Spirocyclic compounds and their bifunctional compounds and applications

Abstract

This invention provides a novel spirocyclic compound having binding interaction with the E3 ligase protein CRBN, and its use in the preparation of a medicament for treating diseases of abnormal cell proliferation. This invention also provides a bifunctional compound targeting protein degradation, and intermediate compounds in the synthesis of the same.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a novel ligand compound that binds to the cereblon E3 ubiquitin ligase protein and a bifunctional compound containing the ligand, which are protein degradation-targeting chimeric compounds (PROTACs). Background Technology

[0002] Protein degradation is a highly regulated process essential for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) enables the selective identification and removal of damaged, misfolded, or excess proteins. UPP removes defective proteins and is characterized by ATP dependence, high efficiency, and high selectivity. Its catalytic component is the ubiquitin-derived E3 ligase, but it requires the prior recruitment of the protein to be degraded. PROTACs technology is designed based on the UPP principle, linking the target protein ligand and the E3 ligase ligand with appropriate chemical bonds. This allows for the recognition of the target protein and enhances the binding affinity of the E3 ligase to the target protein, thereby targeting ubiquitination and forcing the degradation of the target protein. It also features high catalytic activity, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules are covalently linked to terminal lysine residues via E3 ubiquitin ligase to label proteins for proteasomal degradation. The protein is then digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0004] Cereblon is a thalidomide-binding protein and part of the E3 ubiquitin ligase protein complex. It acts as a substrate receptor, selectively targeting ubiquitinated proteins. Encoded by the human CRBN gene, cereblon, along with DNA damage binding protein 1 (DDBl), Cullin-4A (CUL4A), and the Cullin-1 regulator (ROCI), forms the E3 ubiquitin ligase complex. This complex can ubiquitinate a range of proteins, but the specific mechanism is not yet fully understood. Cereblon is currently a commonly used E3 ligase in PROTACs technology.

[0005] This invention discloses a novel class of spirocyclic compounds that can serve as effective CRBN ligands. Furthermore, corresponding bifunctional PROTACs compounds that can target protein degradation chimeras can be synthesized and used to treat various medical conditions, especially abnormal cell proliferation. Summary of the Invention

[0006] This invention provides a compound of Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] Indicates whether oxygen substitution is present or absent;

[0010] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 11 -C 1～4 Alkylene-NR 11 R 12 -C 1～4 Alkylene (3- to 10-membered cycloalkyl), -C 1～4 Alkylene (4- to 10-membered heterocyclic alkyl);

[0011] R 11 R 12 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0012] Ring A is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring, and 5-10 membered heteroaromatic ring; wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring may be further optionally surrounded by one, two, three, or four independent R. A1 replace;

[0013] Each R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace;

[0014] Each R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 ;

[0015] R A2 R A3 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0016] R 2 Independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 -C 1～6 Alkyl, -C2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C 0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-SR 21 -C 0～4 Alkylene-S(O)2R 21 -C 0～4 Alkylene-S(O)R 21 -C 0～4 Alkylene-S(O)2NR 21 R 22 -C 0～4 Alkylene-S(O)NR 21 R 22 -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)OR 21 -C 0～4 Alkylene-C(O)NR 21 R 22 -C 0～4 Alkylene-NR 21 R 22 -C 0～4 Alkylene-NR 21 C(O)R 22 -C 0～4 Alkylene-NR 21 S(O)2R 22 -C 0～4 Alkylene-NR 21 S(O)R 22 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 23 replace;

[0017] Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R22 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C 0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-SR 21 -C 0～4 Alkylene-S(O)2R 21 -C 0～4 Alkylene-S(O)R 21 -C 0～4 Alkylene-S(O)2NR 21 R 22 -C 0～4 Alkylene-S(O)NR 21 R 22 -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)OR 21 -C 0～4 Alkylene-C(O)NR 21 R 22 -C 0～4 Alkylene-NR 21 R 22 -C 0～4 Alkylene-NR 21 C(O)R 22 -C 0～4 Alkylene-NR 21 S(O)2R 22 -C 0～4 Alkylene-NR 21 S(O)R 22 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0018] R 21 R 22Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R 25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R 25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0019] Each R 26Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C 0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0020] R 24 R 25 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0021] Each R 27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0022] Furthermore, the structure shown in Equation I is as shown in Equation IIa or IIb:

[0023]

[0024] The substituent is defined as described above.

[0025] Furthermore,

[0026] Ring A is selected from

[0027] Among them, the ring A selected from the rings can be further arbitrarily selected by one, two, three or four independent R. A1 replace.

[0028] As a preferred option: each R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0029] Furthermore: Ring A is selected from

[0030] As a preferred option: R 1 Selected from hydrogen, methyl, ethyl, and propyl.

[0031] As a preferred option: R 2 Selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 alkenyl, -C2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C 0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)OR 21 -C 0～4 Alkylene-C(O)NR 21 R 22 -C 0～4 Alkylene-NR 21 R 22 ;-C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 23 replace;

[0032] Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C 0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-C(O)R 21 ;-C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0033] R 21 R 22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0034] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-C(O)R 24-C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene rings (5- to 10-membered heteroaryl rings);

[0035] R 24 R 25 Selected independently from hydrogen and -C 1-3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0036] Furthermore: the R 2 Selected from -C(O)NR 21 R 22 -C(O)R 21 -C 0～2 Alkylene-NR 21 R 22 -C(O)OR 21 ;

[0037] R 21 R 22 Selected independently from hydrogen and -C 1～3 Alkyl, -C 0～1 alkylene-(6-membered aromatic ring), -C 0～1 Alkylene rings are defined as -(10-membered heteroaryl rings), -(4-6-membered heterocyclic alkyl rings), or -(3-6-membered cycloalkyl rings), wherein the aromatic ring, heteroaryl ring, heterocyclic alkyl ring, or cycloalkyl ring may be optionally surrounded by one, two, three, or four independent R groups. 26 replace;

[0038] Each R 26 Selected independently from hydrogen and -C 1～3 Alkyl, -(4- to 6-membered heterocyclic alkyl), -C(O)R 24 -C(O)OR 24 、-OC(O)R 24 ;

[0039] R 24Selected from hydrogen, methyl, ethyl, and propyl.

[0040] More specifically: the R 2 Selected from hydrogen,

[0041] More specifically, the compound is shown in Formula III:

[0042]

[0043] in,

[0044] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0045] R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R 25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R 25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0046] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C 0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0047] R 24 R 25 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0048] Each R 27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0049] R 22 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0050] In some embodiments of the present invention, the compound is specifically:

[0051]

[0052] The present invention also provides a compound of formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0053]

[0054] in,

[0055] Indicates whether oxygen substitution is present or absent;

[0056] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 11 -C 1～4 Alkylene-NR 11 R 12 -C 1～4 Alkylene (3- to 10-membered cycloalkyl), -C 1～4 Alkylene (4- to 10-membered heterocyclic alkyl);

[0057] R 11 R 12 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0058] Ring A is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring, and 5-10 membered heteroaromatic ring; wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring may be further optionally surrounded by one, two, three, or four independent R. A1 replace;

[0059] Each R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace;

[0060] Each R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 ;

[0061] R A2 R A3 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0062] X 1 Each is independently selected from chemical bonds, =CR 21 -、C 1～6Alkylene-, C 2～6 imidene group, C 2～6 Alynyl, halogen-substituted C 1～6 Alkylene, halogen-substituted C 2～6 alkenyl, halogen-substituted C 2～6 Ethyne group, -C 0～4 Alkylene -O-, -C 0～4 Alkylene -OC(O)-, -C 0～4 Alkylene-S-, -C 0～4 Alkylene -S(O)2-, -C 0～4 Alkylene-S(O)-, -C 0～4 Alkylene-S(O)2NR 21 -、-C 0～4 Alkylene-S(O)NR 21 -、-C 0～4 Alkylene -C(O)-, -C 0～4 Alkylene -C(O)O-, -C 0～4 Alkylene-C(O)NR 21 -、-C 0～4 Alkylene-NR 21 -、-C 0～4 Alkylene-NR 21 C(O)-、-C 0～4 Alkylene-NR 21 S(O)2-、-C 0～4 Alkylene-NR 21 S(O)-、-C 0～4 alkylene-(3- to 10-membered cycloalkyl)-, -C 0～4 alkylene-(4- to 10-membered heterocyclic alkyl)-, -C 0～4 alkylene-(6- to 10-membered aromatic rings)-, -C 0～4 Alkylene-(5-10 membered heteroaryl ring)-; wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R-rings. 23 replace;

[0063] Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-SR 21 -C 0～4 Alkylene-S(O)2R 21 -C 0～4 Alkylene-S(O)R 21 -C 0～4 Alkylene-S(O)2NR 21 R 22 -C 0～4 Alkylene-S(O)NR 21 R 22 -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)OR 21 -C 0～4 Alkylene-C(O)NR 21 R 22 -C 0～4 Alkylene-NR 21 R 22 -C 0～4 Alkylene-NR 21 C(O)R 22 -C 0～4 Alkylene-NR 21 S(O)2R 22 -C 0～4 Alkylene-NR 21 S(O)R 22 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0064] R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R 25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R 25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0065] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24-C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C 0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0066] R 24 R 25 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0067] Each R27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0068] T is selected from -(L) T ) q -;

[0069] q is selected from integers from 1 to 50;

[0070] Each L T Selected independently from CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -、-C≡C-、3~12-membered cycloalkanes, 3~12-membered heterocyclic alkanes, 6~10-membered aromatic rings, 5~10-membered heteroaromatic rings, 5~12-membered spirocyclic rings, 5~12-membered spiroheterocyclic rings, 5~12-membered bridged rings, 5~12-membered bridged heterocyclic rings; wherein cycloalkanes, heterocyclic alkanes, aromatic rings, aromatic heterocyclic rings, spirocyclic rings, spiroheterocyclic rings, bridged rings, and bridged heterocyclic rings can be further converted by one, two, or three R T1 replace;

[0071] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR, -C 0～4 Alkylene-OC(O)R T2 -C 0～4 Alkylene-SR T2 -C 0～4 Alkylene-S(O)2R T2 -C 0～4 Alkylene-S(O)R T2 -C 0～4 Alkylene-S(O)2NR T2 R T3 -C0～4 Alkylene-S(O)NR T2 R T3 -C 0～4 Alkylene-C(O)R T2 -C 0～4 Alkylene-C(O)OR T2 -C 0～4 Alkylene-C(O)NR T2 R T3 -C 0～4 Alkylene-NR T2 R T3 -C 0～4 Alkylene-NR T2 C(O)R T3 -C 0～4 Alkylene-NR T2 S(O)2R T3 -C 0～4 Alkylene-NR T2 S(O)R T3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... T1 replace;

[0072] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene rings (5- to 10-membered heteroaryl rings);

[0073] X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H, -C(O)OH-;

[0074] RX21 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0075] Furthermore, the compound described in formula V is as shown in formula VIa or formula VIb:

[0076]

[0077] The substituent is defined as described above.

[0078] Furthermore, the compound is as shown in Formula VII:

[0079]

[0080] in,

[0081] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0082] R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R 25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0083] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0084] R 24 R 25 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0085] Each R 27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0086] T is selected from -(L) T ) q-;

[0087] q is selected from integers from 1 to 30;

[0088] Each L T Selected independently from CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -、-C≡C-、3~12-membered cycloalkanes, 3~12-membered heterocyclic alkanes, 6~10-membered aromatic rings, 5~10-membered heteroaromatic rings, 5~12-membered spirocyclic rings, 5~12-membered spiroheterocyclic rings, 5~12-membered bridged rings, 5~12-membered bridged heterocyclic rings; wherein cycloalkanes, heterocyclic alkanes, aromatic rings, aromatic heterocyclic rings, spirocyclic rings, spiroheterocyclic rings, bridged rings, and bridged heterocyclic rings can be further converted by one, two, or three R T1 replace;

[0089] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR, -C 0～4 Alkylene-OC(O)R T2 -C 0～4 Alkylene-SR T2 -C 0～4 Alkylene-S(O)2R T2 -C 0～4 Alkylene-S(O)R T2 -C 0～4 Alkylene-S(O)2NR T2 R T3 -C 0～4 Alkylene-S(O)NR T2 R T3 -C 0～4 Alkylene-C(O)R T2 -C 0～4 Alkylene-C(O)OR T2 -C 0～4 Alkylene-C(O)NR T2 R T3 -C 0～4 Alkylene-NR T2 RT3 -C 0～4 Alkylene-NR T2 C(O)R T3 -C 0～4 Alkylene-NR T2 S(O)2R T3 -C 0～4 Alkylene-NR T2 S(O)R T3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... T1 replace;

[0090] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene rings (5- to 10-membered heteroaryl rings);

[0091] X 2 Selected from -NH2, -NHR X21 -OH, -SH, ethynyl, vinyl, -C(O)H, -C(O)OH-;

[0092] R X21 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 Alkyne group.

[0093] To be more specific,

[0094] T is selected from

[0095]

[0096] In some specific embodiments of the present invention, the compound represented by formula V is specifically:

[0097]

[0098] The present invention also provides the use of any of the compounds described above, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, in the treatment of diseases related to abnormal cell proliferation.

[0099] Furthermore, the disease in question is cancer.

[0100] The present invention also provides the use of any of the compounds described above, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, in the preparation of targeted protein degradation drugs.

[0101] Furthermore, the use of the said compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, as an intermediate in the preparation of a targeted protein degradation drug is provided.

[0102] Furthermore, the targeted protein degradation drug is a drug that relies on the E3 ligase CRBN for protein degradation.

[0103] The present invention also provides a bifunctional compound of formula X, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0104]

[0105] in,

[0106] Indicates whether oxygen substitution is present or absent;

[0107] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 11 -C 1～4 Alkylene-NR 11 R 12 -C 1～4 Alkylene (3- to 10-membered cycloalkyl), -C1～4 Alkylene (4- to 10-membered heterocyclic alkyl);

[0108] R 11 R 12 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0109] Ring A is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring, and 5-10 membered heteroaromatic ring; wherein, the cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaromatic ring may be further optionally surrounded by one, two, three, or four independent R. A1 replace;

[0110] Each R A1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NRA2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... A4 replace;

[0111] Each R A4 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-SR A2 -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 RA3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene-NR A2 S(O)2R A3 -C 0～4 Alkylene-NR A2 S(O)R A3 ;

[0112] R A2 R A3 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0113] X 1 Each is independently selected from chemical bonds, =CR 21 -、C 1～6 Alkylene-, C 2～6 imidene group, C 2～6 Alynyl, halogen-substituted C 1～6 Alkylene, halogen-substituted C 2～6 alkenyl, halogen-substituted C 2～6 Ethyne group, -C 0～4 Alkylene -O-, -C 0～4 Alkylene -OC(O)-, -C 0～4 Alkylene-S-, -C 0～4 Alkylene -S(O)2-, -C 0～4 Alkylene-S(O)-, -C 0～4 Alkylene-S(O)2NR 21 -、-C 0～4 Alkylene-S(O)NR 21 -、-C 0～4 Alkylene -C(O)-, -C 0～4 Alkylene -C(O)O-, -C 0～4 Alkylene-C(O)NR 21 -、-C 0～4 Alkylene-NR 21 -、-C 0～4 Alkylene-NR 21 C(O)-、-C 0～4 Alkylene-NR 21S(O)2-、-C 0～4 Alkylene-NR 21 S(O)-、-C 0～4 alkylene-(3- to 10-membered cycloalkyl)-, -C 0～4 alkylene-(4- to 10-membered heterocyclic alkyl)-, -C 0～4 alkylene-(6- to 10-membered aromatic rings)-, -C 0～4 Alkylene-(5-10 membered heteroaryl ring)-; wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R-rings. 23 replace;

[0114] Each R 23 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 21 -C 0～4 Alkylene-OC(O)R 21 -C 0～4 Alkylene-SR 21 -C 0～4 Alkylene-S(O)2R 21 -C 0～4 Alkylene-S(O)R 21 -C 0～4 Alkylene-S(O)2NR 21 R 22 -C 0～4 Alkylene-S(O)NR 21 R 22 -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)OR 21 -C 0～4 Alkylene-C(O)NR 21 R 22 -C 0～4 Alkylene-NR 21 R 22 -C 0～4 Alkylene-NR 21 C(O)R 22 -C 0～4 Alkylene-NR21 S(O)2R 22 -C 0～4 Alkylene-NR 21 S(O)R 22 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0115] R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R 25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0116] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C 0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0117] R 24 R 25 Selected independently from hydrogen and -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0118] Each R 27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0119] T is selected from -(L) T ) q -;

[0120] q is selected from integers from 1 to 50;

[0121] Each L T Selected independently from CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3-、-C≡C-、3~12-membered cycloalkanes, 3~12-membered heterocyclic alkanes, 6~10-membered aromatic rings, 5~10-membered heteroaromatic rings, 5~12-membered spirocyclic rings, 5~12-membered spiroheterocyclic rings, 5~12-membered bridged rings, 5~12-membered bridged heterocyclic rings; wherein cycloalkanes, heterocyclic alkanes, aromatic rings, aromatic heterocyclic rings, spirocyclic rings, spiroheterocyclic rings, bridged rings, and bridged heterocyclic rings can be further converted by one, two, or three R T1 replace;

[0122] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR, -C 0～4 Alkylene-OC(O)R T2 -C 0～4 Alkylene-SR T2 -C 0～4 Alkylene-S(O)2R T2 -C 0～4 Alkylene-S(O)R T2 -C 0～4 Alkylene-S(O)2NR T2 R T3 -C 0～4 Alkylene-S(O)NR T2 R T3 -C 0～4 Alkylene-C(O)R T2 -C 0～4 Alkylene-C(O)OR T2 -C 0～4 Alkylene-C(O)NR T2 R T3 -C 0～4 Alkylene-NR T2 R T3 -C 0～4 Alkylene-NR T2 C(O)R T3 -C 0～4 Alkylene-NR T2 S(O)2R T3 -C 0～4 Alkylene-NR T2 S(O)R T3 -C 0～4Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... T1 replace;

[0123] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene rings (5- to 10-membered heteroaryl rings);

[0124] Z represents a group that binds to the target protein.

[0125] Furthermore, the compound of formula X is as shown in formula XIa or formula XIb:

[0126]

[0127] The substituent is defined as described above.

[0128] Furthermore, the compound is as shown in Formula XII:

[0129]

[0130] in,

[0131] R 1 Selected from hydrogen, -C 1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0132] R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 2～6alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 1～4 Alkylene-OR 24 -C 1～4 Alkylene-OC(O)R 24 -C 1～4 Alkylene-SR 24 -C 1～4 Alkylene-S(O)2R 24 -C 1～4 Alkylene-S(O)R 24 -C 1～4 Alkylene-S(O)2NR 24 R 25 -C 1～4 Alkylene-S(O)NR 24 R 25 -C 1～4 Alkylene-C(O)R 24 -C 1～4 Alkylene-C(O)OR 24 -C 1～4 Alkylene-C(O)NR 24 R 25 -C 1～4 Alkylene-NR 24 R 25 -C 1～4 Alkylene-NR 24 C(O)R 25 -C 1～4 Alkylene-NR 24 S(O)2R 25 -C 1～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace;

[0133] Each R 26 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 -C1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR 24 -C 0～4 Alkylene-OC(O)R 24 -C 0～4 Alkylene-SR 24 -C 0～4 Alkylene-S(O)2R 24 -C 0～4 Alkylene-S(O)R 24 -C 0～4 Alkylene-S(O)2NR 24 R 25 -C 0～4 Alkylene-S(O)NR 24 R 25 -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene-C(O)OR 24 -C 0～4 Alkylene-C(O)NR 24 R 25 -C 0～4 Alkylene-NR 24 R 25 -C 0～4 Alkylene-NR 24 C(O)R 25 -C 0～4 Alkylene-NR 24 S(O)2R 25 -C 0～4 Alkylene-NR 24 S(O)R 25 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 27 replace;

[0134] R 24 R 25 Selected independently from hydrogen and -C1-6 alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0135] Each R 27 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group;

[0136] T is selected from -(L) T ) q -;

[0137] q is selected from integers from 1 to 30;

[0138] Each L T Selected independently from CR T2 R T3 ,C(O),-C(S)-,O,S,S(O),S(O)2,NR T2 -CR T2 =CR T3 -、-C≡C-、3~12-membered cycloalkanes, 3~12-membered heterocyclic alkanes, 6~10-membered aromatic rings, 5~10-membered heteroaromatic rings, 5~12-membered spirocyclic rings, 5~12-membered spiroheterocyclic rings, 5~12-membered bridged rings, 5~12-membered bridged heterocyclic rings; wherein cycloalkanes, heterocyclic alkanes, aromatic rings, aromatic heterocyclic rings, spirocyclic rings, spiroheterocyclic rings, bridged rings, and bridged heterocyclic rings can be further converted by one, two, or three R T1 replace;

[0139] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene-OR, -C 0～4 Alkylene-OC(O)R T2 -C 0～4 Alkylene-SRT2 -C 0～4 Alkylene-S(O)2R T2 -C 0～4 Alkylene-S(O)R T2 -C 0～4 Alkylene-S(O)2NR T2 R T3 -C 0～4 Alkylene-S(O)NR T2 R T3 -C 0～4 Alkylene-C(O)R T2 -C 0～4 Alkylene-C(O)OR T2 -C 0～4 Alkylene-C(O)NR T2 R T3 -C 0～4 Alkylene-NR T2 R T3 -C 0～4 Alkylene-NR T2 C(O)R T3 -C 0～4 Alkylene-NR T2 S(O)2R T3 -C 0～4 Alkylene-NR T2 S(O)R T3 -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... T1 replace;

[0140] Each R T1 Each group is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, and -C. 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 Alkyne- or halogen-substituted -C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted -C 2～6 alkynyl group, -C 0～4 Alkylene (3- to 10-membered cycloalkyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C0～4 Alkylene rings (5- to 10-membered heteroaryl rings);

[0141] Z represents a group that binds to the target protein.

[0142] To be more specific,

[0143] Z is selected from

[0144] In some specific embodiments of the present invention, the compound represented by formula X is specifically:

[0145]

[0146] The present invention also provides the use of any of the above-mentioned bifunctional compounds, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts, in the preparation of pharmaceuticals.

[0147] Furthermore, the drug is a drug that targets protein degradation.

[0148] Furthermore, the drug is a drug that targets protein degradation via the E3 ligase CRBN.

[0149] The compounds represented by Formula I, Formula V or Formula X of this invention do not include the following compounds:

[0150]

[0151]

[0152] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0153] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0154] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules. "Substitution" can also refer to the replacement of lone pairs of electrons in atoms in a molecule by "=O", "=S", etc.

[0155] "Can be further replaced" means that "replacement" can but does not have to happen, and this statement includes situations where it may or may not happen.

[0156] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～bAlkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0157] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-6 alkoxy groups.

[0158] In this invention, "alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. "C" a ~ b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example, "C 1～6 The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Therefore, the term "propylene" can be exemplified by the following structures: Similarly, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: Furthermore, the term "(C1-6)alkylene" is intended to include such branched hydrocarbon groups, such as cyclopropylmethylene, which can be exemplified by the following structures: For example, -C0 to -4 alkylene groups can be C0 alkylene, C1 alkylene (e.g., -CH2-), C2 alkylene (e.g., -CH2CH2-), C3 alkylene, or C4 alkylene; C0 alkylene refers to the absence of a group here, which is connected by a chemical bond. For example, A-C0 alkylene-B refers to AB, that is, the A group and the B group are directly connected by a chemical bond.

[0159] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms and, in some embodiments, 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one vinyl unsaturated site (>C=C<). For example, C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0160] In this invention, "alkenyl" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C3-C6)alkenyl groups include >C=CH-CH2-, -CH-CH=CH-CH2-, etc.

[0161] "Alynyl" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6) alkynyl is intended to include ethynyl, propynyl, etc.

[0162] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0163] "Halogenated alkyl" or "halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms can be replaced by one or more halogen atoms. For example, C 1～4 Halogenated alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms.

[0164] In this invention, "-OR", "-NRR", etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0165] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0166] In this invention, "cycloalkyl" and "cycloalkane" refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no heterocyclic atoms, and having a single ring or multiple rings (including fused, bridged, spirocyclic, and adamantane systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) is used when the connecting point is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. adamantyl groups include, but are not limited to, the following structures:

[0167] In this invention, "heterocyclic," "heterocyclic alkyl," and "heterocyclic alkane" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where heteroatoms refer to nitrogen, oxygen, sulfur, etc. Generally, it represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with 3 to 9 ring atoms, containing 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring represents two rings consisting of two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclic alkyl groups are oxobutyl, aziridine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoalkyl, thiazoalkyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazine, morpholinyl, etc. Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azacycloheptyl, diazacycloheptyl, periperazinyl, or oxazacycloheptyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl.

[0168] "Spirocycloiden" and "spirocycloheterocycle" are used interchangeably. They refer to non-aromatic saturated rings or non-aromatic unsaturated ring systems with two monocyclic rings sharing a single carbon atom, consisting of a carbon atom and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "5- to 12-membered spirocycloheterocycles" refer to spirocycloheterocycles with 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0169] "Bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples include, but are not limited to:

[0170] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably, referring to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific embodiments include, but are not limited to:

[0171] In this invention, "aromatic ring" and "aryl" refer to aromatic hydrocarbon groups having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aryl groups having 5-20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0172] In this invention, "heteroaromatic ring" and "heteroaromatic cyclic group" refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Typically, it refers to an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which are selected from O, N, and S heteroatoms. Preferably, it has one to three heteroatoms. Examples of heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, benzothiopheneyl, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazoleyl, thiopheneyl, oxadiazolyl, benzimidazoleyl, benzothiazolyl, and benzoxazolyl.

[0173] "Stereoisomers" include enantiomers and diastereomers;

[0174] The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0175] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0176] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds, or their stereoisomers, with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0177] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention. Detailed Implementation

[0178] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0179] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0180] The reagents described in the examples are abbreviated as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0181] DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0182] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the optimal reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0183] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR determinations were performed using Bruker Avance III 400 and Bruker Avance 600 NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl₃), and deuterated methanol (Methol-d4) as solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS determinations were performed using a Shimadzu LC-MS 2020 (ESI) system. HPLC determinations were performed using a Shimadzu LC-20A high-performance liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4mm to 0.5mm for product separation and purification. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0184] Example 1: Preparation of compound A1

[0185]

[0186] Step 1: Preparation of compound A-3

[0187]

[0188] Compound A-2 (177.00 mg, 0.75 mmol), DIPEA (132.25 mg, 1.00 mmol, 178.06 μL), HATU (250.96 mg, 0.66 mmol), and dichloromethane (2 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0 °C, compound A-1 (190.00 mg, 0.65 mmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions to quench the reaction (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The solvent was removed by concentration under reduced pressure to obtain compound A-3 (crude product).

[0189] Step 2: Preparation of compound A-4

[0190]

[0191] Compound A-3 (crude product), sodium hydroxide (44.00 mg, 1.10 mmol), tetrahydrofuran (4 mL), and water (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was quenched after stirring at room temperature for 8 hours (monitored by LC-MS). The pH of the system was adjusted to 6-7 with 1 N hydrochloric acid solution. After concentrating the reaction solution, compound A-4 (crude product) was obtained and used directly in the next reaction.

[0192] Step 3: Preparation of compound A-6

[0193]

[0194] Compound A-5 (crude product), DIPEA (132.25 mg, 1.00 mmol, 178.06 μL), HATU (250.96 mg, 0.66 mmol), and DCM (2 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0 °C, compound A-4 (91.71 mg, 0.65 mmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions to quench the reaction (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. After concentration under reduced pressure to remove the solvent, compound A-6 (80.00 mg, 126.52 μmol, 19.46% yield) was obtained.

[0195] Step 4: Synthesis of Compound A1

[0196]

[0197] Compound A-6 (80.00 mg, 126.52 μmol) was dissolved in a 25 mL reaction flask in a mixed solution (2 mL) of 6N HCl and ethyl acetate. The reaction was stirred at room temperature for 0.5 hours, and then quenched (monitored by LC-MS). Extraction was completed with 10 mL of saturated NaCl solution and 3 × 10 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated, and the mixture was separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 100:1 to 3:1. After concentration under reduced pressure to remove the solvent, compound A1 (25.20 mg, 47.35 μmol, 37.42% yield, 99.4% purity) was obtained. LC-MS: C 28 H 33 N6O3S,[M+H] + :533.2,found 533.3. 1 H NMR(600MHz,Methonal-d4)δ8.12-7.83(m,2H),7.55-7.44(m,2H),7.39-7.04(m,4H),4.96-4.93(m,1H),4.79-4.72(m, 1H),4.50-4.29(m,3H),4.20-3.89(m,3H),3.57-3.54(m,2H),3.31-3.12(m,6H),3.03-2.89(m,2H),2.80-2.45(m,4H).

[0198] Following the synthetic method of compound A-6, compounds A-1, A-2, and A-5 can be obtained by replacing the raw materials listed in Table 1 below with the same raw materials and operating methods.

[0199] Table 1. Compounds A2-A16

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Example 2: Preparation of bifunctional compounds

[0207] Preparation of the bifunctional compound BRD4-linker-CRBN:

[0208]

[0209]

[0210] Step 1: Synthesis of Compound 3

[0211]

[0212] Compound 1 (1.00 g, 4.67 mol), compound 2 (1.50 g, 6.25 mol), K2CO3 (3.86 g, 2.80 mol), and ACN (50 mL) were added to a 250 mL reaction flask. The mixture was heated to 70 °C and stirred until the reaction was complete. The reaction was then quenched with water (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (50 mL) and ethyl acetate (3 x 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and the mixture was concentrated under reduced pressure to remove the solvent, yielding compound 3 (crude product). LCMS (ESI) [M+H]: 373.0.

[0213] The obtained compound was characterized as follows: MS (ESI) m / z = 373.0 (M+1). + .

[0214] Step 2: Preparation of Compound 4

[0215]

[0216] Compound 3 (crude product), sodium hydroxide (3.39 g, 84.75 mmol), ethanol (10 mL), and water (15 mL) were added sequentially to a 150 mL reaction flask. The reaction was quenched after stirring at room temperature for 8 hours (monitored by LC-MS). The pH of the system was adjusted to 6-7 with 1 N hydrochloric acid solution. After concentrating the reaction solution, compound 4 (crude product) was obtained and used directly in the next reaction. LCMS (ESI) [M+H]: 255.0.

[0217] The obtained compound was characterized as follows: MS (ESI) m / z = 254.8 (M+1). + .

[0218] Step 3: Preparation of Compound 6

[0219]

[0220] Under nitrogen protection, compound 4 (255.06 mg, 1.00 mmol), compound 5 (166.97 mg, 1.00 mmol), K₂CO₃ (202.39 mg, 2.00 mmol), 1,4-dioxane and water (4 mL / 1 mL), and Pd(dppf)Cl₂ (0.25 mol%) were added sequentially to a 50 mL reaction flask. The reaction system was sealed and stirred at 80 °C for 2 hours to quench the reaction (monitored by LC-MS). Extraction was performed using saturated NaCl solution (20 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. Separation was performed by column chromatography with a petroleum ether / ethyl acetate volume ratio of 1:100 to 1:5. After removing the solvent by concentration under reduced pressure, compound 6 (200.00 mg, 672.71 μmol, 67.27% yield) was obtained. LCMS (ESI) [M+H]: 298.1.

[0221] The obtained compound was characterized: MS (ESI) m / z = 298.2 (M+1). + .

[0222] Step 4: Preparation of Compound 7

[0223]

[0224] Compound 6 (70.00 mg, 235.45 μmol), DIPEA (91.29 mg, 706.35 μmol, 123.03 μL), HATU (89.30 mg, 235.45 μmol), and DMF (5 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0 °C, compound Linker 1 (50.93 mg, 235.45 μmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions to quench the reaction (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. After removing the solvent by vacuum concentration, compound 7 (100.00 mg, 201.77 μmol, 85.70% yield) was obtained. LCMS (ESI) [M+H]: 496.3.

[0225] The obtained compound was characterized: MS (ESI) m / z = 496.4 (M+1). + .

[0226] Step 5: Synthesis of Compound 8

[0227]

[0228] Compound 7 (80.00 mg, 161.42 μmol), trifluoroacetic acid (18.41 mg, 161.42 μmol, 2 mL), and DCM (5 mL) were added sequentially to a 25 mL reaction flask. The reaction was stirred at room temperature for 0.5 hours, and the reaction was quenched (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 10 mL). The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was evaporated and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 100:1 to 3:1. After removing the solvent by concentration under reduced pressure, compound 8 (crude product) was obtained. LCMS (ESI) [M+H]: 396.2.

[0229] The obtained compound was characterized: MS (ESI) m / z = 396.4 (M+1). + .

[0230] Step 6: Synthesis of Compound 10

[0231]

[0232] Compound 8 (crude product), compound A-1 (44.05 mg, 151.71 μmol), NaBH3CN (47.67 mg, 758.55 μmol), and tetrahydrofuran (5 mL) were added sequentially to a 50 mL reaction flask. The reaction was stirred at room temperature for 2 hours, then quenched (monitored by LC-MS). The solvent was evaporated to dryness, purified by MPLC, and concentrated under reduced pressure to remove the solvent, yielding compound 10 (80.00 mg, 119.43 μmol, 78.72% yield). LCMS (ESI) [M+H]: 670.4.

[0233] The obtained compound was characterized: MS (ESI) m / z = 670.5 (M+1). + .

[0234] Step 7: Synthesis of Compound 11

[0235]

[0236] Compound A-3 (21.16 mg, 89.57 μmol), DIPEA (34.73 mg, 268.72 μmol, 46.81 μL), HATU (34.04 mg, 89.57 μmol), and DMF (5 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0 °C, compound 10 (60.00 mg, 89.57 μmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions to quench the reaction (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. After removing the solvent by vacuum concentration, compound 11 (60.00 mg, 67.56 μmol, 75.43% yield) was obtained. LCMS (ESI) [M+H]: 888.4.

[0237] The obtained compound was characterized: MS (ESI) m / z = 888.3 (M+1). + .

[0238] Step 8: Synthesis of Compound 12

[0239]

[0240] Compound 11 (60.00 mg, 67.56 μmol), sodium hydroxide (18.02 mg, 450.41 μmol), tetrahydrofuran (5 mL), and water (1 mL) were added sequentially to a 50 mL reaction flask. The reaction was quenched after stirring at room temperature for 8 hours (monitored by LC-MS). The pH of the system was adjusted to 6-7 with 1N hydrochloric acid solution. After concentrating the reaction solution, compound 12 (crude product) was obtained and used directly in the next reaction. LCMS (ESI) [M+H]: 847.4.

[0241] The obtained compound was characterized: MS (ESI) m / z = 847.5 (M+1). + .

[0242] Step 9: Synthesis of Compound 13

[0243]

[0244] Compound 12 (crude product), DIPEA (22.18 mg, 171.61 μmol, 29.89 μL), HATU (21.66 mg, 57.20 μmol), and DMF (5 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0 °C, compound A-6 (8.08 mg, 57.20 μmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions to quench the reaction (monitored by LC-MS). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. After removing the solvent by vacuum concentration, compound 13 (40.00 mg, 40.11 μmol, 70.12% yield) was obtained. LCMS (ESI) [M+H]: 998.5.

[0245] The obtained compound was characterized: MS (ESI) m / z = 998.5 (M+1). + .

[0246] Step 10: Synthesis of HGC01

[0247]

[0248] Compound 13 (40.00 mg, 40.11 μmol) was dissolved in a 5 mL mixture of 6 N HCl and 1,4-dioxane in a 25 mL reaction flask. The reaction was stirred at room temperature for 0.5 hours, and the reaction was quenched (monitored by LC-MS). Extraction was completed with 10 mL of saturated NaCl solution and 3 × 10 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and separated by column chromatography. The volume ratio of the eluent used was petroleum ether / ethyl acetate = 100:1 to 3:1. After removing the solvent by concentration under reduced pressure, compound HGC01 (15.50 mg, 15.67 μmol, 39.07% yield) was obtained. LCMS (ESI) [M+H]: 897.41.

[0249] The obtained compound was characterized: MS (ESI) m / z = 897.7 (M+1). + .

[0250] 1 H NMR(600MHz,Methanol-d4)δ7.98-7.80(m,4H),7.67(s,1H),7.52-7.44(m,5H),7. 34-7.21(m,3H),4.86(s,1H),4.72-4.54(m,2H),4.48-4.25(m,4H),4.12(s,1H),3 .69(s,3H),3.47-3.46(m,5H),3.36-3.14(m,5H),2.88-2.85(m,3H),2.75(s,1H), 2.74-2.61(m,4H),2.22(s,3H),1.81-1.63(m,3H),1.52(s,3H),1.21(s,2H).HPLC Purity > 90%.

[0251] Following the synthetic route of HGC01, by replacing compound Linker 1 with the compound shown in the table below as Linker(s), and keeping the rest of the operations unchanged, bifunctional compounds HGC02 and HGC03 can be obtained.

[0252]

[0253]

[0254] bifunctional compound HGC02

[0255] For C 52 H 61 N8O6S,[M+H] + 925.4; found 925.7. 1H NMR(600MHz,Methanol-d4)δ7.99-7.83(m,4H),7.66(s,1H),7.50-7.44(m,5H),7.35-7.23(m,3H),4.8 6(s,1H),4.68-4.57(m,1H),4.39-4.28(m,4H),4.18-4.16(m,1H),4.00-3.98(m,1H),3.67-3.58(m,4H ),3.47-3.44(m,4H),3.31-3.14(m,5H),2.73-2.69(m,1H),2.62-2.60(m,7H),2.21(s,3H),1.78-1.69 (m,3H),1.60-1.59(m,3H),1.21-1.12(m,2H),0.99-0.96(m,2H),0.90-0.88(m,2H).HPLCpurity>95%.

[0256] bifunctional compound HGC03

[0257] For C 54 H 64 N8O6S,[M / 2+H] + 477.2; found 477.8. 1 H NMR(600MHz,Methanol-d4)δ8.00-7.80(m,4H),7.66(s,1H),7.35-7.22(m,8 H),4.93(s,2H),4.87-4.45(m,5H),4.18(s,1H),3.71(s,3H),3.46-3.30(m,6 H),3.25-3.11(m,4H),3.01-2.95(m,2H),2.73-2.61(m,5H),2.23(s,3H),1. 67-1.58(m,4H),1.40–1.30(m,6H),129–1.28(m,2H),1.21-1.09(m,4H).HPLC purity>80%.

[0258] The technical effects of this invention are illustrated by the following experimental examples:

[0259] Experimental Example 1: Detection of compound binding to CRBN / DDB1 using TRIC (temperature-dependent fluorescence intensity change method).

[0260] 1. Experimental materials and reagents

[0261] Disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), Pluronic F-127 (Sigma), His-TagLabeling Kit-RED-tris-NTA (NanoTemper), Dianthus 384well plates (NanoTemper), CRBN / DDB1 protein (HitGen).

[0262] 2. Experimental Methods

[0263] Mix 6.43 μL of 2.8 μM dye with 443.57 μL of 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.1% Pluronic F-127, and pH 7.0 buffer to obtain 450.0 μL of 40.0 nM dye. Dilute the histidine-tagged CRBN / DDB1 protein to 400.0 nM, and mix 445.0 μL of 400.0 nM histidine-tagged CRBN / DDB1 protein with 445.0 μL of 40.0 nM dye. Incubate at room temperature for 30 minutes. Centrifuge at 15000g for 10 minutes at 4°C, and transfer the supernatant to a new centrifuge tube for later use.

[0264] The compound powder was dissolved in DMSO. The compound was then serially diluted with 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.1% Pluronic F-127, and pH 7.0 buffer to a total of 12 concentration gradients. 10.0 μL of each compound was mixed with 10.0 μL of labeled protein and thoroughly mixed. The final concentration of DMSO in the entire reaction system (20.0 μL) was 1.0%. The mixture was incubated at room temperature for 20 minutes, and the readings were taken using DI. Kd was calculated using DI.SA.

[0265] 3. Data Analysis

[0266] Table 1: Binding strength of compounds to CRBN / DDB1 protein

[0267] serial number Kd serial number Kd serial number Kd A1 ++ A3 +++ A7 + A2 + A6 ++ A8 +++

[0268] Where + represents 200μM>Kd>100μM, ++ represents 100μM>Kd>10μM, +++ represents 10μM>Kd>1μM, and ++++ represents Kd<1μM.

[0269] Experimental Example 2: Detection of the inhibitory effect of compounds on CRBN / DDB1 activity (FRET)

[0270] 1. Experimental materials and reagents

[0271] Microplate reader (BMG PHERAstar FSX), ECHO (LABCYTE Echo 665), microplate constant temperature shaker (Hangzhou Ruicheng Instrument Co., Ltd.), disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), bovine serum albumin (Sigma), Anti-6His-Tb crypate Gold (CISBIO), CRBN / DDB1 protein (HitGen), 384-well plate (Grenier Bio-one).

[0272] 2. Experimental Methods

[0273] The compound powder was dissolved in DMSO, and the compound was serially diluted with ECHO and added to a 384-well reaction plate to make the final concentration of DMSO in the entire reaction system (10.0 μL) 1.0%. An equal amount of DMSO was added as a control.

[0274] The CRBN / DDB1 protein was diluted twice to the desired final concentration (5.0 nM) using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, and pH 7.0 buffer. 5.0 μL of the diluted CRBN / DDB1 protein was added to a 384-well plate containing the added compounds. The plate was centrifuged at 1000 rpm for 1 minute and then placed on a microplate shaker at 25°C and 250 rpm for 15 minutes. Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analogue were diluted twice to the desired final concentration using 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, and pH 7.0 buffer. The final concentration of Anti-6His-Tb crypate Gold was 0.2 nM, and the final concentration of FITC-labeled thalidomide analogue was 50.0 nM, resulting in a mixture of Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analogue. 5.0 μL of the Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analogue mixture was added to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and then incubated on a microplate shaker at 25°C and 250 rpm for 30 minutes. After the reaction was completed, the microplate reader read the fluorescence signal values ​​in the 384-well plate (Ex = 337nm Em = 520 / 490nm).

[0275] 3. Data Analysis

[0276] The solvent group (containing 5.0 nM CRBN / DDB1, 0.2 nM Anti-6His-Tb crypate Gold, 50.0 nM FITC-labeled thalidomide analogue and 1.0% DMSO) served as the negative control, and the reaction buffer group (containing 0.2 nM Anti-6His-Tb crypate Gold, 50.0 nM FITC-labeled thalidomide analogue and 1.0% DMSO) served as the blank control.

[0277] The formula for calculating the percentage of remaining activity at each concentration is as follows:

[0278] Remaining vitality (%) = 100% × (Flu) 化合物组 -Flu 空白对照 ) / (Flu 阴性对照 -Flu 空白对照 )

[0279] Then, the IC was calculated by fitting the dose-effect curve using GraphPad 6.0. 50 value.

[0280] Table 2: Relationship between compounds and CRBN / DDB1 protein inhibition

[0281] serial number <![CDATA[IC 50 ]]> serial number <![CDATA[IC 50 ]]> serial number <![CDATA[IC 50 ]]> A1 +++ A4 ++ A7 ++ A2 + A5 + A8 ++ A3 ++ A6 ++ A9 +

[0282] Where + represents 200μM > IC 50 >100μM, ++ means 100μM>IC 50 >10μM, +++ indicates 10μM>IC 50 >1μM, ++++ indicates IC 50 <1μM.

[0283] The above experiments show that the compounds in the embodiments of the present invention have good CRBN binding ability and inhibitory effect, and can be effectively used for the treatment of diseases related to abnormal CRBN activity.

[0284] Experiment Example 3: Evaluation of the effect of a compound on the degradation of BRD4 protein in MV-4-11 cells using Western blot.

[0285] 1. Experimental instruments and reagents:

[0286] SDS-PAGE gel (4-12%) (Genscript), PMSF 100mM (Biyotime), Cocktail 100× (Biyotime), P / S, IMDM modified medium with L-glutamine, HEPES (Hyclone), FBS (Corning), 4× loading buffer (Thermo), BRD4 rabbit mAb (Abcam), c-Myc Rabbit mAb (CST), CRBN Rb mAb (SIGMA), Anti-rabbit IgG-HRP (CST), Anti-β-actin-HRP (Abcam), RIPA (Biyotime), Tween-20, MV-4-11cell (ATCC), BCA Protein Assay Kit (TIANGEN), Immobilon Western Chemilunescent HRP Substrate (Millipore).

[0287] 2. Experimental Methods

[0288] 1) Incubation of the compound with cells: Add 1 mL of 2×10⁻⁶ cells to the cell incubator. 6 MV-4-11 cells (medium: 89% IMDM, 10% FBS, 1% P / S) were seeded in 6-well cell culture plates. The compound was diluted three times with DMSO. The compound diluted in DMSO was then diluted again in MV-4-11 medium. 1 mL of the diluted compound was added directly to the 6-well cell culture plate and incubated for 24 h.

[0289] 2) Protein extraction: After co-incubating the compound with cells for 24 h, the cells were collected in 1.5 mL centrifuge tubes, washed twice with ice-cold PBS, and the supernatant was discarded. 70 μL of RIPA lysis buffer was added, and the cells were lysed on ice for 60 min. The cell lysate was then centrifuged at 15000 rpm for 10 min, and the supernatant was collected. Protein quantification was performed on the cell lysate supernatant using the BCA Protein Assay Kit. 4× loading buffer was added to the cell lysate supernatant, and the mixture was incubated at 95 °C for 10 min to obtain the sample. The obtained sample was stored at -80 °C for use the next day.

[0290] 3) Western blot: 20 μg of sample was used for SDS-PAGE and membrane transfer. The membrane was blocked with 5% skim milk at room temperature for 1 h, and then incubated overnight at 4°C with BRD4 rabbit mAb, c-Myc Rabbit mAb, CRBN Rb mAb, and Anti-β-actin-HRP antibody. After washing three times with TBST, the membrane was incubated with Anti-rabbit IgG-HRP secondary antibody at room temperature for 1 h. After incubation, the membrane was washed three times with TBST, and then developed using Immobilon Western Chemiluminescent HRP Substrate. The analysis was performed using a gel electrophoresis apparatus.

[0291] 3. Data Analysis

[0292] The analysis was performed using grayscale analysis software. After correcting the BRD4 protein level by the amount of β-actin, the degradation of the BRD4 protein was analyzed.

[0293] The compounds prepared in the examples were subjected to BRD4 protein degradation detection according to the above method. The experimental results are shown in Table 3, in which the DC of each compound was measured. 50 According to the classification in the instructions, in Table 3:

[0294] "+" indicates DC 50 The value is between 0.5 and 3 μM;

[0295] Table 3. Effects of compounds on the degradation of BRD4 protein in MV-4-11 cells

[0296] Compound BRD4 c-Myc HGC01 + +

[0297] Experiments show that the compound HGC01 in the embodiments of the present invention has good BRD4 protein degradation activity and can be effectively used for the treatment of diseases related to abnormal BRD4 activity.

Claims

1. The compound represented by formula IIa, or its stereoisomer, or its pharmaceutically acceptable salt: in, R 1 Selected from hydrogen, -C 1-6 Alkyl groups; Ring A is selected from R 2 Independently selected from -C 0～4 Alkylene-C(O)R 21 -C 0～4 Alkylene-C(O)NR 21 R 22 ; R 21 R 22 Selected independently from hydrogen and -C 1～6 Alkyl, -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, heterocyclic alkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace; Each R 26 Selected independently from hydrogen and -C 1～6 Alkyl, -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl); R 24 Selected from hydrogen, -C 1-6 Alkyl groups.

2. The compound according to claim 1, characterized in that: Ring A is selected from 3. The compound according to claim 1, characterized in that: R 1 Selected from hydrogen, methyl, ethyl, and propyl.

4. The compound according to claim 1, characterized in that: The R 2 Selected from -C(O)NR 21 R 22 -C(O)R 21 ; R 21 R 22 Selected independently from hydrogen and -C 1～3 Alkyl, -C 0～1 alkylene-(6-membered aromatic ring), -C 0～1 Alkylene rings (-(10-membered heteroaryl rings) or (-(4-6-membered heterocyclic alkyl groups)), wherein the aromatic ring, heteroaryl ring, or heterocyclic alkyl group may be optionally surrounded by one, two, three, or four independent R groups. 26 replace; Each R 26 Selected independently from hydrogen and -C 1～3 Alkyl, -(4- to 6-membered heterocyclic alkyl), -C(O)R 24 ; R 24 Selected from hydrogen, methyl, ethyl, and propyl.

5. The compound according to claim 1, characterized in that: R 2 Selected from hydrogen, 6. The compound according to claim 1, characterized in that: The compound is shown in Formula III: in, R 1 Selected from hydrogen, -C 1-6 Alkyl groups; R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6- to 10-membered aromatic ring), -C 0～4 Alkylene (5- to 10-membered heteroaryl ring); wherein the alkylene, heterocyclic alkyl, aromatic ring, and heteroaryl ring may be optionally surrounded by one, two, three, or four independent R... 26 replace; Each R 26 Selected independently from hydrogen and -C 1～6 Alkyl, -C 0～4 Alkylene-C(O)R 24 -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl); R 24 Selected from hydrogen, -C 1-6 Alkyl groups; R 22 Selected from hydrogen, -C 1～6 alkyl.

7. The compound according to any one of claims 1 to 6, characterized in that: The compound is specifically:

8. The compound represented by formula VII, or its stereoisomer, or its pharmaceutically acceptable salt: in, R 1 Selected from hydrogen, -C 1-6 Alkyl groups; R 21 Selected from -C 0～4 Alkylene (6- to 10-membered aromatic ring); wherein the alkylene and aromatic ring may be optionally surrounded by one, two, three, or four independent R... 26 replace; Each R 26 Selected independently from hydrogen and -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl); T is selected from X 2 Selected from -NH2.

9. The compound according to claim 8, characterized in that: The compound is specifically:

10. Use of the compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a targeted protein degradation drug.

11. The use according to claim 10, characterized in that: The use of the compound, or its stereoisomer, or its pharmaceutically acceptable salt as an intermediate in the preparation of a drug targeting protein degradation.

12. The use according to claim 11, characterized in that: The targeted protein degradation drug is a drug that relies on the E3 ligase CRBN for protein degradation.

13. The bifunctional compound represented by formula XII, or its stereoisomer, or a pharmaceutically acceptable salt thereof: in, R 1 Selected from hydrogen, -C 1-6 Alkyl groups; R 21 Selected from -C 0～4 Alkylene (6- to 10-membered aromatic ring); wherein the alkylene and aromatic ring may be optionally surrounded by one, two, three, or four independent R... 26 replace; Each R 26 Selected independently from hydrogen and -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl); T is selected from Z is selected from 14. The use of the bifunctional compound of claim 13, or its stereoisomer, or its pharmaceutically acceptable salt, in the preparation of a medicament, wherein the medicament is a protein-targeting degradation drug.

15. The use according to claim 14, characterized in that: The drug is a drug that targets protein degradation via the E3 ligase CRBN.

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