catalog number 87788). SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. After centrifugation, the supernatant (the pull-down product) was collected and detected using Western blotting. Results are as follows: Figure 4 B, Silencing the NCL can block Ori from recruiting MDM2.

[0390] 7. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and incubated with different concentrations (0 μM, 1 μM, 5 μM, 10 μM, 20 μM) of Ori or iSN04 at 4°C for 6 hours. Then, NCL antibody was added and incubated overnight at 4°C. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature with rotation for 1.5 hours. The NCL bound to the magnetic beads and the captured proteins were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. An immunoblotting assay was then performed to detect whether Ori or iSN04 affected the interaction between NCL and MDM2. Figure 5 The results of A indicate that Ori does not affect the interaction between NCL and MDM2. Similar results were obtained using other Formula I compounds, yielding results similar to those for Ori. However, Figure 5 The results of B indicate that iSN04 blocks the binding of NCL to MDM2.

[0391] 8. The above results indicate that compounds of formula I (such as Ori) recruit MDM2 through interaction with NCL, while iSN04, although interacting with NCL, cannot recruit MDM2 through this interaction. Further analysis revealed that compounds of formula I (such as Ori) do not affect the binding of NCL to MDM2, but iSN04 blocks this binding. These data suggest that not all molecules interacting with NCL can recruit MDM2; whether an NCL-interacting molecule can recruit MDM2 depends on whether it affects the formation of the NCL-MDM2 complex. We simulated the three-dimensional structure of the NCL-MDM2 complex using AlphaFold2 and predicted the conformation of the interaction between compounds of formula I (such as Ori) and the NCL-MDM2 complex using HDOCK. The results show that compounds of formula I (such as Ori) do indeed recruit MDM2 through interaction with NCL, and the possible modes of interaction are as follows: Figure 6 As shown in A. Therefore, we believe that compounds of formula I (such as Ori) can act as recruitment elements for MDM2 to prepare PROTACs that target IRAK4 for degradation, with possible modes of action as follows. Figure 6 As shown in B.

[0392] Example 3: Preparation of PROTAC molecules targeting IRAK4 based on compound of formula I

[0393] In this embodiment, Ori, a compound of formula I, was used as the recruitment element for the E3 ligase, and Zimlovisertib was used as the IRAK4 ligand to prepare PROTAC (hereinafter referred to as Ori-Zim) that degrades IRAK4.

[0394] The preparation steps of Ori-Zim are as follows:

[0395] (1) Synthesis of compound INT-3

[0396]

[0397] Under argon protection, KHMDS (12.1 mL, 12.07 mmol, 1 M) was slowly added to a solution of compounds INT-1 (1.1 g, 5.49 mmol) and INT-2 (888 mg, 5.49 mmol) in DMF (14 mL) at -10 °C. The reaction mixture was then stirred at -10 °C for 2 hours under Ar atmosphere. After the reaction was complete, the reaction mixture was diluted with EA (25 mL) and quenched with saturated NH4Cl solution (25 mL) at 10 °C. The reaction mixture was then extracted with EA (25 mL x 3). The organic layer was washed with saturated NaCl (25 mL) and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:EA = 1:1, to give compound INT-3 (pale yellow solid, 1.3 g, yield: 68.96%).

[0398] LCMS: m / z = 344.2 [M+H] + ,Rt=10.162min,Purity:98.78%(214nm).

[0399] (2) Synthesis of compound INT-4

[0400]

[0401] NBS (1.35 g, 7.57 mmol) was added to a solution of compound INT-3 (1.3 g, 3.79 mmol) in ACN (30 mL). The reaction mixture was stirred at 60 °C for 0.75 h under an Ar atmosphere. After the reaction was complete, the reaction mixture was diluted with EA (25 mL) and quenched with Na2S2O3 solution (sat.aq, 10 mL). The reaction mixture was then extracted with EA (25 mL x 3). The organic layer was washed with saturated NaCl (25 mL) and dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:EA = 1:1, to give compound INT-4 (yellow solid, 0.95 g, yield: 59.38%).

[0402] LCMS: m / z = 422.1, 424.1, [M+H] + ,Rt=11.765min,Purity:100%(214nm).

[0403] (3) Synthesis of compound INT-5

[0404]

[0405] Compound INT-4 (950 mg, 2.25 mmol) was slowly added to a solution of DMSO (9 mL) with K₂CO₃ (730 mg, 4.50 mmol) and H₂O₂ (30%, 9 mL). The reaction mixture was then stirred at 15 °C for 0.5 h under an Ar atmosphere. After the reaction was complete, the reaction mixture was diluted with water (10 mL). The mixture was filtered, and the filter cake was concentrated under reduced pressure to give compound INT-5 (white solid, 420 mg, yield: 42.40%).

[0406] LCMS: m / z = 440.0, 442.0, [M+H] + ,Rt=9.239min,Purity:96.60%(214nm).

[0407] (4) Synthesis of compound INT-6

[0408]

[0409] To a solution of compound INT-5 (420 mg, 0.95 mmol) in DMAc (7 mL), K₂CO₃ (395 mg, 2.86 mmol), Xphos (91 mg, 0.19 mmol), Pd(dba)₃ (174 mg, 0.19 mmol), and methyl 5-hexynate (361 mg, 2.86 mmol) were added. The reaction mixture was then stirred at 100 °C for 5.5 hours under an Ar atmosphere. After the reaction was complete, the reaction mixture was concentrated and purified by silica gel column chromatography, eluting with MeOH:DCM = 5%, to give compound INT-6 (yellow oil, 120 mg (crude product), yield: 26.02%).

[0410] LCMS: m / z = 486.2 [M+H] + ,Rt=1.496min,Purity:8.49%(214nm).

[0411] (5) Synthesis of compound INT-7

[0412]

[0413] LiOH (5.4 mL, 5.4 mmol, 1 M) was added to a solution of compound INT-6 (260 mg, 0.54 mmol) in THF (5 mL). The reaction mixture was then stirred at room temperature for 1 hour under an Ar atmosphere. After the reaction was complete, the reaction mixture was diluted with water and extracted with EA (5 mL x 2). The pH of the aqueous phase was adjusted to 2-3 with citric acid. The reaction mixture was then extracted with EA (10 mL x 3). The organic layer was washed with saturated NaCl (10 mL) and then dried over anhydrous Na2SO4. After filtration, the organic layer was concentrated under reduced pressure to give compound INT-7 (yellow oily substance, 150 mg (crude product), yield: 58.92%).

[0414] LCMS: m / z = 472.0 [M+H] + ,Rt=1.254min,Purity:54.15%(214nm).

[0415] (6) Synthesis of compound Ori-Zim

[0416]

[0417] Compounds INT-7 (150 mg, 0.32 mmol) and INT-8 (128 mg, 0.35 mmol) were added to a solution of DMF (4 mL) with EDCI (182 mg, 0.95 mmol) and DMAP (39 mg, 0.32 mmol). The reaction mixture was then stirred overnight at room temperature under an Ar atmosphere. The reaction mixture was concentrated under vacuum and purified by reversed-phase chromatography (ACN / water (FA: 0.1%): 46%–56%) to give the target product Ori-Zim (white solid, 31.40 mg, yield: 12.00%).

[0418] LCMS: m / z = 818.4 [M+H] + ,Rt=10.137min,Purity:100%(214nm).

[0419] 1 H NMR(400MHz,MeOD-d4)δ8.63(s,1H),7.99(s,1H),7.85(s,1H),6.08(s,1H),5.96(s,1H),5.53(s,1H),5.03–4.88(m,1H),4.68–4.62 (m,1H),4.47–4.40(m,1H),4.27-4.25(m,1H),4.23–4.17(m,1H),4.06(s,3H),4.03-4.01(m,1H),3.67-3.65(m,1H),3.46–3.40(m,1 H),3.07-3.05(m,1H),2.76-2.64(m,1H),2.62–2.57(m,2H),2.56–2.47(m,3H),2.25-2.16(m,1H),1.95-1.92(m,3H),1.83–1.74(m, 2H),1.70-1.68(m,1H),1.65–1.53(m,3H),1.44-1.42(m,1H),1.33-1.30(m,1H),1.26-1.24(m,1H),1.14-1.09(m,6H),1.06(s,3H).

[0420] 19 F NMR(377MHz,MeOD-d4)δ-200.51(s).

[0421] Example 4: PROTAC-induced formation of quaternary complexes

[0422] 1. Human T lymphocytes (Jurkat) were incubated with 1 μM Ori or Ori-Zim (prepared in Example 3) for 12 hours, with 5 μM MG132 added during the last 6 hours of incubation. After cell lysis, the cells were incubated overnight at 4°C with an antibody against NCL. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature for 2 hours by rotation. The NCLs bound to the magnetic beads and the proteins they captured were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Immunoblot experiments were then performed. The results are as follows: Figure 7 As shown in Figure A, in the presence of Ori-Zim, the antibody against NCL can capture NCL, MDM2, and IRAK4, indicating that Ori-Zim can form a quaternary complex of MDM2-NCL-PROTAC-IRAK4 with NCL, MDM2, and IRAK4.

[0423] 2. Human T lymphocytes (Jurkat) were incubated with 1 μM Ori or Ori-Zim (prepared in Example 3) for 12 hours, with 5 μM MG132 added during the last 6 hours of incubation. After cell lysis, the cells were incubated overnight at 4°C with an antibody against MDM2. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature for 2 hours by rotation. The MDM2 bound to the magnetic beads and the proteins captured were washed with IP lysis buffer (Thermo Scientific, catalog number 87788), and SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added. The mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. Immunoblot experiments were then performed. The results are as follows: Figure 7 As shown in Figure B, in the presence of Ori-Zim, the antibody against MDM2 can capture MDM2, NCL, and IRAK4, indicating that Ori-Zim can form a quaternary complex of MDM2-NCL-PROTAC-IRAK4 with NCL, MDM2, and IRAK4.

[0424] 3. Transfect human T lymphocytes (Jurkat) with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT) for 48 hours, then incubate the cells with 1 μM Ori-Zim for 12 hours. Add 5 μM MG132 during the last 6 hours of incubation. After cell lysis, incubate with MDM2 antibody overnight at 4°C. Add Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) and incubate at room temperature for 2 hours. Wash the MDM2 bound to the magnetic beads and the captured proteins with IP lysis buffer (Thermo Scientific, catalog number 87788), add SDS-PAGE protein loading buffer (Beyotime, catalog number P0015), and heat to 100°C for 10 minutes. Adsorb the magnetic beads using a magnetic rack and transfer the supernatant to a new tube. Then, an immunoblotting experiment was performed. The results are as follows: Figure 7 As shown in C, in the presence of Ori-Zim, the antibody against MDM2 could not capture IRAK4 after knocking down NCL, indicating that NCL is located between MDM2 and IRAK4 in the Ori-Zim-induced quaternary complex.

[0425] 4. Transfect human T lymphocytes (Jurkat) with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT) for 48 hours, then incubate the cells with 1 μM Ori-Zim for 12 hours. Add 5 μM MG132 during the last 6 hours of incubation. After cell lysis, incubate with NCL antibody overnight at 4°C. Add Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) and incubate at room temperature for 2 hours. Wash the NCL bound to the magnetic beads and the captured proteins with IP lysis buffer (Thermo Scientific, catalog number 87788), add SDS-PAGE protein loading buffer (Beyotime, catalog number P0015), and heat to 100°C for 10 minutes. Adsorb the magnetic beads using a magnetic rack and collect the supernatant into a new tube. Then perform Western blotting experiments. The results are as follows Figure 7 As shown in D, in the presence of Ori-Zim, the antibody against NCL can still capture NCL and IRAK4 after knocking down MDM2, indicating that NCL is located between MDM2 and IRAK4 in the Ori-Zim-induced quaternary complex.

[0426] The above results indicate that PROTAC based on Formula I can induce the formation of a quaternary complex of MDM2-NCL-PROTAC-IRAK4, with NCL positioned between MDM2 and IRAK4 in this quaternary complex. This mode of action differs from the traditional PROTAC molecule-induced formation of an E3-PROTAC-target protein ternary complex.

[0427] Example 5: Ori-Zim can degrade IRAK4

[0428] 1. Human T lymphocytes (Jurkat) were incubated with 0, 0.1, 0.25, 0.5, 1.0, and 2.5 μM Ori-Zim (prepared in Example 3). Cell samples were collected after 18 hours. Total protein was extracted using RIPA lysis buffer (purchased from Beyotime, catalog number: P0013B). IRAK4 protein degradation was detected by Western blotting. The procedure was as follows: Protein samples were separated by SDS-PAGE electrophoresis. The separated proteins were transferred to a PVDF membrane, blocked with TBST buffer containing 5% skim milk for 1 hour at room temperature, and then incubated overnight at 4°C with IRAK4 primary antibody (purchased from CellSignaling Technology, catalog number 4363S). After washing with TBST, the membrane was incubated with HRP-labeled secondary antibody (purchased from Ibrex, catalog number AS014) at room temperature for 1 hour. The protein bands were visualized using an enhanced chemiluminescence detection kit (purchased from Ibrex, catalog number RM00021P). The results are as follows: Figure 8 As shown in Figure A, Ori-Zim can reduce IRAK4 protein levels in a concentration-dependent manner.

[0429] 2. Human T lymphocytes (Jurkat) were incubated with 1 μM Ori-Zim, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting experiments to detect the degradation of IRAK4 protein. Results are as follows: Figure 8 As shown in B, Ori-Zim can reduce IRAK4 protein levels in a time-dependent manner.

[0430] 3. Human T lymphocytes (Jurkat) were incubated with solvent DMSO (Vehicle) or 1 μM of compounds Ori, 1 μM Zim, 1 μM Ori + 1 μM Zim, 1 μM Ori-Zim, or 1 μM KT-474 (positive control). After 12 hours, cell samples were collected for protein extraction and subsequent Western blotting experiments to detect the degradation of IRAK4 protein. Results are as follows: Figure 8 As shown in C, Ori-Zim can reduce the protein level of IRAK4, and the effect is comparable to that of KT-474.

[0431] 4. Human monocytes THP-1 were incubated with 0, 0.25, 0.5, 1.0, 2.5, and 5 μM Ori-Zim (prepared in Example 3). After 18 hours, cell samples were collected, and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, catalog number: P0013B). Western blotting was used to detect the degradation of IRAK4 protein. The results are as follows: Figure 8 As shown in D, Ori-Zim can reduce IRAK4 protein levels in a concentration-dependent manner.

[0432] 5. Human monocytes THP-1 were incubated with 2 μM Ori-Zim, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting experiments to detect the degradation of IRAK4 protein. Results are as follows: Figure 8 As shown in E, Ori-Zim can reduce IRAK4 protein levels in a time-dependent manner.

[0433] 6. Human synovial fibroblasts (RA-FLSs) were incubated with 0, 0.1, 0.25, 0.5, 1.0, and 2.5 μM Ori-Zim (prepared in Example 3). After 18 hours, cell samples were collected, and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, catalog number: P0013B). Western blotting was used to detect the degradation of IRAK4 protein. The results are as follows: Figure 8 As shown in F, Ori-Zim can reduce IRAK4 protein levels in a concentration-dependent manner.

[0434] 7. Human synovial fibroblasts (RA-FLSs) were incubated with 1 μM Ori-Zim, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting experiments to detect the degradation of IRAK4 protein. Results are as follows: Figure 8 As shown in G, Ori-Zim can reduce IRAK4 protein levels in a time-dependent manner.

[0435] 8. Human keratinocytes (HaCaT) were incubated with 0, 0.1, 0.25, 0.5, 1.0, and 2.5 μM Ori-Zim (prepared in Example 3). After 18 hours, cell samples were collected, and total protein was extracted using RIPA lysis buffer (purchased from Beyotime, catalog number: P0013B). Western blotting was used to detect the degradation of IRAK4 protein. The results are as follows: Figure 8 As shown in H, Ori-Zim can reduce IRAK4 protein levels in a concentration-dependent manner.

[0436] 9. Human keratinocytes (HaCaT) were incubated with 1 μM Ori-Zim, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting experiments to detect the degradation of IRAK4 protein. Results are as follows: Figure 8 As shown in Figure I, Ori-Zim can reduce IRAK4 protein levels in a time-dependent manner.

[0437] Example 6: PROTAC promotes IRAK4 ubiquitination

[0438] 1. Human T lymphocytes (Jurkat) were incubated with DMSO (Vehicle) or 1 μM Ori-Zim for 12 hours, with 5 μM MG132 added during the last 6 hours of incubation. Cell samples were collected for protein extraction and subsequent Western blotting to detect IRAK4 protein degradation. Results are as follows: Figure 9 As shown in Figure A, MG132 can block the degradation of IRAK4 by Ori-Zim, indicating that the degradation of IRAK4 by Ori-Zim depends on the ubiquitin-proteasome pathway.

[0439] 2. Human T lymphocytes (Jurkat) were incubated with DMSO (Vehicle) or 1 μM Ori-Zim for 12 hours, with 5 μM MG132 added during the last 6 hours of incubation. After cell lysis, the cells were incubated overnight at 4°C with an antibody against IRAK4. Protein A / G magnetic beads (Thermo Scientific, catalog number 88802) were added and incubated at room temperature for 2 hours by rotation. After washing the IRAK4 bound to the magnetic beads with IP lysis buffer (Thermo Scientific, catalog number 87788), SDS-PAGE protein loading buffer (Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. The magnetic beads were then adsorbed using a magnetic rack, and the supernatant was transferred to a new tube. The ubiquitination level of IRK4 was then detected using Western blotting. The results are as follows: Figure 9 As shown in B, Ori-Zim promotes the ubiquitination of IRAK4.

[0440] Example 7: PROTAC-dependent MDM2 and NCL-mediated degradation of IRAK4

[0441] 1. Human T lymphocytes (Jurkat) were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or NCL siRNA (siNCL: GGAUGACGACGACGACGAAGATT) for 48 hours, and then incubated with DMSO (Vehicle) or 1 μM Ori-Zim (prepared in Example 3) for 24 hours. Cell samples were collected for protein extraction and subsequent Western blotting to detect protein degradation. Results are as follows: Figure 10 As shown in Figure A, silencing NCL can reduce the degradation of IRAK4 by Ori-Zim, indicating that Ori-Zim-dependent NCL-mediated degradation of IRAK4.

[0442] 2. Human T lymphocytes (Jurkat) were transfected with negative control siRNA (siNC: UUCUCCGAACGUGUCACGUTT) or MDM2 siRNA (siMDM2: GCUUGGCCUACAGUCAUCUTT) for 48 hours, and then incubated with DMSO (Vehicle) or 1 μM Ori-Zim (prepared in Example 3) for 24 hours. The corresponding cell samples were collected for protein extraction and subsequent Western blotting experiments to detect protein degradation. Results are as follows: Figure 10 As shown in B, silencing MDM2 can reduce the degradation of IRAK4 by Ori-Zim, indicating that Ori-Zim-dependent MDM2-mediated degradation of IRAK4.

[0443] Example 8: Ori-Zim can inhibit T cell function

[0444] Human T lymphocytes (Jurkat) were incubated with solvents DMSO (Vehicle) or 1 μM Ori, 1 μM Zim, 1 μM Ori + 1 μM Zim, or 1 μM Ori-Zim. After 48 hours, cells were collected, and the mRNA levels of inflammatory cytokines IL-2, TNF-α, and IFN-γ were detected using real-time quantitative PCR. Results are as follows: Figure 11 As shown, Ori-Zim can reduce the mRNA levels of IL-2, TNF-α, and IFN-γ.

[0445] Example 9: Ori-Zim can inhibit the function of monocytes.

[0446] Human monocytes (THP-1) were pre-incubated with 100 nM PMA to induce an M0 macrophage state. Then, 15 ng / mL LPS and 20 mg / mL IFN-γ were added to induce polarization into M1 macrophages. Solvents DMSO (Vehicle) or 2 μM Ori, 2 μM Zim, 2 μM Ori + 2 μM Zim, and 2 μM Ori-Zim were added, and cells were incubated for 48 hours. Cells were then collected, and the mRNA levels of CD68, IL-1β, TNF-α, and IL-6 were detected using real-time quantitative PCR. Results are as follows: Figure 12 As shown, Ori-Zim can reduce the mRNA levels of CD68, IL-1β, TNF-α, and IL-6.

[0447] Example 10: Ori-Zim can inhibit the function of synovial fibroblasts.

[0448] Human synovial fibroblasts (RA-FLSs) were incubated with solvents DMSO (Vehicle) or 1 μM Ori, 1 μM Zim, 1 μM Ori + 1 μM Zim, or 1 μM Ori-Zim. After 48 hours, cells were collected, and the mRNA levels of TNF-α, IL-1β, CXCL8, CXCL11, and CCL2 were detected using real-time quantitative PCR. The results are as follows: Figure 13 As shown, Ori-Zim can reduce the mRNA levels of TNF-α, IL-1β, CXCL8, CXCL11, and CCL2.

[0449] Example 11: Ori-Zim can inhibit the function of keratinocytes

[0450] Human keratinocytes (HaCaT5) were incubated with a pentad of factors (M5, including IL-17A, IL-22, Oncostatin M, IL-1α, and TNF-α, each at a concentration of 2.5 ng / mL). After treatment with DMSO (Vehicle) or 1 μM Ori, 1 μM Zim, 1 μM Ori + 1 μM Zim, or 1 μM Ori-Zim for 24 hours, cells were collected. Real-time quantitative PCR was used to detect the mRNA levels of IL-6, TNF-α, IL-19, S100A7, DEFB4A, CXCL8, and CCL2. Results are as follows: Figure 14 As shown, Ori-Zim can reduce the mRNA levels of IL-6, TNF-α, IL-19, S100A7, DEFB4A, CXCL8, and CCL2.

[0451] Example 12: Ori-Zim can alleviate arthritis in CIA mice.

[0452] A collagen-induced arthritis (CIA) mouse model was established by immunizing 6-8 week old male DBA / 1J mice with bovine type II collagen for 28 days. CIA mice were then administered a solvent or 10 μmol / kg Ori, 10 μmol / kg Zim, 10 μmol / kg Ori + 10 μmol / kg Zim, or 10 μmol / kg Ori-Zim via tail vein injection. Injections were given twice weekly for 28 days. Results are as follows: Figure 15 As shown, Ori-Zim can alleviate arthritis in CIA mice.

[0453] Example 13: Ori-Zim can alleviate psoriasis-like symptoms in a mouse model.

[0454] A mouse model of psoriasis was established by applying IMQ (5%, 62.5 mg) to the skin of the back and ears of 6-8 week old male BALB / c mice for eight consecutive days. Simultaneously, mice were administered a tail vein injection of the solvent or 10 μmol / kg Ori, 10 μmol / kg Zim, 10 μmol / kg Ori + 10 μmol / kg Zim, or 10 μmol / kg Ori-Zim, or a subcutaneous injection of 10 mg / kg dexamethasone. Injections were given once daily. Results are as follows: Figure 16 As shown, Ori-Zim can alleviate psoriasis-like symptoms in mice, with effects comparable to dexamethasone.

[0455] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0456] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0457] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound that targets the degradation of IRAK4 protein, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, said compound having the following structure: in, ML is the recruitment element part of the MDM2 protein; L is a linking group; q is an integer from 1 to 15; V1, V2, and Y are independently selected from: C, N, or -N + -O - ; R P1 It is one or more independent substituents on the ring, selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: D, halogen, cyano, nitro, azide, -OR 101 -C(O)R 101 -C(S)R 101 -C(O)OR 101 -C(S)SR 101 -OC(O)R 101 -OC(S)R 101 -OC(S)SR 101 -C(O)NR 102 R 103 -OC(O)NR 102 R 103 -NR 102 C(O)OR 103 -NR 102 SO2R 103 -SO2NR 102 R 103 -OSO2NR 102 R 103 -NR 102 C(O)R 103 -NR 102 R 103 -SR 101 -SOR 101 -SO2R 101 -OSO2R 101 -SO3H, -PO3H, -OP(O)(OR 101 -P(O)(OR) 102 (OR) 103 -P(O)NR 102 R 103 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic); R P2 Selected from: -(C0-C6 alkylene)-(C3-C 11 Cycloalkyl), -(C0-C6 alkylene)-(3-11 membered heterocyclic group), wherein the C0-C6 alkylene, C3-C 11 The hydrogen atoms in cycloalkyl and 3-11 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: hydrogen, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R P3 The ring may be absent or may contain one or more independent substituents selected from: H, halogen, cyano, nitro, -CF3, -OCF3, C. 1-10 Alkyl, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -SC 0-10 Alkyl, -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C3-C 10 The hydrogen atoms in cycloalkyl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic); Each R 101 R 102 and R 103 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); The MDM2 protein recruitment element has the following structure: in, Represents a single or double bond, and points a and b are shown. Not both are double bonds; R1 to R4, R7 to R 11 Independently selected from: H, =O, =C(H)-R A =NN(R) B R C ), hydroxyl, amino, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, Among them, R A Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R B and R C Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R F Selected from: single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynylene, -O-, -S-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OS(O)2-, -OC(O)N(R) a )-、-C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)O-、-N(R a )C(O)N(R b )-、-N(R a -, -S(O)2-, -S(O)2N(R) a )-、-N(R a -S(O)2-, -S(O)-, -S(O)N(R) a )-、-N(R a )S(O)-、-OP(O)(OR b )O-、-P(O)(OR b -O-, -P(O)-, -OP(O)N(R) a )-、-P(O)N(R a )-、-P(O)(N(R a R b ))-、-OP(O)(OR b )2N(R a )-、-P(O)(OR b )2N(R a )-、-N(R a )P(O)(OR b )O-、-N(R a )P(O)-; where, R a and R b Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R E Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl groups, monosaccharide residues, amino acid residues, and nitric oxide (NO) donor residues; Q represents a single bond or C1-C. 20 Alkylene, wherein 0-6 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) c )-、-N(R c )C(O)-、-N(R c )C(O)O-、-N(R c )C(O)N(R d )-、-N(R c -, -S(O)2-, -S(O)2N(R) c )-、-N(R c -S(O)2-, -S(O)-, -S(O)N(R) c )-、-N(R c )S(O)-、-OP(O)(OR d )O-、-P(O)(OR d -O-, -P(O)-, -OP(O)N(R) c )-、-P(O)N(R c )-、-P(O)(N(R c R d ))-、-OP(O)(OR d )2N(R f )-、-P(O)(OR d )2N(R c )-、-N(R c )P(O)(OR d )O-、-N(R c P(O)-、 Where m1 is selected from integers between 1 and 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and R c and R d Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); each -Cy- is independently a optionally substituted divalent ring selected from the following: arylene, cycloalkylene, heterocyclic; R5 and R6 are independently selected from: H, hydroxyl, amino, halogen, cyano, nitro, azide, -CF3, -OCF3, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); The above C0-C6 alkylene groups, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The H in the aryl or 4-10 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), monosaccharide residues, amino acid residues; Alternatively, R1, R2, R3, R4, R5, R6, R7, R8, and R9 may be selected from one or more of the following schemes: (1) R1 and R2 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (2) R2 and R3 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (3) R1 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (4) R4 and R5 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (5) R4 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (6) R5 and R6 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (7) R5 and R7 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; (8) R8 and R9 together with the carbon atoms they are attached to form aliphatic rings, aromatic rings or heterocycles; The H on the aliphatic ring, aromatic ring, or heterocycle is optionally substituted with one or more groups selected from the following: =O, ... Halogen, cyano, nitro, azide, -OR', -C(O)R', -C(S)R', -C(O)OR', -C(S)SR', -OC(O)R', -OC(S)R', -OC(S)SR', -C(O)NR'R”, -OC(O)NR'R”, -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -OSO2NR'R”, -NR'C(O)R”, -NR'R”, -SR', -SOR', -SO2R', -OSO2R', -SO3H, -PO3H, -OP(O)(OR'), -P(O)(OR')(OR”), -P(O)NR'R”, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues, wherein the 0-4 methylene units in the C0-C6 alkylene group are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)O-, -OC(O)O-, -C(O)N(R) c )-、-N(R e )C(O)-、-N(R e )C(O)O-、-N(R e )C(O)N(R f )-、-N(R e -, -S(O)2-, -S(O)2N(R) e )-、-N(R e -S(O)2-, -S(O)-, -S(O)N(R) e )-、-N(R e )S(O)-、-OP(O)(OR f )O-、-P(O)(OR f -O-, -P(O)-, -OP(O)N(R) f )-、-P(O)N(R f )-、-P(O)(N(R e R f ))-、-OP(O)(OR e )2N(R f )-、-P(O)(OR f )2N(R e )-、-N(R e )P(O)(OR f )O-、-N(R e P(O)-、 Where n1 is selected from integers between 1 and 10, and R e and R f Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C3-C 10 cycloalkyl, C6-C 10 The hydrogen atom on the aryl or 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 Alkyl); wherein, R x and R y Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Each R' and R" is independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); Preferably, the MDM2 protein recruitment element is selected from the following structures: in, R 21 Selected from: H, =O, -O(C) 0-10 Alkyl), -OC(O)(C 0-10 alkyl groups and -O-monosaccharide residues; R 22 Selected from: H, -O(C) 0-10 Alkyl), -OC(O)(C 0-10 alkyl groups and -O-monosaccharide residues; R 23 and R 24 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein, the C 0-10 The hydrogen atom on the alkyl group may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); X is either O or S; R 25 Selected from: H, =O, Cl-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl), Wherein, the C 0-10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R 26 Selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), -(C0-C6 alkenyl)-(C6-C 10 aryl), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); wherein, the C 0-10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R 31 Selected from: H, halogens, C1-C6 alkyl groups, -O(C 0-6 Alkyl), -O(C) 2-12 alkenyl), -N(C) 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(phenyl); R 32 and R 33 Independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or R 32 and R 33 Together with the nitrogen atom it is attached to, they form 4-8 membered heterocyclic groups; More preferably, the MDM2 protein recruitment element has the following structure: in, R 12 Selected from: H, Where Q1 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10 Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E1 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R 13 Selected from: H, Where Q2 is a single bond or C1-C 10 Alkylene, wherein 0-3 methylene units are independently substituted with the following groups: -Cy-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -C(S)S-, -C(O)N(C 0-10 Alkyl)-, -S(O)2-, -S(O)2N(C 0-10 Alkyl group, -PO2-, -P(O)(N(C) 0-10 Alkyl group -, -N(C) 0-10 alkyl)-, -N(C 0-10 Alkyl)C(O)-, -N(C 0-10 Alkyl)S(O)2-, -P(O)-, Where m1 is selected from integers between 0 and 10; R E2 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), monosaccharide residues, amino acid residues, nitric oxide (NO) donor residues; wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 The hydrogen atoms in cycloalkyl, phenyl, and 4-10 membered heterocyclic groups are optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); R 14 and R 15 Independently selected from: H, C1-C 10 Alkyl and monosaccharide residues.

2. The compound according to claim 1, characterized in that, The ML portion is selected from the following structure: Among them, R1', R2', R3', R7', R 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 'Respectively R1, R2, R3, R7, R 21 R 22 R 23 R 24 R 25 R 27 R 31 R 32 The divalent group obtained after the ligation reaction; ①, ②, ③, ④, ⑤, ⑥, ⑦, ⑧, ⑨, and ⑩ are available connection sites. When they are not used as connection sites, the corresponding R1', R2', R3', R7', and R... 21 '、R 22 '、R 23 '、R 24 '、R 25 '、R 27 '、R 31 '、R 32 'Respectively R1, R2, R3, R7, R 21 R 22 R 23 R 24 R 25 R 27 R 31 R 32 ; Preferably, the ML portion is selected from the following structures: Preferably, the ML portion is selected from the following structures:

3. The compound according to claim 1 or 2, characterized in that, L has the following structure: Wherein, L1 is a divalent group connected to ML, which is selected from: single bond, -O-(C0-C6 alkylene)-, -S-(C0-C6 alkylene)-, -N(R L1 )-(C0-C6 alkylene)-, -N(R L2 )C(O)-(C0-C6 alkylene)-、-OP(O)(OR L1 -O-(C0-C6 alkylene)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -CON(R) L1 -(C0-C6 alkylene)-, -SO2-(C0-C6 alkylene)-, -SO-(C0-C6 alkylene)-; L3 is a divalent group attached to the ring, selected from: single bond, -(C0-C6 alkylene)-(C2 ... 10 (-(C0-C6 alkylene)-(C2-C6 ... 10 (-(C0-C6 alkylene)-(C6-C6) 10 aryl)-(C2-C 10 (-(C0-C6 alkylene)-, -(C6-C6)-(C6-C6) 10 aryl)-(C2-C 10 -(C0-C6 alkylene)-, -(C0-C6 alkylene)-O-, -(C0-C6 alkylene)-S-, -(C0-C6 alkylene)-C(O)-, -(C0-C6 alkylene)-C(S)-, -(C0-C6 alkylene)-N(R) L3 )-、-(C0-C6 alkylene)-CON(R L3 )-、-(C0-C6 alkylene)-N(R L3 CO-, -(C0-C6 alkylene)-SO2-, -(C0-C6 alkylene)-SO-, -(C0-C6 alkylene)-(4-10 heterocyclic)-; L2 is a C1-C50 hydrocarbon chain (e.g., a C1-C20 alkyl chain) that is saturated or unsaturated with a single bond or divalent valence, consisting of 0-6 methylene units independently substituted with the following: -CY-, -O-, -S-, -SS-, -C(O)-, -C(S)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 )C(O)O-、-N(R L2 )C(O)N(R L2 )-、-N(R L2 -, -S(O)2-, -S(O)2N(R) L2 )-、-N(R L2 -S(O)2-, -S(O)-, -S(O)N(R) L2 )-、-N(R L2 )S(O)-、-P(O)(OR L2 -O-, -P(O)-, -P(O)N(R) L2 )-、-P(O)(N(R L2 )2)-、-OP(O)(OR L2 )2N(R L2 )-、-P(O)(OR L2 )2N(R L2 )-、-N(R L2 )P(O)(OR L2 )O-、-N(R L2 P(O)-, -Si(R) L2 )2-、-C(=N-CN)-、 Amino acid residues, nucleotide residues, oligonucleotide residues, oligopeptide residues, wherein m2 is selected from an integer selected from 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), and each -CY- is independently a divalent ring selected from the optionally substituted groups: arylene, cycloalkylene, heterocyclic; the H in the hydrocarbon chain may optionally be substituted by one or more groups selected from the group: halogen, cyano, nitro, azido, -OR L0 -C(O)R L0 -C(S)R L0 -C(O)OR L0 -C(S)SR L0 -OC(O)R L0 -OC(S)R L0 -OC(S)SR L0 -C(O)N(R) L0 )2、-OC(O)N(R L0 )2、-N(R L0 )C(O)OR L0 -N(R) L0 SO2R L0 -SO2N(R) L0 )2、-OSO2N(R L0 )2、-N(R L0 )C(O)R L0 -N(R) L0 )2、-SR L0 -SOR L0 -SO2R L0 -OSO2R L0 C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R L0 R L1 R L2 and R L3 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), wherein the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C0-C6 alkylene, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in the aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, hydroxyl, amino, mercapto, carboxyl, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Preferably, each -CY- is independently selected from the following: Among them, R L4 R L5 Independently selected from: H, OH, halogens, C 1-8 Alkyl, O(C) 1-8 Alkyl), S(C) 1-8 Alkyl), NH(C) 1-8 Alkyl), N(C) 1-8 Alkyl)2, C 3-11 Cyclic hydrocarbon group, C 3-11 Heterocyclic hydrocarbon groups, O(C) 1-8 cyclic hydrocarbon group), S(C) 1-8 cyclic hydrocarbon group), NH(C) 1-8 cyclic hydrocarbon group), N(C) 1-8 Cyclohydrogen group)(C 1-8 Alkyl groups), OH, NH2, SH, SO2 (C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(=O)(OC) 1-8 Alkyl)2, C 1-8 Alkyne group, CH=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2、C(=O)(C 1-8 Alkyl groups), CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH (C 1-8 Alkyl), SO2N(C) 1-8 Alkyl)2, S(=O)N(C 1-8 Alkyl)2、C(=O)NH(C 1-8 Alkyl), C(=O)N(C 1-8 Alkyl)2, N(C) 1-8 alkyl)C(=O)NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)C(=O)N(C 1-8 Alkyl)2, NHC(=O)NH(C 1-8 Alkyl), NHC(=O)N(C 1-8 Alkyl)2, NHC(=O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NHSO2N(C 1-8 Alkyl)2 or NHSO2NH2; or, R L4 R L5 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups.

4. The compound according to claim 3, characterized in that, L2 is a C1-C20 straight-chain alkylene group, wherein 0-6 methylene units are independently substituted by the following groups: -O-, -S-, -SS-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 and R L5 Independently selected from: H, OH, C1-C6 alkoxy groups; Preferably, L2 is selected from: C1-C20 straight-chain alkylene groups, -(CH2CH2O). m2 -CH2-, -(CH2CH2O) m2 -CH2CH2-, -CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2-, -CH2CH2-(CH2CH2O) m2 -CH2CH2-、-(C1-C 10 alkylene)-O-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-NH-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-C(O)NH-(C1-C 10 alkylene)-, -(C1-C 10 alkylene)-NHC(O)-(C1-C 10 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-C(O)NH-(C1-C6 alkylene)-, -(C1-C6 alkylene)-O-(C1-C6 alkylene)-NHC(O)-(C1-C6 alkylene)-, Where m2 is selected from integers between 1 and 10, g is 0 or 1, h is selected from integers between 0 and 10, i is selected from integers between 0 and 10, j is selected from integers between 0 and 10, and G is any suitable trivalent group; More preferably, L2 is selected from:

5. The compound according to claim 3, characterized in that, L2 is a C1-C20 straight-chain alkylene group, wherein 1-3 methylene units are independently substituted by the following groups: -CY-, Optionally, L2 also contains groups selected from: -O-, -C(O)-, -N(R)-. L2 )-、-C(O)N(R L2 )-、-N(R L2 C(O)-、 Among them, each R L2 Independently selected from: H, C1-C6 alkyl groups, each R L4 Independently selected from: OH, C1-C6 alkoxy groups; Preferably, each -CY- is selected from: More preferably, L2 is selected from:

6. The compound according to any one of claims 3-5, characterized in that, L1 is either -C(O)- or a single bond; Preferably, L2 is C1-C 10 Straight-chain alkylene; Preferably, L3 is a C2-C6 acetylenoid, such as...

7. The compound according to any one of claims 1-6, characterized in that, Some have the following structure: in particular, Among them, R P11 R P12 R P13 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic); Preferably, R P11 Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 The hydrogen atoms in cycloalkyl or 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: D, halogen, C1-C. 10 alkyl; More preferably, R P11 Selected from: Preferably, R P12 Selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), -OCO(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl); More preferably, R P12 Selected from: Preferably, each R P13 Independently selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -N(C) 0-10 Alkyl)(C 0-10 Alkyl), -O(C) 0-10 alkyl); More preferably, R P13 For H.

8. The compound according to claim 7, characterized in that, R P2 -(C0-C6 alkylene)-R P21 , where R P21 Selected from: in, R P22 R P24 Independently selected from: H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 heterocyclic), -CO(C 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 alkyl; R P23 One or more independent substituents on the ring, selected from: H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 Alkyl); optionally, any two R P23 Together with the carbon atoms it is attached to, they form C3-C 10 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C3-C 10 The hydrogen atoms in cycloalkyl and 3-10 membered heterocyclic groups may optionally be substituted with one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic), C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl), -S(C 0-10 Alkyl), -SO(C) 0-10 alkyl), -SO2(C 0-10 alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 alkyl), -CO(C) 0-10 alkyl); Preferably, R P22 R P24 Independently selected from: H, C1-C 10 Alkyl, -CO(C) 0-10 Alkyl), wherein the C1-C 10 The hydrogen in the alkyl group may optionally be substituted by one or more groups selected from the following: halogen, cyano, nitro, azide, C1-C. 10 alkyl; More preferably, R P22 R P24 Selected independently from: H, Preferably, R P21 Selected from:

9. The compound of claim 8, R P21 for Specifically in, R P23a R P23b R P23c R P23d R P23e Independently selected from: H, halogens, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C 10 Haloalkyl, -O(C) 0-10 alkyl), -N(C) 0-10 Alkyl)(C 0-10 Alkyl), -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), wherein the C0-C6 alkylene, C1-C 10 Alkyl, C2-C 10 alkenyl, C1-C 10 Haloalkyl, C3-C 10 cycloalkyl, C6-C 10 The hydrogen atoms in aryl and 3-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, halogen, cyano, -O(C) 0-10 Alkyl); or, R P23a R P23b R P23c R P23d R P23e Any two groups together with the carbon atoms they are attached to form a C3-C6 cycloalkyl or a 3-6 membered heterocyclic group, wherein the H in the C3-C6 cycloalkyl or 3-6 membered heterocyclic group may optionally be substituted by one or more groups selected from the following: halogen, C1-C... 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, -(C0-C6 alkylene)-O(C 0-10 alkyl); Preferably, R P23a R P23b R P23c R P23d R P23e Independently selected from: H, halogen, -OH, -NH2, Preferably, R P23a With R P23b 、or R P23b With R P23c 、or R P23c With R P23d 、or R P23d With R P23e The C3-C6 cycloalkyl or 3-6 membered heterocyclic group formed together with the carbon atom it is attached to is selected from:

10. The compound according to any one of claims 7-9, characterized in that, Some have the following structure: Among them, R P4 R P5 Independently selected from: H, C1-C 10 alkyl; Preferably, Some have the following structure: More preferably, Some stereoisomers have the following structures:

11. The compound according to any one of claims 7-9, characterized in that, The compound has the following structure: Preferably, the compound has the following structure: Preferably, the compound has the following structure:

12. The compound according to any one of claims 7-9, characterized in that, The compound has the following structure: More preferably, the compound has the following structure: More preferably, the stereoisomers of the compound have the following structure:

13. A pharmaceutical composition comprising the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

14. The use of the compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of IRAK4-related diseases; Preferably, the disease is selected from: tumors, autoimmune diseases, inflammatory diseases, diseases related to pathogen infection, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, metabolic diseases, and fibrotic diseases; Preferably, the tumor is selected from: melanoma, colon cancer, colorectal cancer, gastric cancer, pancreatic ductal adenocarcinoma, and hematologic malignancies; Preferably, the autoimmune disease is selected from: connective tissue diseases, lupus vulgaris, systemic lupus erythematosus (SLE), rheumatoid arthritis, rheumatic diseases, and bacterial sepsis; Preferably, the inflammatory disease is selected from: inflammatory bowel disease (such as ulcerative colitis, Crohn's disease), colitis, necrotizing enterocolitis, arthritis (such as osteoarthritis), acute pancreatitis, endometritis, hidradenitis suppurativa, atopic dermatitis, pelvic inflammatory disease, microscopic polyangiitis, lung injury, alcoholic hepatitis, psoriasis, sepsis, septic shock, chronic kidney disease, hormone-resistant nephrotic syndrome, hemophagocytic lymphohistiocytosis, acute lung injury, acute respiratory distress syndrome, and atopic dermatitis.

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