A KRAS-targeting G12D Protein degrading agents, their preparation methods and applications

Abstract

This invention discloses a method for targeting KRAS G12D This invention discloses a protein degrading agent, its preparation method, and its application. In this invention, the protein degrading agent uses a compound of formula I as an MDM2 recruitment element, which can bring the target protein and E3 ubiquitin ligase closer together in vivo, thereby tagging the target protein with ubiquitin and then degrading it via the ubiquitin-proteasome pathway. Experiments show that the degrading agent can effectively degrade the target protein KRAS. G12D It produces corresponding therapeutic effects, such as inhibiting the proliferation of tumor cells and promoting tumor cell apoptosis, and has very good research and application value.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a method for targeting KRAS. G12D Protein degrading agents, their preparation methods, and applications. Background Technology

[0002] KRAS G12D KRAS is a common gene mutation that frequently occurs in various cancers, including pancreatic, colorectal, and lung cancer. The KRAS gene encodes a small GTPase involved in cell signaling and proliferation regulation. The G12D mutation leads to persistent activation of the KRAS protein, thereby promoting cancer cell proliferation and survival. Although KRAS mutations play a crucial role in cancer, targeting KRAS... G12D Drug development for KRAS protein faces significant challenges. The lack of a clear drug-binding pocket makes it difficult for traditional small molecule drugs to effectively bind to and inhibit its activity. Furthermore, KRAS protein interacts tightly with other intracellular proteins and membrane structures, further increasing the complexity of drug design.

[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 targeted KRAS... G12D Protein degrading agents, their preparation methods, and applications.

[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] G12D is a ligand moiety that can bind to KRAS proteins with G12D mutations, such as the KRAS G12D inhibitors described in patent documents CN115073451A, CN115490709A, CN116253748A, CN117242079A, CN118974055A, WO2022261154A1, WO2023018699A1, WO2023072188A1, WO2023104018A1, and WO2023244713A1.

[0008] E3L is the recruitment element portion of E3 ubiquitin ligase, which is a novel recruitment element of ubiquitin ligase as described in Chinese patent application CN2024114784319, such as compounds represented by its general formula I, for example, compounds represented by formulas V-1 to V-29, particularly the compounds Ori, Ger, CYD, and OriPh described in its examples;

[0009] L is a divalent connector linking G12D and E3L, as described in Chinese patent application CN2024114784319.

[0010] In some embodiments of the present invention, the G12D portion may have the structure described in WO2022266206A1, for example, as shown in claim 15.

[0011] Specifically, the compound has the following structure:

[0012]

[0013] in,

[0014] ML is the recruitment element part of the MDM2 protein;

[0015] L is a linking group;

[0016] 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);

[0017] Z1, Z2, and Z3 are independent linking groups;

[0018] Ring A is a heterocyclic ring;

[0019] Ring B is a carbon ring or a heterocyclic ring;

[0020] The J ring is a carbon ring or a heterocyclic ring;

[0021] R P1 It is one or more independent substituents on ring A, selected from: H, =O, 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);

[0022] R P2 One or more independent substituents on the J ring, selected from: H, =O, 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 0-10alkyl), -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);

[0023] R P3 It is one or more independent substituents on the B ring, selected from: H, =O, 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);

[0024] The MDM2 protein recruitment element is the compound shown in Formula I of Chinese patent application CN2024114784319, and further, the compounds shown in claims 12-16, particularly compounds Ori, Ger, CYD, and OriPh.

[0025] In this invention, the compound is a targeted protein degrader using compound 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 the target protein (KRAS). G12D This produces corresponding therapeutic effects, such as inhibiting the proliferation of tumor cells and promoting tumor cell apoptosis.

[0026] In some embodiments of the present invention, q is 1, that is, the compound has the following structure:

[0027]

[0028] Specifically, the J ring can be an aromatic ring or a heteroaromatic ring, a saturated or partially unsaturated carbon ring or a heterocyclic ring; Some can be in particular

[0029] In some embodiments of the present invention, the compound has the following structure:

[0030]

[0031] Among them, Y1 and Y2 are independently selected from CH and N.

[0032] In some embodiments, Y1 and Y2 are both CH, and the compound has the following structure: In some implementations, both Y1 and Y2 are N; in some implementations, Y1 is CH and Y2 is N; in some implementations, Y1 is N and Y2 is CH.

[0033] Specifically, Z2 is -(C0-C6 alkylene)-Z4-(C0-C6 alkylene)-, and Z4 is selected from: single bond, C2-C4 alkylene, C2 alkenyl, C2 alkyneyl, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl group, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl group, 3-6 membered heteroalkyl group.

[0034] In some implementations, Z2 is selected from: single bond, -O-, -S-, -NH-, -N(CH3)-, -CONH-, -NHCO-,

[0035] in particular

[0036] Specifically, Z1 is -Z6-(C0-C6 alkylene)-Z5-(C0-C6 alkylene)-, and Z5 is selected from: single bond, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10 Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl group, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl group, 3-6 membered heterocyclic alkyl group, 4-6 membered heterocyclic aryl group, wherein the H on the cycloalkyl group, heterocyclic alkyl group, or heterocyclic aryl group is optionally substituted by a group selected from the following groups: halogen (e.g., F), cyano, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy; Z6 is selected from: single bond, -O-, -S-, -N(C 0-6 Alkyl group, -CO group, -CON(C) 0-6 alkyl)-, -N(C 0-6 Alkyl groups) CO-, -SO2-, -SO2N(C 0-6 Alkyl)-, -COO-, -OCO-, -CO-.

[0037] In some implementations, Z5 is selected from: single bonds,

[0038]

[0039] In some implementations, Z6 is a single bond or O.

[0040] In some implementations, Z1 is selected from: single bond, -O-, -S-, -N(C) 0-3 Alkyl group, -CO group, -CON(C) 0-3 alkyl)-, -N(C 0-3 Alkyl)CO-,

[0041] in particular

[0042] In some implementation schemes, Some have the following structure:

[0043] in particular

[0044] Specifically, ring A is a 5-12 member nitrogen-containing saturated or partially unsaturated heterocycle (including monocyclic, bicyclic, and tricyclic heterocycles; for polycyclic systems, including spirocyclic, bridged, and fused rings), such as a 6-10 member nitrogen-containing saturated heterocycle (especially a bridged ring), the ring atom including at least one nitrogen atom, and optionally 1-4 additional heteroatoms (selected from N, O, and S).

[0045] In some implementation schemes, Partially selected from:

[0046] in particular

[0047] Specifically, H on a portion is optionally controlled by one or more independent Rs P1 Group substitution, R P1 It can be selected from: halogen (such as F), cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 Alkyl), -O(C) 0-6 alkyl), -S(C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); more specifically, R P1 Selected from: halogens (such as F), cyano, methyl, ethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl.

[0048] Specifically, Z3 is selected from: -(C0-C6 alkylene)-Z7-(C0-C6 alkylene), and Z7 is selected from: single bond, C2 alkenyl group, C2 alkyne group, -O-, -S-, -N(C 0-10 Alkyl group, -CO group, -CON(C) 0-10 alkyl)-, -N(C 0-10Alkyl groups) CO-, -SO2-, -SO2N(C 0-10 Alkyl group, -COO-, -OCO-, -CO-, 3-6 membered cycloalkyl group, 3-6 membered heteroalkyl group.

[0049] In some embodiments of the present invention, Z3 is a single bond.

[0050] In some embodiments, the compound has the following structure: (VI-3), where R P4 Selected from: halogens (such as F), cyano, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylaminoalkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy. More specifically, R P4 Selected from: halogens (such as F), cyano, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl.

[0051] Specifically, R P2 Selected from: halogens (such as F, Cl), cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 Alkyl), -O(C) 0-6 Alkyl), -O (C3-C6 cycloalkyl), -S (C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); more specifically, R P2 Selected from: halogens (such as F, Cl), cyano, methyl, C1-C3 alkyl, C1-C3 haloalkyl (such as trifluoromethyl), C1-C3 alkoxy, C3-C5 cycloalkyl (such as cyclopropyl), -O-(C3-C4 cycloalkyl) (e.g. -O-cyclopropyl).

[0052] In some implementation schemes, R P2 The group, together with its attached J ring and pyrimidine ring and / or A ring, forms a fused heterocycle. Specifically, the B ring is a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; Some of the selections can be chosen from:

[0053] in particular

[0054] Specifically, H on a portion is optionally controlled by one or more independent Rs P3 Group substitution, R P3 It can be selected from: halogen (such as F), cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CON(C 0-6 Alkyl), -O(C) 0-6 alkyl), -S(C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 Alkyl); more specifically, R P1 Selected from: halogens (such as F), cyano, hydroxyl, amino, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl (such as trifluoromethyl), C1-C3 hydroxyalkyl, C1-C3 alkoxyalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl.

[0055] In some embodiments of the present invention Some have the following structure:

[0056]

[0057]

[0058] in particular

[0059] In some embodiments of the present invention, the aforementioned G12D or Some have the structure shown in the following group (G12D-L1):

[0060]

[0061]

[0062]

[0063]

[0064]

[0065] in particular Furthermore, in addition to the compound shown in CN202411478431.9, other structural analogs have been verified or are under investigation in the prior art, such as patent documents CN105473566A, CN104039796A, CN101139350A, CN101723951A, CN102002051A, CN102295649A, CN102850369A, CN104003998A, CN105524076A, and CN1067493. 05A, CN106866695A, CN106883267A, CN108299458A, CN108864132A, CN110627833A, CN113698415A, CN11447856 6A, CN116621855A, CN114702506A, CN113004241A, CN110950883A, CN110229168A, CN111635395A, CN106749305A Shen 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 Med Chem. 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. The above are incorporated herein by reference in their entirety.

[0066] In some preferred embodiments of the present invention, the ML portion has the following structure:

[0067]

[0068]

[0069] in particular

[0070] In some embodiments of the present invention, the ML portion has the following structure:

[0071] in particular

[0072] In some preferred embodiments of the present invention, the ML portion has the following structure:

[0073]

[0074]

[0075] In some preferred embodiments of the present invention, the ML portion has the following structure:

[0076]

[0077]

[0078] In some embodiments of the present invention, the ML portion has the following structure:

[0079] in particular

[0080] 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(C0-10 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.

[0081] 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. In some embodiments of the present invention, R 16 For H.

[0082] 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) 0-10Alkyl)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); 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.

[0083] 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. In some embodiments of the present invention, R 17 For H.

[0084] In some embodiments of the present invention, R 14 For H.

[0085] In some embodiments of the present invention, R 15 For H.

[0086] In other embodiments of the invention, R 15 These are monosaccharide residues, such as glucosyl, galactosyl, xylose, and mannose.

[0087] 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.

[0088] In some embodiments of the present invention, R 25 Selected 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

[0089] In some embodiments of the present invention, 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. ).

[0090] In some embodiments of the present invention, 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

[0091] In some embodiments of the present invention, X is 0. In some embodiments of the present invention, X is S.

[0092] In some embodiments of the present invention, R 26 Selected from: H, halogen, cyano, nitro, azide, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, -COO(C 0-3 alkyl),

[0093] In some embodiments of the present invention, 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).

[0094] In some embodiments of the present invention, 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). In some embodiments of the invention, R 31 For H.

[0095] In some embodiments of the present invention, 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. More specifically, R 32 and R 33 Independently selected from: H, C1-C6 alkyl groups (such as methyl, ethyl).

[0096] Specifically, L has the following structure: in,

[0097] 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)-;

[0098] L3 is a divalent group attached to Z1, which can be selected from: single bond, -(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)-;

[0099] 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)(ORL 2 -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 optionally substituted from the following: arylene, cycloalkyl, heterocyclic; the H in the hydrocarbon chain may optionally be substituted by one or more groups selected from the following: 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 10Haloalkyl, 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);

[0100] 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 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).

[0101] 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.

[0102] 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.

[0103] In some embodiments of the invention, each -CY- is independently selected from the following:

[0104]

[0105]

[0106] 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.

[0107] 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 ).

[0108] In some embodiments of the present invention, R L1 For H.

[0109] In some embodiments of the present invention, R L3 For H.

[0110] In some embodiments of the present invention, R L4 For H.

[0111] In some embodiments of the present invention, R L4 It is OH.

[0112] In some embodiments of the present invention, R L5 For H.

[0113] In some embodiments of the present invention, R L5 It is OH.

[0114] 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)-、

[0115] 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.

[0116] In some specific embodiments of the present invention, L2 is a C1-C20 straight-chain alkylene group, for example:

[0117] In some specific embodiments of the present invention, L2 is a C1-C20 alkylene (e.g., a C1-C12 straight-chain alkylene, a C1-C10 straight-chain alkylene), wherein at least one methylene unit in the alkylene is independently substituted by the following groups: -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R) L2 )-、-N(R L2 )C(O)-、-N(R L2 -, -S(O)2-, -S(O)-, Furthermore, 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

[0118]

[0119]

[0120] 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 k is selected from an integer between 0 and 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). For example,

[0121]

[0122] 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.

[0123] In some embodiments of the present invention, -CY- is selected from:

[0124]

[0125] In some specific embodiments of the present invention, L2 is selected from:

[0126] In some embodiments of the present invention, L1 is -C(O)-. In one embodiment of the present invention, L1 is a single bond.

[0127] In some embodiments of the present invention, L2 is C1-C 10 Straight-chain alkylene groups, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-.

[0128] In some embodiments of the invention, L2 is a C1-C6 straight-chain alkylene group, wherein at least one methylene unit in the alkylene group is independently substituted with the following groups:

[0129] In one embodiment of the invention, L3 is a single bond. In some embodiments of the invention, L3 is -C(O)-.

[0130] In some embodiments of the present invention, the compound has the following structure:

[0131]

[0132] Where Y3 is CH or N.

[0133] More specifically, the compound has the following structure:

[0134]

[0135] In some embodiments of the present invention, for compounds of formulas VI, VII, and VIII, the ML portion is selected from one of ML-01 to ML-L08, particularly ML-01:

[0136]

[0137] In some embodiments of the present invention, for compounds of formulas VI, VII, and VIII, the ML portion is selected from one of ML-01-1 to ML-L08-1, particularly ML-01-1:

[0138]

[0139]

[0140] In some embodiments of the invention, for the compound shown in Formula A, the E3L portion has one of the structures shown in ML-01-1 to ML-08-1, particularly ML-01-1, and the G12D portion has one of the structures shown in group (G12D-L1), particularly G12D-L01.

[0141] In some embodiments of the present invention, the compound has the following structure:

[0142]

[0143] In some embodiments of the present invention, for compounds represented by formulas VI, VII, VIII, and IX, L has the following structure:

[0144]

[0145] In some embodiments of the present invention, the compound has the following structure:

[0146]

[0147]

[0148] In some embodiments of the present invention, the stereoisomers of the compound have the following structures (numbered sequentially from DMKR001 to DMKR018):

[0149]

[0150]

[0151] 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.

[0152] 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,

[0153] First, prepare ML-L′-R G Then it is linked to a small molecule ligand; or,

[0154] Prepare ML-L″-R separately G′ and Then the two are coupled;

[0155] Where L', L”, and L”' are arbitrarily chosen suitable linking groups, and R G R G '、R G " " represents any suitable reactive group.

[0156] In some embodiments of the present invention, R G It is a carboxyl group.

[0157] In some embodiments of the present invention, the preparation method further includes preparing... The steps.

[0158] Specifically, if necessary, the preparation method may also include steps of protecting and deprotecting certain groups (such as hydroxyl and amino groups).

[0159] In a third aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0160] 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.

[0161] 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.).

[0162] Specifically, the pharmaceutical composition can be prepared into pharmaceutical formulations in the following forms: tablets, capsules, lotions, gels, emulsions, syrups, suspensions, powders, granules, injections, etc.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] In a fourth aspect of the invention, the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof is provided in the preparation of a compound for the prevention and / or treatment of KRAS (especially KRAS). G12D Application of drugs in diseases mediated by )

[0168] Specifically, the disease is caused by the inhibition / degradation of KRAS (especially KRAS protein with G12D mutation). G12D It may be beneficial for the prevention and / or treatment of diseases, such as, but not limited to, tumors, especially malignant tumors.

[0169] Specifically, the tumors are selected from: lung cancer, malignant melanoma, brain tumors, tumors of digestive organs, uterine cancer, testicular cancer, palate cancer, pharyngeal cancer, tongue cancer, oral cancer, various sarcomas, osteosarcoma, hematologic malignancies, nervous system tumors, glioma, glioblastoma, skin cancer, cancer of skin appendages and metastatic skin cancer, medulloblastoma, glioma, blastoma, liposarcoma, neuroendocrine tumors, synovial cell sarcoma, gastrinoma, carcinoid tumors, mesothelioma, pancreatic islet cell carcinoma, etc. Schwannoma, meningioma, melanoma, acoustic neuroma, adenocarcinoma, lymphoid malignancy, epithelial squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, lung cancer, peritoneal cancer, squamous cell carcinoma of the lung, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, thyroid cancer, bladder cancer, breast cancer, metastatic breast cancer, colon cancer, rectal cancer, prostate cancer, salivary gland cancer, kidney cancer, vulvar cancer, anal cancer, penile cancer, esophageal cancer, biliary tract tumors, and head and neck cancer.

[0170] Specifically, the hematologic malignancies include: leukemia, lymphoma, and multiple myeloma (MM).

[0171] Specifically, leukemia can be chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), acute monocytic leukemia, etc.

[0172] Specifically, lymphomas can be Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, and lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia). macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-cell lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and anaplastic large cell lymphoma, NK / T-cell lymphoma, especially diffuse large B-cell lymphoma (DLBCL).

[0173] In some embodiments of the present invention, the tumor is selected from: hematologic malignancies (e.g., acute myeloid leukemia or acute lymphoblastic leukemia), lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, and oral cancer.

[0174] Specifically, the tumors include those that have developed multidrug resistance to anti-tumor drugs.

[0175] In a fifth aspect of the invention, a method for degrading KRAS protein (particularly KRAS protein with a G12D mutation) is provided. G12D A method for (protein) 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.

[0176] Specifically, the method is performed in vivo or in vitro.

[0177] In a sixth aspect of the invention, a method for preventing and / or treating KRAS (especially KRAS) is provided. G12D Methods for treating diseases mediated by the invention include 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.

[0178] Specifically, the disease is as described in the fourth aspect of the present invention.

[0179] Specifically, the subjects were mammals, particularly humans.

[0180] 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.).

[0181] The inventors of this invention have creatively discovered that a compound recruits MDM2 through its interaction with nucleolin (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 degrading agents, among other applications. Utilizing this discovery, the inventors prepared a target for KRAS (especially KRAS-1). G12D A novel protein degrading compound was developed, and experiments showed that the prepared targeted protein degrading agent can effectively induce KRAS. G12D Degradation, used for KRAS G12D The treatment of diseases mediated by this technology has a very promising future in the medical field. Attached Figure Description

[0182] Figure 1 The results of the experiment described in Example 1 are shown, which demonstrate that NCL can bind to MDM2.

[0183] Figure 2 The results of the experiment described in Example 2 are shown, indicating that the compound Ori of Formula I recruits MDM2 in response to its interaction with NCL; iSN04 can only bind to NCL, but cannot recruit MDM2 in response to NCL.

[0184] Figure 3 The results of the experiment described in Example 2 are shown, indicating that the compound Ori of Formula I can capture NCL and MDM2; iSN04 can capture NCL but cannot capture MDM2.

[0185] Figure 4 The results of the experiment described in Example 2 are shown, which indicate that the compound Ori, represented by Formula I, can capture NCL and MDM2, and silencing NCL can block Ori from recruiting MDM2.

[0186] Figure 5 The results of the experiment described in Example 2 are shown, which indicate that the compound Ori of Formula I does not affect the interaction between NCL and MDM2, while iSN04 blocks the binding of NCL and MDM2.

[0187] Figure 6 The diagram illustrates the interaction mode by which compounds of Formula I (such as Ori) recruit MDM2 through their interaction with NCL.

[0188] Figure 7The results shown in Example 4 demonstrate that the targeted KRAS prepared in this invention... G12D PROTAC molecules can degrade KRAS G12D .

[0189] Figure 8 The results of the experiment described in Example 5 are shown, demonstrating that the PROTAC prepared according to this invention can promote KRAS. G12D ubiquitination.

[0190] Figure 9 The results of the experiment described in Example 6 are shown, which demonstrate that the PROTAC prepared in this invention can inhibit the proliferation of tumor cells. Detailed Implementation

[0191] 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.

[0192] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0193] In this invention, 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 "aliphatic ring" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units, connected to other parts 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.

[0194] The term "carbon ring" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0195] 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).

[0196] 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).

[0197] 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.

[0198] 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.

[0199] 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...

[0200] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0201] 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.

[0202] 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.

[0203] 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...

[0204] In this invention, "D" refers to deuterium; "replaced by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0205] 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.

[0206] 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).

[0207] 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.

[0208] 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).

[0209] 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.

[0210] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0219] 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.

[0220] The compound Ori described in the following examples is a compound of formula I and has the following structure: In addition, compounds such as Ger, CYD, and OriPh, similar to Ori, can also serve as recruitment elements for the MDM2 protein.

[0221] The KRAS described in the following embodiments G12D The inhibitor (G12D-L) has the following structure:

[0222] Example 1: NCL can be combined with MDM2

[0223] 1. Co-immunoprecipitation (Co-IP) is a classic method for studying protein-protein interactions based on the specific interaction between antibodies and antigens. Hep3B liver cancer cells were lysed with IP lysis buffer (Thermo Scientific, catalog number 87788) and 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 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 blotting 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 of A indicate that NCL can bind to MDM2.

[0224] 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.

[0225] Example 2: Compound Ori recruits MDM2 in a NCL-dependent manner.

[0226] 1. We prepared Ori (Bio-Ori-1), a compound of formula I, with a C-14 hydroxyl group biotinylated. The specific preparation steps are as follows:

[0227]

[0228] 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%.

[0229] LCMS: m / z = 591.6 [M+H] + ,t R =8.447min.Purity:100%(254nm).

[0230] 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).

[0231] 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.

[0232] 2. We also prepared Ori (Bio-Ori-2), a compound of formula I, with a C-1 hydroxyl group biotinylated. The specific preparation steps are as follows: (1)

[0234]

[0235] 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.

[0236] LCMS: m / z = 387.2 [M-OH] + ,Rt=1.894min.Purity:92.4%(214nm). (2)

[0238]

[0239] 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.

[0240] LCMS: m / z = 613.3 [M-OH] + ,Rt=1.610min.Purity:96.31%(214nm). (3)

[0242]

[0243] 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.

[0244] LCMS: m / z = 573.6 [M-OH] + ,Rt=8.691min.Purity:100%(214nm).

[0245] 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).

[0246] 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.

[0247] 3. The procedure for the pull-down assay involves immobilizing a known substance (bait) on a carrier and using it to capture binding proteins (prey) and protein complexes that interact with the binding proteins from a complex mixture. 6 μg / mL of recombinant human NCL (rhNCL) and 6 μg / mL of recombinant human MDM2 (rhMDM2) were mixed and 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. Finally, 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, then SDS-PAGE protein loading buffer (purchased from Beyotime, catalog number P0015) was added, and the mixture was heated to 100°C for 10 minutes. The supernatant was collected after centrifugation. The product was then analyzed using an immunoblot assay. 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.

[0248] 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 3The 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.

[0249] 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.

[0250] 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, Silent NCL can block Ori from recruiting MDM2.

[0251] 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, with results similar to those for Ori. However, Figure 5 The results of B indicate that iSN04 blocks the binding of NCL to MDM2.

[0252] 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 be used to 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. Therefore, we believe that compounds of formula I (such as Ori) can serve as recruitment elements for MDM2 to prepare KRAS-targeting compounds. G12D PROTAC undergoes degradation.

[0253] Example 3: Preparation of targeted KRAS based on compound of formula I G12D PROTAC molecules

[0254] In this embodiment, compound Ori of formula I is used as the recruitment element for the E3 ligase, and KRAS is used as the recruitment element for the ligase. G12D Inhibitor compound (G12D-L) was used as a target protein ligand to prepare KRAS-degrading compounds. G12D PROTAC (hereinafter referred to as DMKR005).

[0255] The preparation steps are as follows:

[0256] (1) Synthesis of compound 5-2

[0257]

[0258] At 0 °C and N2, NaOH (21 g, 541.5 mmol, 50% solution, 40 mL) and tetrabutylammonium bromide (11.6 g, 36.1 mmol) were added to a DCM (300 mL) solution of compound 5-1 (30 g, 180.48 mmol), tert-butyl acrylate (23.1 g, 180.5 mmol), and tert-butylammonium bromide (11.6 g, 36.1 mmol). The mixture was stirred at 25 °C for 2 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (200 mL) and extracted with DCM (100 mL × 2). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (EA in PE = 0 to 100%) to give compound 5-2 (25 g, yield: 47%) as a yellow oil.

[0259] LCMS: m / z = 239.2 [M+H-56] + ,Rt=1.774min,Purity:100%(254nm).

[0260] (2) Synthesis of compound 5-3

[0261]

[0262] Pd / C (1.4 g, 10%) was added to a solution of compound 5-2 (25 g, 60.57 mmol) in THF (75 mL) and MeOH (75 mL) at 25 °C under N2. The mixture was degassed and purged three times with N2. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated under vacuum to give compound 5-3 (12 g, yield: 69%) as a yellow oil, which could be used for the next step without further purification.

[0263] LCMS: m / z = 226.98 [M+H] + ,Rt=1.70min,Purity:100%(254nm).

[0264] (3) Synthesis of compound 5-4

[0265]

[0266] At 25 °C and N2, DMAP (756.2 mg, 6.2 mmol) and TsCl (17.7 g, 93.3 mmol) were added to a DCM (120 mL) solution of compound 5-3 (12.0 g, 62.2 mmol) and Et3N (18.8 g, 186.6 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed that the reaction was complete. The mixture was quenched with water (500 mL) and extracted with DCM (500 mL × 2). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by rapid column chromatography (EA in PE = 0 to 100%) to give compound 5-4 (19 g, yield: 91%) as a white solid.

[0267] LCMS: m / z = 381.2 [M + Na] + ,Rt=1.280min,Purity:100%(254nm).

[0268] (4) Synthesis of compounds 5-6

[0269]

[0270] K₂CO₃ (22.7 g, 164.04 mmol) was added to a DMF (70 mL) solution of compounds 5-4 (19.6 g, 54.68 mmol) and 5-5 (18.6 g, 54.68 mmol) at 25 °C and N₂. The mixture was then stirred at 25 °C for 16 h. LC-MS showed that the reaction was complete. The mixture was quenched with water (500 mL) and extracted with DCM (500 mL × 2). The organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by rapid column chromatography (EA in PE = 0 to 100%) to give compound 5-6 (23 g, yield: 80%) as a yellow oil.

[0271] LCMS: m / z = 526.4 [M+H] + ,Rt=1.720min,Purity:100%(254nm).

[0272] (5) Synthesis of compound 5

[0273]

[0274] At 25°C, TBAF (54 mL, 53.63 mmol) was added to a THF (250 mL) solution of compounds 5-6 (23 g, 44.7 mmol). The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The resulting residue was purified by rapid column chromatography (MeOH in DCM = 0% to 10%) to give compound 5 (6 g, yield: 48%) as a yellow oil.

[0275] LCMS: m / z = 288.65 [M+H] + ,Rt=1.10min,Purity:100%(214nm).

[0276] (6) Synthesis of compound 5-5

[0277]

[0278] To a DMF (100 mL) solution of compound 5-7 (10.2 g, 98.86 mmol), TBDPSCl (32.6 g, 118.6 mmol), TEA (30 g, 296.58 mL), and DMAP (1.2 g, 9.8 mmol) were added. LC-MS showed that the reaction was complete. The mixture was quenched with water (500 mL) and extracted with EA (500 mL × 3). The organic layer was washed with brine (500 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (EA in PE = 0% to 100%) to give compound 5-5 (30 g, yield: 89%) as a white solid.

[0279] LCMS: m / z = 340.2 [M+H] + ,Rt=1.936min,Purity:100%(254nm).

[0280] (7) Synthesis of compound 7

[0281]

[0282] To a mixture of compound 7-1 (3 g, 8.08 mmol) in dioxane (60 mL), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (1.5 g, 20 mmol), KOAc (3.97 g, 40 mmol), and Pd(dppf)Cl2 (689 mg, 0.8 mmol) were added. The mixture was stirred at 90 °C for 16 hours. LC-MS showed that the reaction was complete. The reactants were concentrated under vacuum. The resulting residue was purified by rapid column chromatography to give compound 7 (2 g, yield: 60%) as a white solid.

[0283] LCMS: m / z = 363.0 [M+H-56] + ,Rt=1.402min,Purity:97%(214nm).

[0284] 1 H NMR (400MHz, CDCl3) δ7.89(s,1H),7.83–7.76(m,1H),7.07–6.93(m,1H),1.58(s,9H),1.43(s,12H).

[0285] (8) Synthesis of compound 3

[0286]

[0287] DIEPA (10.6 g, 81.72 mmol) was added to a THF (100 mL) solution of compound 1 (9 g, 27.24 mmol) and compound 2 (7 g, 32.69 mmol) at 25 °C and N2. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The resulting residue was quenched with water (200 mL) and extracted with DCM (100 mL × 2). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by rapid column chromatography (EA in PE = 0 to 100% elution) to give compound 3 (12 g, yield: 87%) as a white solid.

[0288] LCMS:[M+H] + =507.0,R t =1.391min, purity:100% (254nm) (9) Synthesis of compound 4

[0289]

[0290] CsF (6.3 g, 41.47 mmol) was added to a DMSO (100 mL) solution of compound 3 (5.5 g, 10.86 mmol) at 25 °C under N2 conditions. The mixture was stirred at 110 °C for 16 hours. LCMS showed that the reaction was complete. The mixture was quenched with water (200 mL) and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL × 1), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (EA in PE = 0 to 100% elution) to give compound 4 (3.3 g, yield: 62%) as a white solid.

[0291] LCMS: m / z = 489.0 [M+H] + ,Rt=1.893min,purity:92.75%(254nm)

[0292] (10) Synthesis of Compound 6

[0293]

[0294] Compound 4 (1.4 g, 4.86 mmol), 1,4-diazabicyclo[2.2.2]octane (36 mg, 0.32 mmol), and Cs₂CO₃ (1.58 g, 4.86 mmol) were added to a DMF (10 mL) solution of compound 4 (1.58 g, 3.24 mmol). The reaction mixture was stirred at 50 °C for 16 h. The mixture was diluted with EA (100 mL), washed with H₂O (100 mL × 2) and brine (100 mL), dried over Na₂SO₄, and filtered. The organic phase was concentrated under vacuum. The residue was purified by rapid column chromatography (DCM:MeOH = 10:1) to give compound 6 (800 mg, yield: 32%) as a yellow solid.

[0295] LCMS: m / z = 758.2 [M+H] + Rt=1.298min, purity:100% (254nm) (11) Synthesis of compound 8

[0296]

[0297] Compound 7 (288 mg, 0.69 mmol), Cs₂CO₃ (345 mg, 1.06 mmol), and Pd(DPEphos)Cl₂ (71 mg, 0.10 mmol) were added to a 20 mL solution of compound 6 (400 mg, 0.53 mmol) in toluene. The reaction mixture was stirred at 110 °C for 16 h. The mixture was concentrated under vacuum. The residue was purified by rapid column chromatography (DCM:MeOH = 10:1, v / v) to give compound 8 (250 mg, yield: 48%) as a yellow solid.

[0298] LCMS: m / z = 968.4 [M + Na] + Rt=1.428min, purity:90% (254nm) (12) Synthesis of compound 9

[0299]

[0300] LiOH (36 mg, 1.50 mmol) was added to a mixture of compound 8 (290 mg, 0.30 mmol) in THF (4 mL), MeOH (4 mL), and H₂O (4 mL). The mixture was stirred at 40 °C for 16 h. LC-MS showed that the reaction was complete. The mixture was purified by reversed-phase column chromatography to give compound 9 (170 mg, yield: 62%) as a yellow solid.

[0301] LCMS: m / z = 912.2 [M+H] + Rt=1.22min, purity:100% (254nm) (13) Synthesis of compound 11

[0302]

[0303] DMAP (16 mg, 0.13 mmol) and EDCI (75 mg, 0.39 mmol) were added to a DMF (5 mL) solution of compound 9 (120 mg, 0.13 mmol) and compound 10 (71 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 16 hours. LMCS showed that the reaction was complete. The reaction mixture was diluted with DCM (100 mL) and washed with H2O (3 mL × 2) and brine (30 mL). The organic phase was concentrated under vacuum. The resulting residue was purified by rapid column chromatography (DCM:MeOH = 10:1, v / v) to give compound 11 (130 mg, yield: 79%) as a yellow solid.

[0304] LCMS: m / z = 630.0 [1 / 2M+H] + ,Rt=1.30min,purity:96%(254nm)1 H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.42-6.99(m,3H),5.98(s,1H),5.90-5.76( m,2H),5.58(s,1H),4.65-4.22(m,8H),4.09-4.05(m,1H),3.89-3.80(m,1H),3.77 -3.53(m,4H),3.02-2.90(m,2H),2.44-2.35(m,2H),2.09-1.78(m,10H),1.75-1. 62(m,4H),1.47(s,18H),1.43-1.27(m,6H),1.22-1.06(m,8H),1.02-1.00(m,6H).

[0305] (14) Synthesis of target compound DMKR005

[0306]

[0307] TFA (2 mL) was added to a mixture of compound 11 (100 mg, 0.079 mol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The resulting residue was diluted with DMF (3 mL). The mixture was adjusted to pH 6 with saturated NaHCO3 aqueous solution. The mixture was purified by reversed-phase column chromatography to give the target compound DMKR005 (40 mg, yield: 47%) as a pale yellow solid.

[0308] LCMS: m / z = 1058.8 [M+H] + ,Rt=7.752min,purity:100%(254nm).

[0309] 1 H NMR(400MHz,DMSO-d6)δ8.35(s,2H),7.89(s,1H),7.32–7.11(m,2H),6.10–5.8 1(m,1H),5.80–4.63(m,1H),4.62–4.22(m,3H),4.21–4.10(m,1H),3.77–3.62(m ,3H),3.56–3.25(m,8H),3.21–2.61(m,6H),2.51–2.13(m,4H),2.09–1.88(m,4 H),1.87–1.63(m,8H),1.61–1.40(m,4H),1.38–1.03(m,4H),0.99-0.95(m,6H).

[0310] Example 4: Targeting KRAS G12D PROTAC molecules can degrade KRAS G12D

[0311] 1. Colorectal cancer cells GP2d were incubated with 0, 100, 250, 500, 1000, and 2000 nM DMKR005 (prepared in Example 3). After 24 hours, cell samples were collected, and total protein was extracted using RIPA lysis buffer. KRAS was detected by Western blotting. G12D Protein degradation. Results as follows: Figure 7 As shown in Figure A, DMKR005 can reduce KRAS in a concentration-dependent manner. G12D Protein levels.

[0312] 2. Colorectal cancer cells GP2d were incubated with 500 nM DMKR005, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting to detect KRAS. G12D Protein degradation. Results as follows: Figure 7 As shown in B, DMKR005 can reduce KRAS in a time-dependent manner. G12D Protein levels.

[0313] 3. Pancreatic cancer cells (AsPC-1) were incubated with 0, 100, 250, 500, 1000, and 2000 nM DMKR005. Cell samples were collected after 24 hours, and total protein was extracted using RIPA lysis buffer. KRAS was detected by Western blotting. G12D Protein degradation. Results as follows: Figure 7 As shown in Figure C, DMKR005 can reduce KRAS in a concentration-dependent manner. G12D Protein levels.

[0314] 4. Pancreatic cancer cells AsPC-1 were incubated with 500 nM DMKR005, and cell samples were collected at time gradients of 0, 3, 6, 9, 12, and 24 hours for protein extraction and subsequent Western blotting to detect KRAS. G12D Protein degradation. Results as follows: Figure 7 As shown in Figure D, DMKR005 can reduce KRAS in a time-dependent manner. G12D Protein levels.

[0315] Example 5: PROTAC promotes KRAS G12D ubiquitination

[0316] 1. Colorectal cancer cells GP2d were incubated with DMSO (Vehicle) or 500 nM DMKR005 for 12 hours, with 10 μM proteasome inhibitor MG132 added during the last 6 hours of incubation. Cell samples were collected for protein extraction and subsequent Western blotting to detect KRAS. G12D Protein degradation. Results are as follows: Figure 8 As shown in Figure A, MG132 can block DMKR005 from KRAS. G12D The degradation of DMKR005 indicates that it affects KRAS. G12D Its degradation depends on the ubiquitin-proteasome pathway.

[0317] 2. Colorectal cancer cells GP2d were incubated with DMSO (Vehicle) or 500 nM DMKR005 for 12 hours. During the last 6 hours of incubation, 10 μM of the proteasome inhibitor MG132 was added. After cell lysis, the cells were incubated with KRAS. G12D The antibody was incubated overnight at 4°C. Protein A / G magnetic beads were added and incubated at room temperature for 2 hours by rotation. The KRAS bound to the magnetic beads was lysed with IP lysis buffer. G12D After washing, add SDS-PAGE protein loading buffer, heat to 100°C and maintain for 10 minutes. Use a magnetic rack to pick up magnetic beads, and transfer the supernatant to a new tube. Then, perform an immunoblotting assay to detect KRAS. G12D The ubiquitination level. The results are as follows: Figure 8 As shown in B, DMKR005 promotes KRAS G12 Ubiquitination of D.

[0318] This invention also prepared other KRAS-targeting methods. G12D The PROTACs, named DMKR001 to DMKR004 and DMKR006 to DMKR018 respectively, have the structure shown in the invention description and can also promote KRAS G12D ubiquitination of KRAS G12 Targeted degradation of D reduces KRAS G12D The protein levels were measured, and the experimental procedure will not be described in detail here.

[0319] Example 6: PROTAC inhibits tumor cell proliferation

[0320] GP2d colorectal cancer cells were seeded into 96-well cell culture plates. During the experiment, the culture medium containing DMSO (Vehicle) or 500 nM Ori, 500 nM G12D-L, 500 nM Ori + 500 nM G12D-L, or 500 nM DMKR005 was changed daily. Cell proliferation was performed using a CCK-8 assay kit, and absorbance at 450 nm was measured using a microplate reader on days 1, 2, 3, and 4. Results are as follows: Figure 9 As shown, DMKR005 can more effectively inhibit the proliferation of GP2d cells.

[0321] 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.

[0322] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0323] 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 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, characterized in that, The compound has 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 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15); Z1, Z2, and Z3 are independent linking groups; Ring A is a heterocyclic ring; Ring B is a carbon ring or a heterocyclic ring; The J ring is a carbon ring or a heterocyclic ring; R P1 It is one or more independent substituents on ring A, selected from: H, =O, 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); R P2 One or more independent substituents on the J ring, selected from: H, =O, 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); R P3 It is one or more independent substituents on the B ring, selected from: H, =O, 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); The MDM2 protein recruitment element has the following structure: in, Represents a single bond or a double bond. Furthermore, the bonds shown at points a and b are not both 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 divalent ring optionally substituted 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 (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); 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).

2. The compound according to claim 1, characterized in that, The compound has the following structure: Z2 is selected from: single bond, -O-, -S-, -NH-, -N(CH3)-, -CONH-, -NHCO-, in particular Z1 is selected from: single bond, -O-, -S-, -N(C) 0-3 Alkyl group, -CO group, -CON(C) 0-3 alkyl)-, -N(C 0-3 Alkyl)CO-, Z3 is a single bond; Preferably, Some have the following structure: in particular 3. The compound according to claim 1, characterized in that, Partially selected from: in particular H on a portion is optionally controlled by one or more independent Rs P1 Group substitution, R P1 Selected from: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -O(C) 0-6 alkyl), -S(C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 alkyl).

4. The compound according to any one of claims 1-3, characterized in that, R P2 Selected from: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -O(C) 0-6 Alkyl), -O (C3-C6 cycloalkyl), -S (C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 alkyl); Preferably, R P2 Selected from: halogen, cyano, methyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, -O-(C3-C4 cycloalkyl).

5. The compound according to any one of claims 1-4, characterized in that, Partially selected from: in particular H on a portion is optionally controlled by one or more independent Rs P3 Group substitution, R P3 Selected from: halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -N(C 0-6 Alkyl)(C 0-6 alkyl), -N(C) 0-6 Alkyl)CO(C 0-6 alkyl), -N(C) 0-6 Alkyl)CON(C 0-6 alkyl), -O(C) 0-6 alkyl), -S(C 0-6 alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -CON(C) 0-6 Alkyl)(C 0-6 alkyl).

6. The compound according to any one of claims 1-4, characterized in that, Some have the following structure: in particular 7. The compound according to any one of claims 1-6, characterized in that, The ML part is selected from one of ML-01 to ML-L08, especially ML-01: 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; 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); 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 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; Preferably, the ML portion is selected from one of ML-01-1 to ML-L08-1, especially ML-01-1:

8. The compound according to any one of claims 1-7, characterized in that, L has the following structure: in, L1 is a divalent group attached to ML, 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 Z1, selected from: single bond, -(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, L1 is -C(O)- or a single bond; Preferably, L3 is a single bond or -C(O)-; Preferably, L2 is a C1-C20 straight-chain alkylene group, or L2 is a C1-C6 straight-chain alkylene group, wherein at least one methylene unit in the alkylene group is independently substituted with the following groups: or, L2 is selected from: Where h is selected from integers between 0 and 10, i is selected from integers between 0 and 10, and k is selected from integers between 0 and 10; More preferably, L2 is selected from:

9. The compound according to claim 7 or 8, characterized in that, The compound has the following structure: Preferably, the compound has the following structure: More preferably, L is selected from one of the following structures:

10. The compound according to claim 1, characterized in that, The stereoisomers of the compound are selected from the following structures:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a compound for the prevention and / or treatment of KRAS. G12D Application in drugs for mediated diseases; Preferably, the disease is a tumor; More preferably, the tumor is selected from: hematologic malignancies (e.g., acute myeloid leukemia or acute lymphoblastic leukemia), lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, and oral cancer.

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