Heterocyclic compound and use thereof

Abstract

The invention provides a compound which is shown in a formula I and has a binding effect with E3 ligase protein BIRC7, and application of the compound in preparation of a medicine for treating cell abnormal proliferation diseases. The invention also provides an intermediate compound in the synthesis process of the difunctional compound for targeting protein degradation. # imgabs0 #

Description

Heterocyclic compounds and uses thereof Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a novel heterocyclic ligand compound containing baculovirus IAP repeat protein 7 (BIRC7) E3 ubiquitin ligase protein binding and an intermediate compound for synthesizing a protein degradation targeting chimera (PROTACs) bifunctional compound containing the same. Background Art

[0002] Protein degradation is a highly regulated process that is essential for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is responsible for removing defective proteins and is ATP-dependent, highly efficient and highly selective. Its catalytic part is the ubiquitination E3 ligase, but it needs to first recruit the protein to be degraded. PROTACs technology is designed based on the UPP principle. The target protein ligand and the ligand of the E3 ligase are connected with a suitable chemical bond, so that the target protein can be recognized and the binding ability of the ligase E3 to the target protein can be enhanced, thereby targeting ubiquitination to force degradation of the target protein, and it has the characteristics of catalytic quantity, high efficiency and high selectivity.

[0003] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags proteins for proteasomal degradation, where they are digested into small peptides and ultimately into their 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] BIRC7 is a member of the inhibitor of apoptosis protein (IAP) family. It possesses specific BIR and RING domains, which can induce apoptosis through various pathways. The BIR domain is a key site for binding and inhibiting caspases and also serves as the substrate recognition region for their E3 ubiquitin ligase function (such as the natural substrate Smac). BIRC7 has highly specific tissue expression characteristics. This E3 ubiquitin ligase is highly expressed in skin cancer cells and absent or at low levels in normal tissues. Therefore, the development of BIRC7-based ligand molecules and PROTACs provides important research tools for tissue-specific targeting of protein degradation.

[0005] The present invention discloses a novel class of compounds that can serve as effective BIRC7 ligands and further enable the synthesis of corresponding PROTACs bifunctional compounds capable of protein degradation targeting chimeras, which can be used to treat various medical conditions, particularly abnormal cell proliferation.

[0006] Summary of the Invention

[0007] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0008] wherein Y1 is selected from N or C, Y2 is selected from N or CH, and Y3 is selected from NH or CH;

[0009] Ring B is selected from 6-10 membered aromatic ring, 6-10 membered aromatic heterocyclic ring, 3-10 membered cycloalkyl ring, 3-10 membered heterocyclic ring; the ring B may be further optionally replaced by one, two, three or four independent R B1 replace;

[0010] The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 、-C 0～4 Alkylene-OC(O)R B2 、-C 0～4 Alkylene-SR B2 、-C 0～4 Alkylene-S(O)2R B2 、-C 0～4 Alkylene-S(O)R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C 0～4 Alkylene-S(O)NR B2 R B3 、-C 0～4 Alkylene-C(O)R B2 、-C 0～4 Alkylene-C(O)OR B2 、-C 0～4 Alkylene-C(O)NR B2 R B3 、-C 0～4 Alkylene-NR B2 RB3 、-C 0～4 Alkylene-NR B2 C(O)R B3 、-C 0～4 Alkylene-NR B2 S(O)2R B3 、-C 0～4 Alkylene-NR B2 S(O)R B3 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0011] R B2 、R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R B4 replace;

[0012] The R B4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0013] R 21 、R 22 are independently selected from hydrogen, -C 1～5 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0014] Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace;

[0015] R 24 、R 25 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0016] Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

[0017] Preferably, Y1 is N, Y2 is N, and Y3 is CH; or, Y1 is N, Y2 is CH, and Y3 is CH; or, Y1 is C, Y2 is CH, and Y3 is NH.

[0018] Preferably, in some embodiments of the present invention, the compound is represented by Formula IIA, Formula IIB, or Formula IIC:

[0019] Among them, R 21 、R 22 The substituents of the B ring are as defined above.

[0020] Furthermore, the compound is represented by Formula IIE, Formula IIF, Formula IIG, and Formula IIH:

[0021] Among them, R 21 、R 22 、R B1 The substituents of are as defined above.

[0022] Preferably, the B ring is selected from a 6-membered aromatic ring, a 6-membered nitrogen-containing heterocyclic ring; the B ring can be further optionally replaced by one, two, three or four independent R B1 replace;

[0023] The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -S(O)2R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C(O)OR B2 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0024] R B2 、R B3 are independently selected from hydrogen, -C 1～6 alkyl, -(3- to 10-membered cycloalkyl), -(4- to 10-membered heterocycloalkyl), -(6- to 10-membered aromatic ring), -(5- to 10-membered heteroaromatic ring).

[0025] More preferably,

[0026] The R B1 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -S(O)2R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C(O)OR B2 , 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring;

[0027] R B2 、R B3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring. In some embodiments, R B3 More preferred is hydrogen.

[0028] Further: the B ring is selected from

[0029] As a preference: the R B1 Selected from hydrogen, -C(O)O(C 1～6 alkyl),

[0030] As a preference: the R 21 、R 22 are independently selected from hydrogen, -C 1～4 Alkyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R26 replace;

[0031] Each R 26 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, -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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0032] R 24 、R 25 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

[0033] More preferably, the R 21 、R 22 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, 9-membered heteroaromatic ring, 10-membered heteroaromatic ring, -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene-(7-membered cycloalkyl), - C1 alkylene-(4-membered heterocycloalkyl), -C1 alkylene-(5-membered heterocycloalkyl), -C1 alkylene-(6-membered heterocycloalkyl), -C1 alkylene-(7-membered heterocycloalkyl), -C1 alkylene-(6-membered aromatic ring), -C1 alkylene-(10-membered aromatic ring), -C1 alkylene-(5-membered heteroaromatic ring), -C1 alkylene-(6-membered heteroaromatic ring), -C1 alkylene-(9-membered heteroaromatic ring), -C1 alkylene-(10-membered heteroaromatic ring); wherein, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0034] Each R 26 are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, butyl, pentyl, -C(O)OR 24 、-C(O)NR 24 R 25 、-NR 24 R 25 , 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring, 9-membered heteroaromatic ring, 10-membered heteroaromatic ring, -C1 alkylene-(3-membered cycloalkyl), -C1 alkylene-(4-membered cycloalkyl), -C1 alkylene-(5-membered cycloalkyl), -C1 alkylene-(6-membered cycloalkyl), -C1 alkylene- (7-membered cycloalkyl), -C1 alkylene-(4-membered heterocycloalkyl), -C1 alkylene-(5-membered heterocycloalkyl), -C1 alkylene-(6-membered heterocycloalkyl), -C1 alkylene-(7-membered heterocycloalkyl), -C1 alkylene-(6-membered aromatic ring), -C1 alkylene-(10-membered aromatic ring), -C1 alkylene-(5-membered heteroaromatic ring), -C1 alkylene-(6-membered heteroaromatic ring), -C1 alkylene-(9-membered heteroaromatic ring), -C1 alkylene-(10-membered heteroaromatic ring);

[0035] R 24 、R 25 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, monofluoromethyl, difluoromethyl, trifluoromethyl. 25 Preferred is hydrogen.

[0036] Further: the R 21 、R 22 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, Preferably, R 21 is selected from hydrogen, methyl; R 22 Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl,

[0037] In some specific embodiments of the present invention, the compound represented by formula I is specifically:

[0038] The present invention also provides a compound represented by Formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0039] wherein Y1 is selected from N or C, Y2 is selected from N or CH, and Y3 is selected from NH or CH;

[0040] Ring B is selected from 6-10 membered aromatic ring, 6-10 membered aromatic heterocyclic ring, 3-10 membered cycloalkyl ring, 3-10 membered heterocyclic ring; the ring B may be further optionally replaced by one, two, three or four independent R B1 replace;

[0041] The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 、-C 0～4 Alkylene-OC(O)R B2 、-C 0～4 Alkylene-SR B2 、-C 0～4 Alkylene-S(O)2R B2 、-C 0～4 Alkylene-S(O)R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C 0～4 Alkylene-S(O)NR B2 R B3 、-C 0～4 Alkylene-C(O)R B2 、-C 0～4 Alkylene-C(O)OR B2 、-C 0～4 Alkylene-C(O)NR B2 R B3 、-C 0～4 Alkylene-NR B2 R B3 、-C 0～4 Alkylene-NR B2 C(O)R B3 、-C 0～4 Alkylene-NR B2 S(O)2R B3 、-C 0～4 Alkylene-NR B2 S(O)R B3 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0042] R B2 、R B3 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R B4 replace;

[0043] The R B4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0044] R 21 Selected from hydrogen, -C 1～5 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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)2NR24 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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0045] Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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)2NR24 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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace;

[0046] R 24 、R 25 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0047] Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0048] T is selected from -(L T ) q -;

[0049] q is an integer selected from 1 to 50;

[0050] Each L T A structural fragment consisting of any one or more members independently selected from the group consisting of the following groups, wherein the group is 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 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring, 5-12 membered spiro ring, 5-12 membered spiro heterocycle, 5-12 membered bridged ring, 5-12 membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle can be further replaced by one, two or three R T1 replace;

[0051] Each R T1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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)NRT2 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-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R T4 replace;

[0052] Each R T2 、R T3 、R T4 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0053] X 2 Selected from -NH2, -NHR X21 , -OH, -SH, ethynyl, vinyl, -C(O)H, -C(O)OH;

[0054] R X21 Selected from -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl.

[0055] Preferably, Y1 is N, Y2 is N, and Y3 is CH; or, Y1 is N, Y2 is CH, and Y3 is CH; or, Y1 is C, Y2 is CH, and Y3 is NH.

[0056] As a preference: the compound of formula V is as shown in formula VIa, VIb or VIc:

[0057] Among them, R 21 , T, X 2 The substituents of the B ring are as defined above.

[0058] Preferably, the B ring is selected from a 6-membered aromatic ring, a 6-membered nitrogen-containing heterocyclic ring; the B ring can be further optionally replaced by one, two, three or four independent R B1 replace;

[0059] The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -S(O)2R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C(O)OR B2 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0060] R B2 、R B3 are independently selected from hydrogen, -C 1～6 alkyl, -(3- to 10-membered cycloalkyl), -(4- to 10-membered heterocycloalkyl), -(6- to 10-membered aromatic ring), -(5- to 10-membered heteroaromatic ring).

[0061] More preferably,

[0062] The R B1 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -S(O)2R B2 、-C 0～4 Alkylene-S(O)2NR B2 R B3 、-C(O)OR B2 , 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring;

[0063] R B2 、R B3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 7-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered heteroaromatic ring, 6-membered heteroaromatic ring. In some embodiments, R B3 More preferred is hydrogen.

[0064] Further: the B ring is selected from

[0065] More specifically: the compound of formula V is as shown in formula VIE, formula VIF, formula VIG, or formula VIH:

[0066] Among them, R 21 , T, X 2 、R B1 The substituents of are as defined above.

[0067] As a preference: the R B1 Selected from hydrogen, -C(O)O(C 1～6 alkyl),

[0068] As a preference: R 21 Selected from hydrogen and methyl.

[0069] As a preference: the T is selected from

[0070] In some specific embodiments of the present invention, the compound represented by formula V is specifically:

[0071] The present invention also provides the use of any of the above-mentioned compounds, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts in the treatment of diseases related to abnormal cell proliferation.

[0072] Furthermore, the disease is cancer.

[0073] The present invention also provides use of any of the above-mentioned compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in the preparation of targeted protein degradation drugs.

[0074] Furthermore, provided is the use of the 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.

[0075] Furthermore, the targeted protein degradation drug is a drug that relies on E3 ligase BIRC7 for protein degradation.

[0076] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0077] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0078] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule. "Substitution" can also refer to the replacement of a lone pair of electrons in an atom in a molecule by "=O", "=S", etc.

[0079] "May be further optionally substituted" means that "substitution" may but need not occur, and the description includes cases where it occurs or does not occur.

[0080] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0081] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C 1～6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups, such as C 1～6 Alkoxy.

[0082] The "alkylene" mentioned in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. 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 1～6The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structures: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: In addition, the term “(C 1～6 )alkylene" is intended to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which can be exemplified by the following structure: For example, -C 0～4 The alkylene group can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-, etc.), a C3 alkylene group, or a C4 alkylene group; a C0 alkylene group means that the group here does not exist and is connected in the form of a chemical bond, such as A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0083] "Alkenyl" refers to a straight or branched chain hydrocarbon group having the 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 site of vinyl unsaturation (>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, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0084] As used herein, "alkenylene" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C3-C6)alkenylene includes >C=CH-CH2-, -CH-CH=CH-CH2-, and the like.

[0085] "Alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0086] "Halogen" is fluorine, chlorine, bromine or iodine.

[0087] "Halogen alkyl" or "halogen substituted alkyl" means that the hydrogen atoms in the alkyl group may be substituted by one or more halogen atoms. 1～4 The halogenalkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0088] The "-OR", "-NRR" and the like described in the present invention refer to that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0089] The oxygen atom in "-C(O)R", "-S(O)2R" and the like described in the present invention 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.

[0090] The "cycloalkyl" and "cycloalkane" described in the present invention refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro and adamantane systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (for example, 5,6,7,8,-tetrahydronaphthalene-5-yl) is applicable when the point of attachment is at 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 polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. For example Adamantyl groups include, but are not limited to, the following structures:

[0091] The "heterocycle", "heterocycloalkyl" and "heterocycloalkane" described in the present invention refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to 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, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Bicyclic means composed of two rings with two ring atoms in common, that is, the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1-thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.

[0092] "Spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system having two monocyclic rings sharing a common carbon atom, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "5- to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0093] "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:

[0094] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples include, but are not limited to:

[0095] As used herein, "aromatic ring" or "aryl" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having 5 to 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.

[0096] As used herein, "heteroaromatic ring" or "heteroaromatic ring group" refers to an aromatic unsaturated ring containing at least one heteroatom; a heteroatom is a nitrogen atom, an oxygen atom, or a sulfur atom. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heteroaromatic ring groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0097] In the present invention, It indicates that the 5-membered ring is an aromatic ring.

[0098] "Stereoisomers" include enantiomers and diastereomers.

[0099] The "deuterated compound" of the present 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.

[0100] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0101] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0102] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made. DETAILED DESCRIPTION

[0103] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0104] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0105] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0106] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a (Bruker AvanceIII 400 and Bruker Avance 600) nuclear magnetic spectrometer, with the solvents being deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and the internal standard being tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu LC-MS 2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) was performed using a Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0107] The reagent abbreviations used in the examples are as follows: Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCE: dichloroethane; DMF: N,N-dimethylformamide.

[0108] Example 1, Synthesis of Compounds 1 and 2:

[0109] Step 1, synthesis of compound 1-3:

[0110] Substrate 1-1 (357 mg, 1.48 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (4 mL) solution. 1-2 (522 mg, 1.93 mmol), Pd(dppf)Cl2 (120 mg, 0.148 mmol) and Cs2(CO)3 (964 mg, 2.96 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to proceed for 16 hours, monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 1-3 (432 mg, 1.11 mmol, 75%). LCMS (ESI + )m / z:388.1[M+H] + .

[0111] Step 2, synthesis of compound 2:

[0112] Add substrate 1-3 (430 mg, 1.11 mmol) to a dry single-necked bottle, add DMF (5 mL) thereto, and stir to dissolve. Then, add DIPEA (1.42 g, 11.1 mmol) to the reaction system and cool in an ice-water bath. Add HATU (501 mg, 1.32 mmol), stir at 0°C for 5 minutes, and then add 1-4 (246 mg, 1.32 mmol) to the reaction solution. React at 0°C for 20 minutes, and LC-MS monitors the complete reaction. Quench with water, extract with ethyl acetate 3 times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 2 (506 mg, 0.91 mmol, 82%). LCMS (ESI + )m / z:555.3[M+H] + .

[0113] 1 H NMR (600MHz, DMSO-d6) δ9.19 (s, 1H), 9.12-9.07 (m, 3H), 8.16 (d, J = 7.5Hz, 1H), 8.08(s,1H),8.00(s,1H),7.96-7.89(m,2H),7.77(s,1H),7.71(d,J=9.1Hz,1H ),7.68(d,J=7.7Hz,1H),7.55-7.46(m,2H),7.43(d,J=7.7Hz,1H),7.13(d,J=6 .9Hz,1H),4.57(d,J=6.3Hz,2H),3.64(t,J=4.6Hz,4H),2.96(t,J=4.6Hz,4H).

[0114] Step 3, synthesis of compound 1:

[0115] Add NaH (4.3 mg, 0.108 mmol) to a dry single-necked bottle, seal it, and replace nitrogen three times. Add DMF (1 mL) and cool it in an ice-water bath. Dissolve substrate 2 (30 mg, 0.054 mmol) in 0.5 mL DMF and add it dropwise to the above reaction bottle. After the addition, maintain the temperature and stir for 20 minutes. Then add CH3I (11.5 mg, 0.081 mmol) and react at 0°C for 1 hour. Quench with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain product 1 (15 mg, 0.026 mmol, 49%). LCMS (ESI + )m / z:569.3[M+H] + .

[0116] 1H NMR(400MHz,DMSO-d6)δ6.93(s,1H),6.10(s,1H),4.42(s,2H),4.43-4.41(m,1H), 4.10-4.05(m,1H),3.98-3.92(m,1H),3.02-2.96(m,1H),2.35(s,3H),2.32(s,3H),2.24(s,3H),2.17(s,3H),2. 17-2.13(m,1H),2.12-2.05(m,2H),2.03-1.98(m,1H),1.80-1.75(m,1H),1.72-1.68(m,1H),1.62-1.56(m,2H).

[0117] Example 3, synthesis of compound 3:

[0118] Step 1, synthesis of compound 3:

[0119] Add substrate 1-3 (38.8 mg, 0.1 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (65 mg, 0.5 mmol) to the reaction system and cool in an ice-water bath. Add HATU (45.6 mg, 0.12 mmol), stir at 0°C for 5 minutes, and then add methylamine hydrochloride (10 mg, 0.15 mmol) to the reaction solution. React at 0°C for 20 minutes, and the reaction is complete after LC-MS monitoring. Quench with water, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 3 (12 mg, 0.03 mmol, 30%). LCMS (ESI + )m / z:401.1[M+H] + .

[0120] 1 H NMR (600MHz, DMSO-d6) δ8.43(q,J=4.7Hz,1H),8.15(d,J=7.5Hz,1H),8.02(s,1H),8.00(s,1H),7.97-7.88(m,2H),7.69(d,J=9. 1Hz, 1H), 7.49 (dd, J = 9.1, 6.9Hz, 1H), 7.12 (d, J = 6.9Hz, 1H), 3.65 (t, J = 4.7Hz, 4H), 2.96 (t, J = 4.6Hz, 4H), 2.78 (d, J = 4.8Hz, 3H).

[0121] Example 4, Synthesis of Compound 4:

[0122] Step 1, synthesis of compound 4:

[0123] Substrate 1-3 (10 mg, 0.026 mmol) was added to a dry single-necked bottle, and DMF (1 mL) was added thereto, and the mixture was stirred and dissolved. Subsequently, DIPEA (33 mg, 0.26 mmol) was added to the reaction system and cooled in an ice-water bath. HATU (12 mg, 0.031 mmol) was added, and after stirring at 0°C for 5 minutes, dimethylamine (50 uL, 0.05 mmol) was added to the reaction solution. The reaction was allowed to proceed at 0°C for 20 minutes, and the reaction was complete after monitoring by LC-MS. The mixture was quenched with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 4 (8.1 mg, 0.019 mmol, 75%). LCMS (ESI + )m / z:415.1[M+H] + .

[0124] 1 H NMR(400MHz, DMSO-d6)δ8.14(dt,J=7.2,1.7Hz,1H),8.02-7.98(m,2H),7.97-7.88(m,2H),7.73(d,J=9.1Hz,1H),7.4 8(dd,J=9.1,7.0Hz,1H),7.12(dd,J=6.9,1.1Hz,1H),3.68-3.61(m,4H),3.42(s,3H),2.99(s,3H),2.98-2.93(m,4H).

[0125] Example 5, Synthesis of Compound 5:

[0126] Step 1, synthesis of compound 5:

[0127] Add substrate 1-3 (20 mg, 0.051 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (33 mg, 0.26 mmol) to the reaction system and cool in an ice-water bath. Add HATU (23 mg, 0.061 mmol), stir at 0°C for 5 minutes, and then add 5-amino-1-pentanol (20 mg, 0.2 mmol) to the reaction solution. React at 0°C for 20 minutes, and the reaction is complete after LC-MS monitoring. Quench with water, extract 3 times with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 5 (8.5 mg, 0.018 mmol, 35%). LCMS (ESI + )m / z:473.2[M+H] +.

[0128] 1 H NMR (600MHz, DMSO-d6) δ8.41(t,J=6.1Hz,1H),8.16(d,J=7.4Hz,1H),8.02(s,1H),8.01(s, 1H),7.97-7.89(m,2H),7.70(d,J=9.1Hz,1H),7.49(dd,J=9.1,6.9Hz,1H),7.12(d,J=6.9Hz ,1H),4.34(t,J=5.1Hz,1H),3.65(t,J=4.6Hz,4H),3.37(q,J=6.2Hz,2H),3.26(q,J=6.8Hz, 2H), 2.96 (t, J = 4.7Hz, 4H), 1.52 (p, J = 7.3Hz, 2H), 1.43 (p, J = 6.8Hz, 2H), 1.35-1.26 (m, 2H).

[0129] Example 6, Synthesis of Compound 6:

[0130] Step 1, synthesis of compound 6:

[0131] Substrate 1-3 (20 mg, 0.051 mmol) was added to a dry single-necked bottle, and DMF (1 mL) was added thereto and stirred to dissolve. Subsequently, DIPEA (33 mg, 0.26 mmol) was added to the reaction system and cooled in an ice-water bath. HATU (23 mg, 0.061 mmol) was added, and after stirring at 0°C for 5 minutes, 9-amino-1-nonanol (31.8 mg, 0.2 mmol) was added to the reaction solution. The reaction was allowed to proceed at 0°C for 20 minutes, and the reaction was complete after monitoring by LC-MS. The mixture was quenched with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 6 (10.2 mg, 0.019 mmol, 38%). LCMS (ESI + )m / z:529.3[M+H] + .

[0132] 1H NMR (600MHz, DMSO-d6) δ8.41(t,J=6.1Hz,1H),8.15(d,J=7.5Hz,1H),8.02(s,1H),8.00(s, 1H),7.97-7.89(m,2H),7.69(d,J=9.2Hz,1H),7.49(dd,J=9.2,6.9Hz,1H),7.12(dd,J=6.9 ,1.2Hz,1H),4.31(t,J=5.2Hz,1H),3.65(t,J=4.6Hz,4H),3.38-3.35(m,2H),3.25(q,J=6. 8Hz,2H),2.96(t,J=4.6Hz,4H),1.54-1.46(m,2H),1.42-1.34(m,2H),1.31-1.20(m,10H).

[0133] Example 7, Synthesis of Compound 7:

[0134] Step 1, synthesis of compound 7:

[0135] Add substrate 1-3 (10 mg, 0.026 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (46 uL, 0.26 mmol) to the reaction system and cool in an ice-water bath. Add HATU (12 mg, 0.031 mmol), stir at 0°C for 5 minutes, and then add benzylamine (6 mg, 0.052 mmol) to the reaction solution. React at 0°C for 20 minutes, and the reaction is complete when monitored by LC-MS. Quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 7 (5.2 mg, 0.011 mmol, 42%). LCMS (ESI + )m / z:477.1[M+H] + .

[0136] 1H NMR(400MHz,DMSO-d6)δ9.00(t,J=6.4Hz,1H),8.16(dt,J=7.2,1.7Hz,1H),8.0 7(d,J=0.8Hz,1H),8.03-7.99(m,1H),7.97-7.87(m,2H),7.71(d,J=9.1Hz,1H) ,7.50(dd,J=9.1,7.0Hz,1H),7.38-7.26(m,4H),7.26-7.18(m,1H),7.13(dd,J =7.0,1.1Hz,1H),4.47(d,J=6.3Hz,2H),3.76-3.58(m,4H),3.05-2.88(m,4H).

[0137] Example 8, Synthesis of Compound 8:

[0138] Step 1, synthesis of compound 8:

[0139] Add substrate 1-3 (10 mg, 0.026 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (46 uL, 0.26 mmol) to the reaction system and cool in an ice-water bath. Add HATU (12 mg, 0.031 mmol), stir at 0°C for 5 minutes, and then add N-methylbenzylamine (6.5 mg, 0.052 mmol) to the reaction solution. React at 0°C for 20 minutes, and LC-MS monitors the complete reaction. Quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 8 (6.2 mg, 0.013 mmol, 49%). LCMS (ESI + )m / z:491.2[M+H] + .

[0140] 1 H NMR (400MHz, DMSO-d6) δ8.15(t,J=7.1Hz,1H),8.08(d,J=4.9Hz,1H),8.01(s,1H),7.97-7.88(m,2H),7.72(dd,J=13.6,9.3Hz,1H),7.48(q,J =7.6Hz,1H),7.40-7.22(m,5H),7.13(d,J=7.0Hz,1H),5.37(s,1H),4. 69(s,1H),3.65(t,J=4.7Hz,4H),3.02-2.94(m,4H),2.91-2.84(m,3H).

[0141] Example 9, Synthesis of Compound 9:

[0142] Step 1, synthesis of compound 9:

[0143] Substrate 1-3 (55 mg, 0.14 mmol) was added to a dry single-necked bottle, and DMF (3 mL) was added thereto and stirred to dissolve. Subsequently, DIPEA (0.25 mL, 1.4 mmol) was added to the reaction system and cooled in an ice-water bath. HATU (60 mg, 0.17 mmol) was added, and after stirring at 0°C for 5 minutes, methyl 4-(aminomethyl)benzoate (34 mg, 0.17 mmol) was added to the reaction solution. The reaction was allowed to proceed at 0°C for 20 minutes, and the reaction was complete after LC-MS monitoring. The product was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 9 (30 mg, 0.056 mmol, 40%). LCMS (ESI + )m / z:535.1[M+H] + .

[0144] 1 H NMR (600MHz, DMSO-d6) δ9.15(t,J=6.4Hz,1H),8.16(d,J=7.5Hz,1H),8.08(s,1H),8.01(s,1H),7.96-7.87(m,4H),7.71(d,J=9.1Hz,1H),7.51(dd,J= 9.1,7.0Hz,1H),7.44(d,J=8.0Hz,2H),7.14(dd,J=7.0,1.2Hz,1H),4.54( d,J=6.4Hz,2H),3.83(s,3H),3.64(t,J=4.7Hz,4H),2.96(t,J=4.7Hz,4H).

[0145] Example 10, Synthesis of Compound 10:

[0146] Step 1, synthesis of compound 9-1:

[0147] Substrate 9 (26 mg, 0.048 mmol) was added to a dry, single-necked flask. Methanol (4 mL) and water (1 mL) were added and stirred to dissolve. NaOH (40 mg, 0.48 mmol) was then added. The mixture was heated to 80°C and stirred under reflux for 2 hours. LC-MS monitored the reaction completion. Dilute hydrochloric acid (1 M) was added to adjust the pH to 5-6. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford crude product 9-1 (25 mg).

[0148] Step 2, synthesis of compound 10:

[0149] Add substrate 9-1 (12 mg, 0.023 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (0.2 mL) to the reaction system and cool in an ice-water bath. Add HATU (10 mg, 0.028 mmol), stir at 0°C for 5 minutes, and then add 5-amino-1-pentanol (5 mg, 0.046 mmol) to the reaction solution. React at 0°C for 20 minutes, and the reaction is complete after LC-MS monitoring. Quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 10 (8.9 mg, 0.015 mmol, 64%). LCMS (ESI + )m / z:606.1[M+H] + .

[0150] 1 H NMR (600MHz, DMSO-d6) δ9.09(t,J=6.5Hz,1H),8.36(t,J=5.7Hz,1H),8.16(d,J=7.6Hz,1H),8.07(s,1H),8.01(s, 1H),7.97-7.86(m,2H),7.77(d,J=8.0Hz,2H),7.71(d,J=9.1Hz,1H),7.51(dd,J=9.1,6.9Hz,1H),7.37(d,J=8.0Hz ,2H),7.13(d,J=6.9Hz,1H),4.50(d,J=6.4Hz,2H),4.34(t,J=5.1Hz,1H),3.64(t,J=4.7Hz,4H),3.38(q,J=6.3Hz, 2H), 3.22 (q, J = 6.7Hz, 2H), 2.96 (t, J = 4.7Hz, 4H), 1.50 (p, J = 7.4Hz, 2H), 1.43 (p, J = 6.7Hz, 2H), 1.36-1.26 (m, 2H).

[0151] Example 11, Synthesis of Compound 11:

[0152] Step 1, synthesis of compound 11:

[0153] Add substrate 9-1 (12 mg, 0.023 mmol) to a dry single-necked bottle, add DMF (1 mL) thereto, and stir to dissolve. Then, add DIPEA (0.2 mL) to the reaction system and cool in an ice-water bath. Add HATU (10 mg, 0.028 mmol), stir at 0°C for 5 minutes, and then add 9-amino-1-nonanol (7 mg, 0.046 mmol) to the reaction solution. React at 0°C for 20 minutes, and LC-MS monitors the complete reaction. Quench with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify with medium pressure liquid chromatography to obtain product 11 (7.1 mg, 0.011 mmol, 47%). LCMS (ESI + )m / z:662.2[M+H] + .

[0154] 1 H NMR (600MHz, DMSO-d6) δ9.09(t,J=6.4Hz,1H),8.36(t,J=5.6Hz,1H),8.16(d,J=7.4Hz,1H),8.08(s,1H),8.01(s, 0H),7.97-7.87(m,2H),7.77(d,J=7.9Hz,2H),7.71(d,J=9.1Hz,1H),7.51(dd,J=9.2,6.9Hz,1H),7.37(d,J=8.0H z,2H),7.14(d,J=6.9Hz,1H),4.51(d,J=6.3Hz,2H),4.31(t,J=5.2Hz,1H),3.64(t,J=4.7Hz,4H),3.39-3.35(m,2 H),3.22(q,J=6.7Hz,2H),2.96(t,J=4.7Hz,4H),1.49(t,J=6.9Hz,2H),1.38(q,J=6.7Hz,2H),1.32-1.21(m,10H).

[0155] Example 12, Synthesis of Compound 12:

[0156] Step 1, synthesis of compound 12:

[0157] Substrate 1-3 (10 mg, 0.026 mmol) was added to a dry single-necked bottle, and DMF (1 mL) was added thereto and stirred to dissolve. Subsequently, DIPEA (0.05 mL, 0.26 mmol) was added to the reaction system and cooled in an ice-water bath. HATU (12 mg, 0.031 mmol) was added, and after stirring at 0°C for 5 minutes, quinoxalin-6-ylmethanamine (10 mg, 0.052 mmol) was added to the reaction solution. The reaction was allowed to proceed at 0°C for 20 minutes, and the reaction was complete after monitoring by LC-MS. The product was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 12 (4.2 mg, 0.008 mmol, 31%). LCMS (ESI + )m / z:529.2[M+H] + .

[0158] 1 H NMR(600MHz,DMSO-d6)δ9.30(t,J=6.4Hz,1H),8.91(d,J=4.5Hz,1H),8.17(d,J=7 .6Hz,1H),8.10(s,1H),8.07(d,J=8.7Hz,1H),8.01(s,1H),7.98-7.89(m,4H),7.8 5(dd,J=8.7,2.0Hz,1H),7.73(d,J=9.2Hz,1H),7.52(dd,J=9.2,6.9Hz,1H),7.14 (d,J=7.3Hz,1H),4.73(d,J=6.3Hz,2H),3.70-3.56(m,4H),2.96(t,J=4.7Hz,4H).

[0159] Example 13, Synthesis of Compound 13:

[0160] Step 1, synthesis of compound 13-2:

[0161] Substrate 13-1 (25 mg, 1.04 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (2 mL) solution. IM-1 (33.88 mg, 1.25 mmol), Pd(dppf)Cl2 (3.78 mg, 0.05 mmol), and K2CO3 (28.8 mg, 2.09 mmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 13-2 (20.0 mg, 51.76 μmol, 49.7% yield). LCMS (ESI + )m / z:387.1[M+H] + .

[0162] Step 2, synthesis of compound 13:

[0163] Substrate 13-2 (20 mg, 51.76 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (23.62 mg, 62.11 μmol) and DIPEA (66.89 mg, 517.57 μmol) were added to the reaction solution in sequence, and the reaction temperature was lowered to zero. IM-2 (11.50 mg, 62.11 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was allowed to proceed at 0°C for 0.5 hours, monitored by LC-MS. After the reaction was completed, the reaction solution was allowed to return to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain product 13 (6.4 mg, 11.56 μmol, 22.34% yield). LCMS (ESI + )m / z:554.2[M+H] +

[0164] 1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.10(s,2H),8.86-8.81(m,1H),8.14-8.08(m, 1H),7.93-7.90(m,3H),7.87(s,1H),7.72(s,1H),7.68(d,J=7.7Hz,1H),7.58(d,J=9 .0Hz,1H),7.52-7.46(m,1H),7.40(d,J=7.7Hz,1H),7.00(s,1H),6.93-6.87(m,1H) ,6.73(d,J=6.1Hz,1H),4.53(d,J=5.9Hz,2H),3.67-3.59(m,4H),2.98-2.92(m,4H).

[0165] Example 14, Synthesis of Compound 14:

[0166] Step 1, synthesis of compound 14-2:

[0167] Substrate 14-1 (100.0 mg, 0.42 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (4 mL) solution. IM-1 (135.5 mg, 0.50 mmol), Pd(dppf)Cl2 (34 mg, 0.04 mmol) and Cs2(CO)3 (217.4 mg, 0.84 mmol) were added. The temperature was raised to 80°C for 16 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 14-2 (38.2 mg, 98.8 μmol, 23.7% yield). LCMS (ESI + )m / z:387.1[M+H] + .

[0168] Step 2, synthesis of compound 14:

[0169] Substrate 14-2 (15.0 mg, 38.8 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (17.7 mg, 46.6 μmol) and DIPEA (15.1 mg, 116.3 μmol) were added to the reaction solution in sequence and the temperature of the reaction system was lowered to zero degrees. IM-2 (7.6 mg, 40.7 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was carried out at 0°C for 2 hours and monitored by LC-MS. After the reaction was completed, the reaction solution was returned to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 14 (3.6 mg, 6.5 μmol, 16.8% yield). LCMS (ESI + )m / z:554.2[M+H] +

[0170] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.19(s,1H),9.14-9.09(m,3H),8.00(dt,J=7.5,1.6Hz,1H),7.87-7.75(m,4H),7.76-7.67(m,2H),7.52 (t,J=7.6Hz,1H),7.49-7.42(m,1H),7.30(d,J=1.8Hz,1H),7.27-7.18(m,2H),4.61(d,J=5.8Hz,2H),3.64(t,J=4.7Hz,4H),3.01-2.87(m,4H).

[0171] Example 15, Synthesis of Compound 15:

[0172] Step 1, synthesis of compound 15-2:

[0173] Substrate 15-1 (30 mg, 0.15 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio Dioxane / H2O (2 mL) solution. IM-1 (48.3 mg, 0.18 mmol), Pd(dppf)Cl2 (5.3 mg, 7.5 μmol) and K2CO3 (41.5 mg, 0.3 mmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 15-2 (33.2 mg, 95.3 μmol, 64.17% yield). LCMS (ESI +)m / z:349.1[M+H] +

[0174] Step 2, synthesis of compound 15:

[0175] Substrate 15-2 (10 mg, 28.70 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (13.10 mg, 34.45 μmol) and DIPEA (37.10 mg, 287.05 μmol) were added to the reaction solution in sequence and the reaction temperature was lowered to zero degrees. IM-2 (6.91 mg, 37.32 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was allowed to proceed at 0°C for 30 minutes and monitored by LC-MS. After the reaction was completed, the reaction solution was allowed to return to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 15 (3 mg, 5.82 μmol, 20.27% yield). LCMS (ESI + )m / z:516.2[M+H] +

[0176] 1 H NMR (600MHz, DMSO-d6) δ9.54-9.52(m,1H),9.19(s,1H),9.12(s,2H),8.78(d,J=5.1Hz,1H),8.37-8.34(m,1H),8.25-8.23(m,1H),8.10-8 .01(m,2H),7.89-7.78(m,3H),7.75-7.67(m,1H),7.55-7.42(m,2H),4.63(d,J=6.4Hz,2H),3.63(t,J=4.7Hz,4H),2.94(t,J=4.7Hz,4H).

[0177] Example 16, Synthesis of Compound 16:

[0178] Step 1, synthesis of compound 16-2:

[0179] Substrate 16-1 (100.0 mg, 0.42 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio Dioxane / H2O (4 mL) solution. IM-1 (161.8 mg, 0.50 mmol), Pd(dppf)Cl2 (34 mg, 0.04 mmol) and Cs2(CO)3 (271.4 mg, 0.84 mmol) were added. The temperature was raised to 80°C for 16 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 16-2 (78.8 mg, 22.7 μmol, 53.9% yield). LCMS (ESI + )m / z:348.4[M+H] +

[0180] Step 2, synthesis of compound 16:

[0181] Substrate 16-2 (15.0 mg, 38.8 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (19.7 mg, 51.8 μmol) and DIPEA (15.1 mg, 116.3 μmol) were added to the reaction solution in sequence and the temperature of the reaction system was lowered to zero degrees. IM-2 (8.4 mg, 45.3 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was carried out at 0°C for 2 hours and monitored by LC-MS. After the reaction was completed, the reaction solution was returned to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 16 (3.8 mg, 7.4 μmol, 19.1% yield). LCMS (ESI + )m / z:514.6[M+H] +

[0182] 1H NMR (400MHz, DMSO-d6) δ9.28(t,J=5.9Hz,1H),9.19(s,1H),9.13(s,2H),8.23(t,J=1 .8Hz,1H),8.13(dt,J=7.5,1.7Hz,1H),8.01-7.94(m,2H),7.93(ddd,J=7.8,1.9,1.1H z,1H),7.84-7.75(m,3H),7.74-7.69(m,1H),7.64(t,J=7.8Hz,1H),7.52(t,J=7.6Hz ,1H),7.49-7.45(m,1H),4.63(d,J=5.8Hz,2H),3.73-3.57(m,4H),2.99-2.87(m,4H).

[0183] Example 17, Synthesis of Compound 17:

[0184] Step 1, synthesis of compound 17-2:

[0185] Substrate 17-1 (30 mg, 0.16 mmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio Dioxane / H2O (4 mL) solution. IM-1 (43 mg, 0.15 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol) and Cs2(CO)3 (208 mg, 0.64 mmol) were added. The temperature was raised to 80°C for 16 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 17-2 (23 mg, 68.4 μmol, 45.6% yield). LCMS (ESI + )m / z:337.1[M+H] + .

[0186] Step 2, synthesis of compound 17:

[0187] Substrate 17-2 (23 mg, 68.4 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (31 mg, 82.1 μmol) and DIPEA (40 mg, 0.34 mmol) were added to the reaction solution in sequence and the temperature of the reaction system was lowered to zero degrees. IM-2 (15.2 mg, 82.1 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was carried out at 0°C for 0.5 hours and monitored by LC-MS. After the reaction was completed, the reaction solution was returned to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 17 (4.2 mg, 8.3 μmol, 12.1% yield). LCMS (ESI + )m / z:504.2[M+H] + .

[0188] 1 H NMR (600MHz, DMSO-d6) δ11.87(s,1H),9.20(s,1H),9.13(s,2H),8.73(t,J=6.0Hz,1H),7.93(d,J=7.7Hz,1H),7.78(d,J=6.9Hz,2H),7.71(d,J=7.6H z,1H),7.62(t,J=7.7Hz,1H),7.56-7.48(m,3H),7.45(d,J=7.7Hz,1H),7. 35(s,1H),4.56(d,J=5.9Hz,2H),3.63(t,J=4.8Hz,4H),2.92-2.84(m,4H).

[0189] Example 18, Synthesis of Compound 18:

[0190] Substrate 18-1 (16 mg, 98.68 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (45.02 mg, 118.41 μmol) and DIPEA (127.53 mg, 986.77 μmol) were added to the reaction solution in sequence, and the reaction temperature was lowered to zero degrees. IM-2 (21.93 mg, 118.41 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was allowed to proceed at 0°C for 30 minutes, monitored by LC-MS. After the reaction was completed, the reaction solution was allowed to return to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain product 18 (18.1 mg, 54.96 μmol, 55.69% yield). LCMS (ESI +)m / z:330.1[M+H] +

[0191] 1 H NMR (600MHz, DMSO-d6) δ9.19(s,1H),9.11(s,2H),9.03-9.01(m,1H),8.59-8.57(m,1H),8.38(s,1H),7.79(d,J=2.3Hz,1H),7.68(d,J=7 .8Hz,1H),7.59(d,J=9.2Hz,1H),7.52-7.50(m,1H),7.45(d,J=7.6Hz,1H),7.36-7.33(m,1H),7.01-6.93(m,1H),4.57(d,J=6.4Hz,2H).

[0192] Example 19, Synthesis of Compound 19:

[0193] Substrate 19-1 (110 mg, 456.35 μmol) was added to a dry single-necked flask and dissolved in 1 mL of DMF. HATU (208.22 mg, 547.62 μmol) and DIPEA (589.79 mg, 4.56 μmol) were added to the reaction solution in sequence, and the reaction temperature was lowered to zero degrees. IM-2 (101.43 mg, 547.62 μmol) was dissolved in 0.5 mL of DMF and slowly added to the reaction solution with a syringe. The reaction was allowed to proceed at 0°C for 30 minutes, monitored by LC-MS. After the reaction was completed, the reaction solution was allowed to return to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium-pressure liquid chromatography to obtain product 19 (140.6 mg, 344.40 μmol, 75.47% yield). LCMS (ESI + )m / z:408.2[M+H] +

[0194] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.16-9.14(m,1H),9.11(s,2H),8.30(s,1H),7.79(s,1H),7.70-7.68(m, 2H),7.51-7.49(m,1H),7.45(d,J=7.7Hz,1H),7.41(d,J=7.2Hz,1H),7.36-7.34(m,1H),4.58(d,J=6.3Hz,2H).

[0195] Example 20, Synthesis of Compound 20:

[0196] Substrate 19 (20 mg, 48.99 μmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (1 mL) solution. IM-1 (7.17 mg, 58.79 μmol), Pd(dppf)Cl2 (1.78 mg, 2.45 μmol), and K2CO3 (71.10 mg, 97.98 μmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 20 (10.4 mg, 25.65 μmol, 52.36% yield). LCMS (ESI + )m / z:406.2[M+H] +

[0197] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.11(s,3H),8.04(s,1H),7.79-7.72(m,3H),7.71-7.65(m,2H),7. 65-7.58(m,3H),7.50-7.48(m,2H),7.44(d,J=7.7Hz,1H),7.02(d,J=6.9Hz,1H),4.56(d,J=6.3Hz,2H).

[0198] Example 21, Synthesis of Compound 21:

[0199] Step 1, synthesis of compound 21-2:

[0200] Substrate 19 (20 mg, 48.99 μmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (1 mL) solution. IM-1 (21.76 mg, 58.79 μmol), Pd(dppf)Cl2 (1.78 mg, 2.45 μmol) and K2CO3 (13.54 mg, 97.98 μmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 21-2 (30.3 mg, 46.35 μmol, 94.61% yield). LCMS (ESI + )m / z:654.3[M+H] + .

[0201] Step 2, synthesis of compound 21:

[0202] Substrate 21-2 (20 mg, 30.59 μmol) was added to a dry single-necked bottle and dissolved in 1 mL of DCM. TFA (1 mL) was added to the reaction solution and the reaction was allowed to proceed for 30 minutes at room temperature with LC-MS monitoring. After the reaction was completed, the solvent was removed by concentration under reduced pressure and purified by medium pressure liquid chromatography to obtain product 21 (10.2 mg, 18.42 μmol, 60.22% yield). LCMS (ESI + )m / z: 554.2[M+H] +

[0203] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.10(s,3H),8.17-8.10(m,1H),8.05(s,1H) ,8.00(s,1H),7.95-7.88(m,2H),7.77(s,1H),7.71(d,J=9.2Hz,1H),7.68(d,J=7. 8Hz,1H),7.54-7.46(m,2H),7.43(d,J=7.7Hz,1H),7.12(d,J=6.9Hz,1H),4.57(d, J=6.3Hz,2H),3.17(d,J=5.1Hz,1H),2.86(t,J=4.8Hz,4H),2.72(t,J=4.8Hz,4H).

[0204] Example 22, Synthesis of Compound 22:

[0205] Substrate 19 (15 mg, 36.74 μmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (1 mL) solution. IM-1 (7.93 mg, 44.09 μmol), Pd(dppf)Cl2 (1.33 mg, 1.84 μmol) and K2CO3 (10.16 mg, 73.48 μmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 22 (5.3 mg, 11.44 μmol, 31.12% yield). LCMS (ESI + )m / z:464.2[M+H] +

[0206] 1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),9.10(s,3H),8.23-4-8.22(m,1H),8.17-8.15(m,1H),8.07-8.01(m,2H),7 .83-7.75(m,2H),7.73-7.65(m,2H),7.52-7.41(m,3H),7.09-7.07(m,1H),4.56(d,J=6.3Hz,2H),3.89(s,3H).

[0207] Example 23, Synthesis of Compound 23:

[0208] Substrate 19 (10 mg, 24.49 μmol), IM-1 (21.10 mg, 244.95 μmol), DIPEA (15.83 mg, 122.47 μmol) and NMP (0.2 mL) were added to a dry microwave tube. The reaction was carried out at 200°C for 2 hours and monitored by LC-MS. After the reaction was completed, the reaction solution was cooled to room temperature and purified by medium pressure liquid chromatography to obtain product 23 (2.04 mg, 4.93 μmol, 20.14% yield). LCMS (ESI + )m / z:414.2[M+H] +

[0209] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.11(s,2H),9.06-9.04(m,1H),8.00(s,1H),7.79(s,1H),7.68(d,J=7.6Hz,1H),7.52 -7.44(m,2H),7.39-7.32(m,2H),6.52(d,J=7.1Hz,1H),4.57(d,J=6.4Hz,2H),2.99(d,J=4.8Hz,4H),2.94(t,J=4.5Hz,4H).

[0210] Example 24, Synthesis of Compound 24:

[0211] Substrate 19 (15 mg, 36.74 μmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (1 mL) solution. IM-1 (8.82 mg, 44.09 μmol), Pd(dppf)Cl2 (1.33 mg, 1.84 μmol) and K2CO3 (10.16 mg, 73.48 μmol) were added. The temperature was raised to 100°C for 2 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 24 (5.2 mg, 10.75 μmol, 29.27% ​​yield). LCMS (ESI + )m / z:484.2[M+H] +

[0212] 1 H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.10(s,3H),8.25-8.23(m,1H),8.15-8.12(m,2H),8.06(s,1H),7.91-7.88(m,1H),7.77(d, J=2.1Hz,1H),7.72-7.69(m,2H),7.56-7.46(m,2H),7.43(d,J=7.8Hz,1H),7.16-7.08(m,1H),4.56(d,J=6.3Hz,2H),3.32(m,1H).

[0213] Example 25, Synthesis of Compound 25:

[0214] Substrate 19 (10 mg, 24.49 μmol) was added to a dry single-necked flask and dissolved in a 4:1 volume ratio of dioxane / H2O (0.5 mL) solution. IM-1 (7.09 mg, 29.39 μmol), Pd(dppf)Cl2 (0.9 mg, 1.22 μmol) and K2CO3 (6.77 mg, 48.98 μmol) were added. The temperature was raised to 100°C for 3 hours and monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by medium pressure liquid chromatography to obtain product 25 (5.5 mg, 10.48 μmol, 42.81% yield). LCMS (ESI + )m / z:525.2[M+H] +

[0215] 1H NMR(600MHz,DMSO-d6)δ9.19(s,1H),9.10(s,3H),8.09(d,J=1.8Hz,1H),8.05(d,J=7 .5Hz,3H),8.00(d,J=7.8Hz,1H),7.87-7.86(m,1H),7.77(s,1H),7.71(d,J=9.1Hz,1 H),7.68(d,J=7.6Hz,1H),7.54-7.46(m,2H),7.43(d,J=7.7Hz,1H),7.10(d,J=6.9Hz ,1H),4.56(d,J=6.3Hz,2H),2.22-2.18(m,1H),0.54-0.48(m,2H),0.41-0.37(m,2H).

[0216] Example 26, Synthesis of Compound 26:

[0217] Step 1, synthesis of compound 26:

[0218] Substrate 21 (5.2 mg, 9.4 μmol) was added to a dry single-necked flask and dissolved in DCE (2 mL). Formaldehyde (10 μL) was added and stirred for 10 minutes before the addition of NaBH(OAc)3 (6 mg, 0.028 mmol). The mixture was stirred overnight, quenched with water, extracted with ethyl acetate, concentrated, and purified by medium-pressure liquid chromatography to afford product 26 (4 mg, 7.0 μmol, 75% yield). LCMS (ESI+) m / z: 568.3 [M+H] + .

[0219] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 9.21-9.16 (m, 3H), 8.23 ​​(d, J = 7.4Hz, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 8.07-7.95 (m, 2H), 7.86 (s, 1H) ),7.83-7.75(m,2H),7.64-7.50(m,3H),7.21(d,J=7.0Hz,1H),4.66(d,J=6.3Hz,2H),3.06(s,4H),2.45(t,J=5.0Hz,4H),2.22(s,3H).

[0220] Experimental Example 1: SPR Binding Assay of BIRC7 Compounds

[0221] 1. Experimental materials and reagents:

[0222] 2. SPR test method

[0223] Prepare running buffer: Protein Fixation Buffer and Running Buffer A: NaH2OP4 concentrations of 7.6 mM, Na2HOP4 concentrations of 12.4 mM, NaCl concentrations of 150.0 mM, Tween 20 content of 0.1%, pH adjusted to 7.0; Running Buffer B: NaH2OP4 concentrations of 7.6 mM, Na2HOP4 concentrations of 12.4 mM, NaCl concentrations of 150.0 mM, Tween 20 content of 0.1%, pH adjusted to 7.0, DMSO content of 1.00%, pH adjusted to 7.0. After preparation, filter the running buffers through a 0.22 μm filter.

[0224] Immobilization of His antibody: The CM5 chip surface was washed three times with 50 mM NaOH at a flow rate of 60 μL / min for 60 seconds each wash. The chip was then activated with a 1:1 volume ratio of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) from the amino coupling kit for 420 seconds at a flow rate of 6.0 μL / min. 50.0 μg / mL of His antibody was prepared using the His immobilization buffer provided with the His capture kit. The prepared His antibody was injected at a flow rate of 5.0 μL / min for 600 seconds. Following injection of the His antibody, the chip surface was blocked with 1 M ethanolamine from the amino coupling kit at 6.0 μL / min for 7 minutes. The final immobilized His antibody concentration was approximately 12,000 RU.

[0225] BIRC7 protein immobilization: Running buffer A was used as the protein immobilization buffer. BIRC7 protein was prepared at a 40.0 μg / mL solution in protein buffer and injected at 5.0 μL / min for 1200 seconds. BIRC7 protein was captured on a CM5 chip using a His antibody. After the BIRC7 injection, a 1:1 volume ratio mixture of EDC (75.00 mg / mL) and NHS (11.50 mg / mL) was cross-linked at 10.0 μL / min for 120 seconds. Finally, the chip surface was blocked with 1 M ethanolamine (pH 8.5) at 6.0 μL / min for 7 minutes. The final BIRC7 immobilization level was approximately 3500.00 RU.

[0226] Compound Dilution: Dilute the test compound to 100x the desired final concentration with 100% DMSO. Mix thoroughly, pipette 4.0 μL into 396 μL of Running Buffer A, and centrifuge at 15,000 rpm for 5 minutes to obtain a 1X compound solution containing 1% DMSO for subsequent dilutions. Serially dilute the compound 2-fold starting from the starting concentration in Running Buffer B for eight concentrations. Transfer the diluted compound to a 96-well plate for sample injection.

[0227] Run the protocol: Open the Biacore 8K Control software and run the experiment at 25°C using running buffer B at a flow rate of 30.0 μL / min. After equilibration with three injections of running buffer B, the compounds were injected sequentially from the lowest to the highest concentration, with association and dissociation times of 60 seconds. The injection needle was rinsed with 50% DMSO after each injection. Solvent variability caused by DMSO was corrected using 0.50%, 0.75%, 1.00%, 1.25%, and 1.50% DMSO.

[0228] 3. Data Analysis

[0229] The response values ​​of the compounds binding to BIRC7 were analyzed after deducting the reference channel and 0 concentration, and the affinity Kd was fitted using the steady state affinity model (1:1 binding model) using Biacore Insight Evaluation Software.

[0230] The affinity of the example compounds to BIRC7 was tested according to the above method. The test results are shown in Table 1, where the Kd values ​​of the compounds were determined and classified as follows:

[0231] “-” indicates that the Kd value is greater than 10 μM;

[0232] “+” indicates that the Kd measured value is less than or equal to 10 μM and greater than 1 μM;

[0233] “++” indicates that the Kd measured value is less than or equal to 1 μM and greater than 100 nM;

[0234] Table 1. Affinity of the compounds of the present invention for BIRC7 protein

[0235] The experimental data above demonstrate that the compounds of this invention have excellent binding activity to the BIRC7 protein and may be novel drugs targeting BIRC7. Furthermore, the compounds of this invention may also serve as effective BIRC7 ligands and intermediates for the synthesis of compounds that target protein degradation for the treatment of various medical conditions, particularly abnormal cell proliferation.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, Y1 is selected from N or C, Y2 is selected from N or CH, and Y3 is selected from NH or CH; The B ring is selected from a 6- to 10-membered aromatic ring, a 6- to 10-membered aromatic heterocyclic ring, a 3- to 10-membered cycloalkyl ring, and a 3- to 10-membered heterocyclic ring; the B ring may be further optionally replaced by one, two, three or four independent R B1 replace; The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 , -C 0～4 Alkylene-OC(O)R B2 , -C 0～4 Alkylene-SR B2 , -C 0～4 Alkylene-S(O)2R B2 , -C 0～4 Alkylene-S(O)R B2 , -C 0～4 Alkylene-S(O)2NR B2 R B3 , -C 0～4 Alkylene-S(O)NR B2 R B3 , -C 0～4 Alkylene-C(O)R B2 , -C 0～4 Alkylene-C(O)OR B2 , -C 0～4 Alkylene-C(O)NR B2 R B3 , -C 0～4 Alkylene-NR B2 R B3 , -C 0～4 Alkylene-NR B2 C(O)R B3 , -C 0～4 Alkylene-NR B2 S(O)2R B3 , -C 0～4 Alkylene-NR B2 S(O)R B3 , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R B4 replace; The R B4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; R 21 , R 22 are independently selected from hydrogen, -C 1～5 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace; R 24 , R 25 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

2. The compound according to claim 1, characterized in that: The compound is shown in Formula IIA, Formula IIB, Formula IIC: Among them, R 21 , R 22 , The substituents of ring B are defined as in claim 1.

3. The compound according to claim 1 or 2, characterized in that: The B ring is selected from a 6-membered aromatic ring and a 6-membered nitrogen-containing heterocyclic ring; the B ring can be further optionally replaced by one, two, three or four independent R B1 replace; The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -S(O)2R B2 , -C 0～4 Alkylene-S(O)2NR B2 R B3 、-C(O)OR B2 , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); R B2 , R B3 are independently selected from hydrogen, -C 1～6 alkyl, -(3- to 10-membered cycloalkyl), -(4- to 10-membered heterocycloalkyl), -(6- to 10-membered aromatic ring), -(5- to 10-membered heteroaromatic ring).

4. The compound according to claim 3, characterized in that: The B ring is selected from 5. The compound according to claim 4, characterized in that: The R B1 Selected from hydrogen, -C(O)O(C 1～6 of alkyl), 6. The compound according to claim 1, characterized in that: The R 21 , R 22 are independently selected from hydrogen, -C 1～4 Alkyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; Each R 26 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, -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-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); R 24 , R 25 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

7. The compound according to claim 6, characterized in that: The R 21 , R 22 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, 8. The compound according to any one of claims 1 to 7, characterized in that: The compound is specifically:

9. A compound represented by formula V, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, Y1 is selected from N or C, Y2 is selected from N or CH, and Y3 is selected from NH or CH; The B ring is selected from a 6- to 10-membered aromatic ring, a 6- to 10-membered aromatic heterocyclic ring, a 3- to 10-membered cycloalkyl ring, and a 3- to 10-membered heterocyclic ring; the B ring may be further optionally replaced by one, two, three or four independent R B1 replace; The R B1 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 , -C 0～4 Alkylene-OC(O)R B2 , -C 0～4 Alkylene-SR B2 , -C 0～4 Alkylene-S(O)2R B2 , -C 0～4 Alkylene-S(O)R B2 , -C 0～4 Alkylene-S(O)2NR B2 R B3 , -C 0～4 Alkylene-S(O)NR B2 R B3 , -C 0～4 Alkylene-C(O)R B2 , -C 0～4 Alkylene-C(O)OR B2 , -C 0～4 Alkylene-C(O)NR B2 R B3 , -C 0～4 Alkylene-NR B2 R B3 , -C 0～4 Alkylene-NR B2 C(O)R B3 , -C 0～4 Alkylene-NR B2 S(O)2R B3 , -C 0～4 Alkylene-NR B2 S(O)R B3 , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R B4 replace; The R B4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; R 21 Selected from hydrogen, -C 1～5 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace; R 24 , R 25 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; T is selected from -(L T ) q -; q is selected from an integer of 1 to 50; Each L T A structural fragment consisting of any one or more members independently selected from the group consisting of the following groups, wherein the group is 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 cycloalkyl, 3-12-membered heterocycloalkyl, 6-10-membered aromatic ring, 5-10-membered heteroaromatic ring, 5-12-membered spiro ring, 5-12-membered spiro heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further replaced by one, two or three R T1 replace; Each R T1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR T2 R T3 , -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, - 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 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R T4 replace; Each R T2 , R T3 , R T4 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); X 2 Selected from -NH2, -NHR X21 , -OH, -SH, ethynyl, vinyl, -C(O)H or -C(O)OH; R X21 Selected from -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl.

10. The compound according to claim 9, characterized in that: The compound of formula V is shown in formula VIa, VIb or VIc: Among them, R 21 , T, X 2 , The substituents of ring B are defined as described in claim 10.

11. The compound according to claim 10, characterized in that: The T is selected from 12. The compound according to any one of claims 9 to 11, characterized in that: The compound described in formula V is specifically:

13. Use of the compound according to any one of claims 1 to 12, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the treatment of diseases related to abnormal cell proliferation.

14. The use according to claim 13, characterized in that: The disease is cancer.

15. Use of the compound according to any one of claims 1 to 12, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a targeted protein degradation drug.

16. The use according to claim 15, characterized in that: The compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt is used as an intermediate in the preparation of targeted protein degradation drugs.

17. The use according to claim 16, characterized in that: The targeted protein degradation drug is a drug that relies on the E3 ligase BIRC7 for protein degradation.

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