Lactam derivative and use thereof

Abstract

A compound represented by formula (I), a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof or a mixture thereof, which is a molecular glue degradation agent for degrading a GSPT1 protein. The compound can be used for preparing a drug for treating and / or preventing GSPT1-related diseases.

Description

Lactam derivatives and their applications Technical Field

[0001] The present application relates to the field of medicinal chemistry, and specifically to a molecular glue degrader capable of degrading GSPT1 protein. Background Art

[0002] There are currently two main types of protein degraders: one is the protein degradation targeting chimera (Protac). As a bifunctional molecular degrader, protac connects the ligand that binds to the E3 ligase and the ligand that binds to the intracellular protein through a linker. By recruiting the target protein to the vicinity of the E3 ubiquitin ligase, the ubiquitination and proteasomal degradation of the target protein are achieved. Unlike the target occupancy-driven mode of small molecule inhibitors, protac mediates the ubiquitination and continuous degradation of the target protein, and has more effective and lasting drug activity. The reduction in dosage and frequency of administration also reduces potential toxicity, and can also overcome drug resistance caused by overexpression and mutation of the target protein. However, the molecular weight of protac is generally large (over 700 Da), and its water solubility and permeability are poor, which affects the permeability of physiological barriers and cell membranes. As another protein-targeting technology, molecular glue can identify and degrade new substrates (Neo-substrates) by covalently modifying the surface of E3 ligases. Currently available molecular glues, such as the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide, generally have relatively small molecular weights and can inhibit the growth of multiple myeloma by binding to the E3 ligase CRBN and ubiquitinizing and degrading the transcription factor IKZF1 / 3 (Kronke et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343: 301-305).

[0003] eRF3 (also known as GSPT1) is a key eukaryotic peptide release factor involved in the termination of intracellular protein synthesis. eRF3 is located on region 13 of the long arm of human chromosome 16 and is encoded by the gene regulating the G1 to S phase transition 1 of the cell cycle (GSPT1). GSPT1 is a small GTPase that binds to eRF1 when a stop codon binds to the ribosome's A site, terminating protein translation (Le Goff et al. Mouse GSPT2, but not GSPT1, can substitute for yeast eRF3 in vivo. Genes Cells 2002;7:1043-57). Studies have shown that GSPT1 is highly expressed in a variety of tumors, such as gastric cancer, colon cancer, lung cancer, and breast cancer (Nishiguchi et al. Identification of potent, selective, and orally bioavailable small-molecule GSPT1 / 2 degraders from a focused library of cereblon modulators. J Med Chem 2021; 64: 7296-7311). GSPT1 is an essential protein for tumor cell survival. GSPT1 deficiency can lead to abnormal expression of key genes associated with tumor cell proliferation, thereby inhibiting tumor growth. Currently, multiple GSPT1 molecular glues, such as CC-885, can induce ubiquitination and degradation of GSPT1, thereby inhibiting the growth of hematological and solid tumor cells (Hansen et al. Discovery of CRBN ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J Med Chem 2022; 63: 6648-76). CC-885 can simultaneously degrade the key proteins Ikaros and Aiolos, has strong toxicity, and has not been further developed.CC-90009, an optimized derivative of CC-885, has been shown in a Phase I clinical trial in patients with relapsed or refractory acute myeloid leukemia (R / R AML) to cause G3 / 4 toxicity in 51% of patients, including side effects such as hypophosphatemia, hypotension, and sepsis (Uy et al. Clinical activity of CC-90009, a cereblon E3 ligase modulator and first-class GSPT1 degrader, as a single agent in patients with relapsed or refractory acute myeloid leukemia (R / R AML): first results form a phase I dose-finding study. Blood 2019;134:232). The development of GSPT1 degraders is an urgent unmet clinical need.

[0004] Summary of the Invention

[0005] In response to the above-mentioned problems existing in the prior art, the present application provides a compound represented by formula (I), its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof:

[0006] in:

[0007] Ring A is selected from 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group or C3-C 10 Carbocyclic group;

[0008] Ring B is selected from 6-12 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group or C3-C 10 Carbocyclic group;

[0009] Ring C is selected from

[0010] represents a single bond or a double bond;

[0011] X is selected from CR 10 or NR 10 ;

[0012] R a 、R bindependently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, substituted by halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

[0013] R c independently selected from H or deuterium;

[0014] L is selected from a chemical bond, a 4-10 membered heterocyclic group, -CR2R3-, -O-, -S- or -NR4-;

[0015] L1 is selected from chemical bonds, -CR 2’ R 3’ -, -O-, -S-, or -NR 4’ -;

[0016] R1 is selected from a chemical bond, -CR5R6-, -OCR5R6-, -SCR5R6-, -NCR5R6-, -O-, -S- or -NR7-;

[0017] R2, R3, R4, R 2’ 、R 3’ 、R 4’R5, R6, and R7 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-8 membered heterocyclyl; the C1-C6 alkyl C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl may be optionally unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, amino, hydroxyl, and thiol;

[0018] Alternatively, R2 and R3 together with the carbon atom to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group;

[0019] Alternatively, R2 and R a or R4 and R a Together with ring A, it forms C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group;

[0020] Alternatively, R5 or R6 and R2 or R3 together with the carbon atom to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group;

[0021] Alternatively, R5 and R4 or R6 and R4 together with the atoms to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group;

[0022] When multiple R2, R3, R4, R 2’ 、R 3’ 、R 4’ , R5, R6 or R7, each R2, R3, R4, R 2’ 、R 3’ 、R 4’ , R5, R6 or R7 are the same or different;

[0023] R8 is selected from a chemical bond, C1-C3 alkylene or -C(O);

[0024] R9 is selected from H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkyl Acyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfonyl, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or substituted with substituents selected from one or more H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfonyl, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0025] R 10 Selected from H, deuterium or absent;

[0026] m is selected from 0, 1, 2, 3 or 4;

[0027] n is selected from 0, 1, 2, 3 or 4;

[0028] p is selected from 0, 1, 2, 3 or 4;

[0029] q is selected from 1 or 2.

[0030] In some preferred embodiments, in the above compounds of formula (I), the ring C is selected from represents a single bond or a double bond; X is selected from CR 10 or NR 10 ; R 10 Selected from H, deuterium or absent; further preferably, ring C is selected from Preferably, X is selected from CH.

[0031] In some more preferred embodiments, in the above compounds of formula (I), the ring C is selected from

[0032] Preferably, the ring C is

[0033] In some preferred embodiments, Ring A is selected from * indicates the site of connection with L; preferably, ring A is

[0034] In some preferred embodiments, ring B is selected from a 6-12 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms, or S atoms; preferably, ring B is selected from a 6-10 membered aryl group, or a 5-6 membered heteroaryl group containing 1-2 heteroatoms selected from N atoms, O atoms, or S atoms; more preferably, ring B is selected from a benzene ring or pyridine, for example, ring B is a benzene ring.

[0035] In some preferred embodiments, L is selected from a chemical bond, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, -CR2R3-, -O-, -S- or -NR4-; preferably, L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR2R3- or -NR4-, R2 and R3 are each independently selected from H, halogen, cyano or C1-C6 alkyl; more preferably, L is selected from -CH2-, azetidinyl.

[0036] In some preferred embodiments, R1 is selected from a chemical bond, -CR5R6-, -O-, -S- or -NR7-, and R5, R6, and R7 are each independently selected from H, halogen or C1-C6 alkyl; preferably, R1 is selected from -O-, -S- or -NR7-, and R7 is selected from H or C1-C5 alkyl; more preferably, R1 is selected from -O-, -S- or -NH- (for example, R1 is -O- or -NH-).

[0037] In some preferred embodiments, L1 is selected from a chemical bond, -CR 2’ R 3’ -, or -NR 4’ -, R 2’ 、R 3’ 、R 4’ Each is independently selected from H, halogen, C1-C6 alkyl; preferably, L1 is selected from -NR 4’ -, R 4’ is H or C1-C6 alkyl; more preferably, L1 is -NH-.

[0038] In some preferred embodiments, R bIndependently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino;

[0039] R8 is selected from a chemical bond, C1-C3 alkylene or -C(O);

[0040] R9 is selected from -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-12 membered heterocyclyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 aminoalkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylamino;

[0041] n is selected from 0, 1, 2, 3 or 4.

[0042] In some preferred embodiments, R b Independently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; the C1-C6 alkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C1-C6 alkoxy, or C1-C6 alkylamino;

[0043] R8 is selected from a chemical bond, C1-C3 alkylene or -C(O);

[0044] R9 is selected from C1-C6 alkoxy, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C1-C6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkylamino;

[0045] n is selected from 1, 2, 3 or 4.

[0046] In some preferred embodiments, R bIndependently selected from H, deuterium, halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy being unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino;

[0047] R8 is selected from a chemical bond, a C1-C3 alkylene group;

[0048] R9 is selected from C1-C6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C1-C6 alkoxy is unsubstituted or substituted with a C1-C6 alkylamino group, and the 4-8 membered heterocyclic group is unsubstituted or substituted with a C1-C6 alkyl group;

[0049] n is selected from 1, 2 or 3.

[0050] In some preferred embodiments, R b Independently selected from halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino;

[0051] R8 is selected from a chemical bond, a C1-C3 alkylene group;

[0052] R9 is selected from C1-C6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, wherein the C1-C6 alkoxy is unsubstituted or substituted by a C1-C6 alkylamino group;

[0053] n is selected from 1, 2 or 3.

[0054] In some preferred embodiments, R a are independently selected from H, deuterium, halogen, C1-C6 alkyl; m is selected from 0, 1, 2 or 3. In some preferred embodiments, ring A is R a are independently selected from H, deuterium or halogen, m is 1, 2 or 3; or Ring A is m is 0. In some preferred embodiments, ring A is R a are independently selected from halogen, and m is 2. In some preferred embodiments, ring A is m is 0.

[0055] In some preferred embodiments, R c Independently selected from H or deuterium, p is selected from 0, 1 or 2. Preferably, p is 0.

[0056] In some embodiments, the compound represented by the above general formula (I), its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, has the structure shown below:

[0057] Wherein, the ring A, ring B, ring C, L, R1, R a 、R b 、R c , m, n, p, and X are as defined above.

[0058] In some embodiments, in the compound represented by the above general formula (I), its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, the compound has a structure represented by formula (II):

[0059] in:

[0060] Ring A is selected from * indicates the site of connection with L;

[0061] Ring B is selected from a 6-12 membered aryl group or a 5-10 membered heteroaryl group; preferably, ring B is selected from a benzene ring or pyridine;

[0062] R a 、R b , X, L, L1, R1, m, and n are as defined above.

[0063] In some preferred embodiments, the compound represented by the above general formula (II), its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or its mixture is limited to the condition that when ring A is selected from When n=1, R b Selected from SF5; or

[0064] When ring A is selected from When n is selected from 1, 2, 3 or 4, and at least one R b Selected from C1-C6 haloalkoxy or SF5.

[0065] In some embodiments, in the compound represented by the above general formula (I), its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, the compound has a structure represented by formula (III):

[0066] in:

[0067] R b2Selected from C1-C6 haloalkoxy or SF5;

[0068] R b1 is selected from H, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1- C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, halogen, cyano, SF5, -O-(CH2), 2- O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0069] R8 is selected from a chemical bond, C1-C3 alkylene or -C(O);

[0070] R9 is selected from H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C 1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; the C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfonyl, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C 1- C6 haloalkoxy, C 1- Substituted with a C6 haloalkyl group, a C1-C6 haloalkoxyalkyl group, a C1-C6 alkylamino group, a C1-C6 aminoalkyl group, a C1-C6 alkylacyl group, a C1-C6 alkylcarbamoyl group, a C1-C6 alkylthiol group, a C1-C6 alkylsulfone group, a C3-C8 cycloalkyl group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group;

[0071] n1 is selected from 0, 1 or 2;

[0072] Ring A, Ring B, Ring C, R a 、R c , L, L1, R1, m, and p are as defined in any of the above items.

[0073] In some more preferred embodiments, in the compound represented by the above general formula (III), its deuterated form, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, Ring A is selected from a 6-10 membered aryl group, a 5-12 membered heteroaryl group, or a 5-12 membered heterocyclic group;

[0074] More preferably, ring A is selected from * indicates the site of connection with L;

[0075] More preferably, when ring A is selected from When R b2 Selected from C1-C6 haloalkoxy or SF5; when ring A is selected from When R b2 Selected from SF5.

[0076] In some more preferred embodiments, in the compound represented by the above general formula (III), its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, ring B is selected from a 6-12-membered aryl group or a 5-10-membered heteroaryl group; preferably, ring B is selected from a 6-10-membered aryl group or a 5-6-membered heteroaryl group.

[0077] In some more preferred embodiments, the compound represented by the above general formula (III), its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, ring C is selected from

[0078] In some preferred embodiments, in the compound represented by any one of the above general formulas (I), (II), and (III), its deuterated form, its stereoisomers, its tautomers, its pharmaceutically acceptable salts, or a mixture thereof, L is selected from -CR2R3- or a 4-6 membered heterocyclic group; R2 and R3 are independently selected from H or a C1-C6 alkyl group.

[0079] In some preferred embodiments, the compound represented by the above formula (I) is selected from:

[0080] Among them, R 11 and R 12 are each independently H, deuterium, halogen or C1-C6 alkyl, or R 11 and R 12 The carbon atoms to which it is attached together form a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms;

[0081] L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR2R3- or -NR4-;

[0082] R2 and R3 are each independently selected from H, halogen, cyano or C1-C6 alkyl;

[0083] R4 is selected from H, C4-C6 cycloalkyl, or a 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms;

[0084] R1 is selected from -O-, -S- or -NR7-;

[0085] R7 is selected from H, halogen, or C1-C6 alkyl;

[0086] R bIndependently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; the C1-C6 alkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C1-C6 alkoxy, or C1-C6 alkylamino;

[0087] R8 is selected from a chemical bond, C1-C3 alkylene or -C(O);

[0088] R9 is selected from C1-C6 alkoxy, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C1-C6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkylamino;

[0089] n is selected from 1, 2, 3 or 4;

[0090] or,

[0091] wherein R1 is selected from a chemical bond, -CR5R6-, -O-, -S- or -NR7-;

[0092] R5, R6, R7 are each independently selected from H or C1-C6 alkyl;

[0093] R b Selected from H, deuterium, halogen, cyano, SF5, C1-C6 alkyl; the C1-C6 alkyl is unsubstituted or substituted by halogen;

[0094] or,

[0095] R b Selected from H, deuterium, halogen, cyano, SF5, C1-C6 alkyl; the C1-C6 alkyl is unsubstituted or substituted by halogen.

[0096] In some preferred embodiments, in the compound represented by formula (IV), R 11 and R 12 are each independently H, or R 11 and R 12 Together with the carbon atom to which it is attached, it forms a phenyl group;

[0097] L is selected from -CH2-, azetidinyl;

[0098] R1 is selected from -O-, -S- or -NH- (preferably -O- or -NH-);

[0099] R bIndependently selected from H, deuterium, halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy being unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino;

[0100] R8 is selected from a chemical bond, a C1-C3 alkylene group;

[0101] R9 is selected from C1-C6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C1-C6 alkoxy is unsubstituted or substituted with a C1-C6 alkylamino group, and the 4-8 membered heterocyclic group is unsubstituted or substituted with a C1-C6 alkyl group;

[0102] n is selected from 1, 2 or 3.

[0103] In some preferred embodiments, in the compound represented by formula (IV), R 11 and R 12 Together with the carbon atom to which it is attached, it forms a phenyl group;

[0104] L is selected from -CH2-, azetidinyl;

[0105] R1 is selected from -O-, or -NH-;

[0106] R b Independently selected from halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino;

[0107] R8 is selected from a chemical bond, a C1-C3 alkylene group;

[0108] R9 is selected from C1-C6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, wherein the C1-C6 alkoxy is unsubstituted or substituted by a C1-C6 alkylamino group;

[0109] n is selected from 1, 2 or 3.

[0110] In some preferred embodiments, the compound represented by the above formula (I) is the following compound:

[0111] Among them, L, R1, R b and n are as defined above; preferably, L is selected from -CH2-, azetidinyl; R1 is selected from -O-, or -NH-; R bIndependently selected from fluorine, chlorine, bromine, iodine, SF5, (C1-C6 alkyl)-NH-(C1-C6 alkoxy)-(C1-C3 alkylene)-(e.g., CH3NH(CH2)2-O-(CH2)2-), (C1-C6 alkyl)-NH-(C1-C6 alkoxy)-(e.g., CH3NH(CH2)2-O-), (5-7 membered heterocyclyl)-(C1-C3 alkylene)-(e.g., morpholinyl-(C1-C3 alkylene)-, 1,3-oxazinyl-(C1-C3 alkylene)-, 1,2-oxazinyl-(C1-C3 alkylene)-, piperazinyl-(C1-C3 alkylene)-; preferably ), -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy (for example, C1-C5 haloalkoxy, C1-C4 haloalkoxy or C1-C3 haloalkoxy; preferably -OCHF2, -OCF3, -OCH2F), the 5-7 membered heterocyclic group contains 1-2 heteroatoms selected from N atoms or O atoms; n is selected from 1, 2 or 3.

[0112] In some preferred embodiments, the compound represented by the above formula (I) is the following compound:

[0113] or

[0114] Among them, R1, R b and n are as defined above; preferably, R1 is selected from -O-, or -NH-; R b Independently selected from fluorine, chlorine, bromine, SF5, CH3NH(CH2)2-O-(CH2)2-, CH3NH(CH2)2-O-, -O-(CH2)2-O-CH3, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl), C1-C6 fluoroalkoxy (e.g., C1-C5 fluoroalkoxy, C1-C4 fluoroalkoxy or C1-C3 fluoroalkoxy; preferably -OCHF2, -OCF3, -OCH2F); n is selected from 1, 2 or 3.

[0115] In some preferred embodiments, in the compound represented by formula (IV-2), R b Independently selected from fluorine, chlorine, bromine, SF5, CH3NH(CH2)2-O-(CH2)2-, CH3NH(CH2)2-O-, -O-(CH2)2-O-CH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, C1-C3 fluoroalkoxy; n is selected from 1, 2 or 3.

[0116] In some preferred embodiments, the compound of any one of the above general formulas (I), (II), and (III), its deuterated form, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, has the structure shown below:

[0117] Among them, R in formula (III-1) b2 Selected from C1-C6 haloalkoxy or SF5;

[0118] In formula (III-2), formula (III-3) and formula (III-4), R b2 is selected from SF5; other variables are as defined in any one of the above items.

[0119] In some embodiments, the compound described in any one of the above, its deuterated form, its stereoisomer, its tautomer, or a mixture thereof, is characterized in that the compound is selected from but not limited to the following compounds:

[0120] Another aspect of the present application is to provide the use of any of the above-mentioned compounds, their deuterated forms, stereoisomers, tautomers, pharmaceutically acceptable salts, or mixtures thereof, in the preparation of a medicament for treating and / or preventing a disease associated with GSPT1, preferably a disease associated with GSPT1 dysfunction. Alternatively, the present application relates to any of the above-mentioned compounds, their deuterated forms, stereoisomers, tautomers, pharmaceutically acceptable salts, or mixtures thereof, for treating and / or preventing a disease associated with GSPT1. Alternatively, the present application relates to a method for treating and / or preventing a disease associated with GSPT1 in a subject in need thereof, comprising administering to the subject a preventively and / or therapeutically effective amount of any of the above-mentioned compounds, their deuterated forms, stereoisomers, tautomers, pharmaceutically acceptable salts, or mixtures thereof. As used herein, the preventively and / or therapeutically effective amount refers to an amount sufficient to prevent, ameliorate, inhibit, delay, or slow the progression of a disease associated with GSPT1, and can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, sex, weight, and other factors.

[0121] Herein, a GSPT1-related disease refers to a disease or its related symptoms that can achieve clinically beneficial therapeutic effects such as alleviation, improvement, cessation of progression, reduction or non-aggravation by degrading GSPT1. In some embodiments, the GSPT1-related disease is cancer.

[0122] In some preferred embodiments, the cancer comprises a solid tumor or a hematological malignancy.

[0123] In some more preferred embodiments, the cancer is selected from, but is not limited to, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, upper respiratory tract cancer, cervical cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, neuroblastoma, glioblastoma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion-mesothelioma syndrome, peritoneal cancer, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, leiomyosarcoma, fallopian tube cancer, leiomyoma, leiomyoma, leukemia, and lymphoma.

[0124] It should be noted that any of the above-mentioned implementation methods of the present application can be freely combined to form a new technical solution. DETAILED DESCRIPTION

[0125] In order to make the present application easier to understand, the present application will be described in detail below with reference to embodiments. These embodiments are merely illustrative and do not limit the scope of application of the present application.

[0126] Terms and Definitions

[0127] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the following terms have the meanings ascribed to them below unless otherwise indicated.

[0128] The term "substituted" herein refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom with a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. It should be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as needed to satisfy the valence of the atoms.

[0129] When the present application refers to the number of substituents, the number of substituents on the group can range from 0 to the maximum possible number of substituents. As used herein, Indicates the attachment site of a group.

[0130] The term "independently" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different; or when a substituent occurs multiple times, each occurrence may be selected from the same or different.

[0131] The term "C m -C n " means that the number of carbon atoms is at least m and at most n, including the two endpoints m and n; m and n are integers not equal to 0, where m<n.

[0132] The term "aryl" used in this application, alone or in combination, refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms, including dicyclic and tricyclic) group with a conjugated π electron system. For fused polycyclics, at least one ring is aromatic, and the other rings can be aromatic, saturated or unsaturated carbocyclic, such as aryl and aryl carbocyclic, and at least one point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system. In some embodiments, specific examples of 6-12 membered aryl groups (e.g., 6-membered and 10-membered aryl groups) include, but are not limited to:

[0133] The term "heteroaryl" herein refers to a monocyclic or polycyclic group (at least one of which is a heteroaromatic ring) containing one to multiple heteroatoms (preferably 1-3) selected from N, O, or S, and having aromaticity, wherein at least one of the points of attachment to the parent group must be on the heteroaryl group, for example: aryl-heteroaryl, heteroaryl-heteroaryl, heteroaryl-carbocyclic, heteroaryl-heterocyclic, etc. In some embodiments, specific examples of 5-10 membered heteroaryl groups (including 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered heteroaryl groups) include, but are not limited to:

[0134] The term "heterocyclyl" in this application refers to a stable, saturated or unsaturated (non-aromatic) monocyclic or polycyclic ring (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic ring system) composed of carbon atoms and one or more heteroatoms or heteroatoms selected from O, S, and N (e.g., C(=O), S(=O), S(=O)2), and for polycyclic systems, each ring can be connected to the rest of the molecule through a single bond via any suitable carbon atom, and at least one point of attachment to the parent must be on the heterocycle, for example: heterocyclyl and aryl, heterocyclyl and heteroaryl, heterocyclyl and carbocyclic, heterocyclyl and heterocyclyl. In some embodiments, specific examples of 3-12 membered heterocyclyl (including 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered heterocyclyl) include, but are not limited to: wait.

[0135] The term "carbocyclyl" herein refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group (including fused ring, bridged ring or spirocyclic system) consisting only of carbon atoms and hydrogen atoms, which may be connected to the rest of the parent group via one or more single bonds via any suitable carbon atom. 10 Carbocyclic groups (including C3, C4, C5, C6, C7, C8, C9 or C 10 Specific examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, For the purpose of this application, the carbocyclic groups described herein include cycloalkyl and cycloalkenyl groups.

[0136] The term "alkyl" appearing alone or in combination in this application refers to a straight or branched saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms. As non-limiting examples of alkyl, the following straight or branched saturated hydrocarbon groups can be enumerated: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and its other seven isomers, n-hexyl and its other sixteen isomers. In some embodiments, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and its whole isomers. The alkyl group can be further substituted with halogen to form a haloalkyl group, and specific non-limiting examples include but are not limited to: -CF3, -CHCF2, -CH2CH2F, -CH2CF3.

[0137] As used herein, the term "alkoxy" refers to an "-O-alkyl" group. For example, the term "C1-C6 alkoxy" refers to a saturated, straight-chain or branched hydrocarbon moiety having at least one and up to six carbon atoms attached through an oxygen linker. Specific exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

[0138] The term "haloalkoxy" in this application refers to that the carbon atoms in the alkoxy group are substituted by one or more substituents independently selected from F, Cl, and Br. In some embodiments, specific non-limiting examples of C1-C6 haloalkoxy include but are not limited to: -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH(CH3)CF3, etc.

[0139] The term "alkoxyalkyl" herein refers to an alkyl group in which one or more hydrogen atoms are replaced by an alkoxy group (preferably a C1-C3 alkoxy group), i.e., a group having a "-WOW" structure, wherein W is an alkyl group. In some embodiments, non-limiting examples of C1-C6 alkoxyalkyl groups include, but are not limited to, -CH2-OCH3, -CH2CH2-OCH3, -CH2-OCH2CH3, and the like.

[0140] The term "haloalkoxyalkyl" in this application refers to a carbon atom in an alkoxyalkyl group that is substituted by one or more substituents independently selected from F, Cl, and Br. In some embodiments, specific non-limiting examples of C1-C6 haloalkoxyalkyl groups include, but are not limited to, -CH2-OCF3, -CHF-OCH3, -CH2-OCH2CF3, and the like.

[0141] The term "alkylamino" in the present application means that the H in -NH2 is replaced by an alkyl group, that is, -NH-alkyl or -N-(alkyl)(alkyl). For example, "C1-C6 alkylamino" means that one or two hydrogens in -NH2 are replaced by a branched or straight-chain alkyl group having 1 to 6 carbon atoms. Specific non-limiting examples include but are not limited to -NHCH3, -NHCH2CH3, -N(CH3)CH3, etc.

[0142] The term "aminoalkyl" in the present application refers to an alkyl group in which at least one hydrogen atom is replaced by an amino group. For example, "C1-C6 aminoalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms in which at least one hydrogen atom is replaced by -NH2. Non-limiting examples include but are not limited to -CH2NH2, -CH2CH2NH2, -CH(CH3)CH2NH2, etc.

[0143] The term "alkylacyl" herein refers to a group having an "alkyl-C(=O)-" structure, wherein alkyl is as defined above. In some embodiments, specific non-limiting examples of C1-C6 alkylacyl include, but are not limited to, formyl, acetyl, and the like.

[0144] The term "alkylcarbamoyl" herein refers to a group having a "-C(O)N(C1-C6 alkyl)2 structure". The term "alkylthiol" herein refers to a group having a "-S-(C1-C6 alkyl)" structure. The term "alkylsulfone" herein refers to a group having a "-S(O)2-(C1-C6 alkyl)" structure. The term "amino" herein refers to a -NH2 group. The term "hydroxyl" herein refers to a -OH group. The term "thiol" herein refers to a -SH group.

[0145] The above-mentioned alkyl, cycloalkyl / carbocyclic group, heterocyclic group, aryl and heteroaryl groups may be unsubstituted or optionally substituted with one or more substituents, for example, substituted with the following substituents: alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, halogen, hydroxyl, alkoxy, cyano, nitro, amino, aminohydroxyl groups. Preferably, they may be optionally substituted with groups independently selected from C1-C6 alkyl, haloalkyl, C3-C6 cycloalkyl, halogen, hydroxyl, hydroxyl, alkoxy, cyano, amino, aryl, heteroaryl groups, specific examples of which include but are not limited to methyl, ethyl, propyl, F, Cl, trifluoromethyl, cyclopropyl, methoxy, phenyl, naphthyl, pyridyl, pyrazinyl and the like.

[0146] The compounds of the present invention contain one or more asymmetric centers (also known as chiral centers), and the compounds and intermediates of the present invention may exist in different tautomeric forms, all of which are included in the scope of protection of the present invention. The present invention includes all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)) of the structure.

[0147] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane-polarized light;

[0148] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (or prototropic tautomers) include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, etc.

[0149] In addition, the compounds of the present application may contain one or more isotopic forms, i.e., hydrogen isotopic forms of D or T, or isotopes of any atoms, such as all isotopic forms of C and N. All isotopic forms of any C, N or H in the compounds of the optional structures of the present application are included in the scope of protection of the present application.

[0150] The words "include," "comprising," and "containing" and their equivalents should be understood as having an open, non-exclusive meaning, i.e., "including but not limited to," meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included. In this document, singular terms encompass plural referents and vice versa unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0151] Unless otherwise specified in the present application, the solution mentioned in the reaction of the present application is an aqueous solution.

[0152] The term "room temperature" in this application refers to a temperature between 10°C and 25°C.

[0153] All patents, patent applications, and other publications are expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

[0154] Example

[0155] The present invention is described in detail below by way of examples, but this does not necessarily limit the scope of protection of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the present invention without departing from the spirit and scope of the present invention. Unless otherwise indicated, the reagents, materials, etc. mentioned in the following examples are those commercially available in this area.

[0156] Example 1: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl (3-chloro-4-methylphenyl)carbamate

[0157] The preparation scheme is shown in the figure below:

[0158] Step 1: 5-Bromo-1H,3H-benzo[de]isochromene-1,3-dione (1-2)

[0159] Add 1H,3H-benzo[de]isochromene-1,3-dione (5 g, 25.2 mmol, CAS: 81-84-5) to concentrated sulfuric acid (20 mL) and stir for 30 minutes. Then cool to -5 to -10°C. Then slowly add dibromohydantoin (3.96 g, 13.86 mmol) in batches. After the addition is complete, stir below 0°C for 1 hour, then slowly warm to room temperature and stir for 18 hours. After the reaction is complete, pour the reaction mixture into ice water. A large amount of white solid precipitates. Filter, wash the filter cake with methanol, and dry to obtain the title compound as a white solid (2.75 g, 40% yield). MS: m / z [M+H] + =277.0; 1H NMR (400MHz, CDCl3) δ 8.74 (s, 1H); 8.69 (m, 1H); 8.53 (s, 1H); 8.31 (d, 1H); 7.93 (m, 1H).

[0160] Step 2: 4-bromobenz[cd]indol-2(1H)-one (1-3)

[0161] 5-Bromo-1H,3H-benzo[de]isochromene-1,3-dione (2.75 g, 10 mmol) and hydroxylamine hydrochloride (0.69 g, 10 mmol) were added to a pyridine (20 mL) solution, refluxed at 90 ° C for 2 hours, cooled to 80 ° C, and p-toluenesulfonyl chloride (3.81 g, 20 mmol) was added. The reaction system was heated to 90 ° C and refluxed for 2 hours, cooled to room temperature, and the reaction solution was poured into water (200 mL) and stirred for 30 minutes. The solid was filtered and the filter cake was washed with saturated sodium bicarbonate in succession. The solution was washed with an aqueous solution and water, filtered, and dried to remove most of the water, yielding a pale yellow solid. The solid was dissolved in ethanol (50 mL) and water (60 mL), stirred at room temperature, and a 1.5 M aqueous sodium hydroxide solution (33 mL) was slowly added. The reaction temperature was raised to 90°C and stirred under reflux for 3 hours while the water and ethanol were distilled off. The solution was then cooled to 75°C and 5.5 mL of concentrated hydrochloric acid was slowly added to adjust the pH of the reaction system to 2-3. The solution was cooled to room temperature and filtered to yield a white solid (0.78 g, 28.5% yield). MS: m / z [M+H] + =249.9; 1 H NMR (400MHz, DMSO) δ 10.9 (s, 1H); 8.49 (s, 1H); 8.14 (s, 1H); 7.57 (m, 2H); 7.04 (m, 1H).

[0162] Step 3: 3-(4-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1-5)

[0163] Sodium hydroxide (60%) (156 mg, 3.9 mmol) was dissolved in dry tetrahydrofuran (3 ml). The mixture was cooled to below 0°C under nitrogen. 4-Bromobenz[cd]indol-2(1H)-one (96 mg, 0.39 mmol) was slowly added. The mixture was stirred at 0°C for 30 minutes. A solution of 3-bromopiperidine-2,6-dione (337 mg, 1.8 mmol, 1-4) in tetrahydrofuran (3 mL) was slowly added. The reaction system was allowed to warm to room temperature and heated to 65°C. Stirring was continued for 18 hours. Upon completion, the reaction was terminated by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to dryness to afford the crude product. The crude product was purified by flash chromatography on a silica gel column to afford the title compound (116 mg, 83% yield) as a white solid. MS: m / z [M+H] + =359.0.

[0164] Step 4: 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-4-carboxylic acid (1-6)

[0165] 3-(4-Bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (116 mg, 0.32 mmol), palladium acetate (3 mg, 0.018 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (19 mg, 0.036 mmol), potassium carbonate (110.4 mg, 0.8 mmol), and water (11 mg, 0.6 mmol) were dissolved in N-methylpyrrolidone (3 ml). The mixture was heated to 140°C under a carbon monoxide atmosphere and stirred for 24 hours. After the reaction was complete, the mixture was cooled to room temperature and the pH was adjusted to 3 with 1 M aqueous hydrochloric acid. Ethyl acetate (20 mL x 5) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried to dryness to obtain the crude product. The crude product was purified by medium-pressure column chromatography to afford the title compound (76 mg, 73% yield) as a white solid. MS: m / z [MH] - =323.0.

[0166] Step 5: 3-(4-(Hydroxymethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (1-7)

[0167] Dissolve 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indole-4-carboxylic acid (76 mg, 0.23 mmol) in tetrahydrofuran (3 mL), add N,N'-carbonyldiimidazole (57 mg, 0.35 mmol), and stir at room temperature for 3 hours to obtain a tetrahydrofuran reaction solution for use.

[0168] Sodium borohydride (26 mg, 0.68 mmol) was added to water (15 mL) and stirred for 10 minutes. The mixture was then slowly added to the tetrahydrofuran reaction solution and stirred at room temperature for 10 minutes. Ethyl acetate (30 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography afforded the title compound as a white solid (17 mg, 27.4% yield). MS: m / z [M+H] + =311.6.

[0169] Step 6: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-chloro-4-methylphenyl)carbamate

[0170] 3-(4-(Hydroxymethyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (17 mg, 0.055 mmol) and 3-chloro-4-methylphenylisocyanate (11 mg, 0.066 mmol) were dissolved in dry tetrahydrofuran (3 mL). Triethylamine (6.7 mg, 0.066 mmol) and 4-dimethylaminopyridine (0.7 mg, 0.006 mmol) were added. After the addition was complete, the reaction system was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by HPLC to obtain the title compound as a white solid (5 mg, HPLC purity: 97.6%, yield 19%). 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),8.11(s,1H),8.06(s,1H),7.59(d,J=8.7Hz,1H),7.50–7.44(m,2H),7. 14(s,2H),6.78(d,J=7.4Hz,1H),6.69(s,1H),5.45(s,2H),5.33(m,1H),2.88(m,3H),2.33-2.29(m,4H).

[0171] Example 2: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate

[0172] The preparation scheme is shown in the figure below:

[0173] Step 1: (3-nitro-5-(trifluoromethoxy)phenyl)methanol (2-2)

[0174] Dissolve 3-nitro-5-(trifluoromethoxy)benzoic acid (300 mg, 1.20 mmol) in 5 mL of tetrahydrofuran. Slowly add borane tetrahydrofuran complex (2 mL) dropwise under ice-cooling. Incubate at 25°C for 3 h under nitrogen. After completion of the reaction, monitor by LCMS. Slowly add methanol (2 mL) dropwise under ice-cooling to quench the reaction. Concentrate under reduced pressure to remove the solvent, yielding a crude white oil (3-nitro-5-(trifluoromethoxy)phenyl)methanol (309 mg). MS: m / z [MH] - =282.1.

[0175] Step 2: 1-(Chloromethyl)-3-nitro-5-(trifluoromethoxy)benzene (2-3)

[0176] (3-Nitro-5-(trifluoromethoxy)phenyl)methanol (309 mg, 1.30 mmol) was dissolved in dichloromethane (5 mL), and pyridine (1 mL) was added to the reaction system. Under nitrogen protection, thionyl chloride (1 mL) was added under an ice bath, and the mixture was warmed to room temperature and stirred for 16 h. TLC monitoring confirmed the completion of the reaction. The reaction solution was directly concentrated under reduced pressure to remove residual solvent and thionyl chloride. Water (100 mL) was added, and ethyl acetate (40 mL) was added and extracted three times. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 1-(chloromethyl)-3-nitro-5-(trifluoromethoxy)benzene (125 mg, 38% yield) as a yellow oil.

[0177] Step 3: 4-(3-nitro-5-(trifluoromethoxy)benzyl)morpholine (2-4)

[0178] 1-(Chloromethyl)-3-nitro-5-(trifluoromethoxy)benzene (125 mg, 0.49 mmol) was dissolved in tetrahydrofuran (2 mL). N,N-diisopropylethylamine (126 mg, 0.98 mmol) was added to the reaction system. Morpholine (63 mg, 0.74 mmol) was added under nitrogen protection, and the temperature was raised to 50°C and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reaction solution was added to water (80 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford 4-(3-nitro-5-(trifluoromethoxy)benzyl)morpholine (121 mg, 81% yield) as a yellow oil. MS: m / z [M+H] + =306.8.

[0179] Step 4: 3-(morpholinomethyl)-5-(trifluoromethoxy)aniline (2-5)

[0180] 4-(3-nitro-5-(trifluoromethoxy)benzyl)morpholine (121 mg, 0.39 mmol) was dissolved in ethanol (2 mL) and water (1 mL). Ammonium chloride (211 mg, 3.90 mmol) and iron powder (221 mg, 3.90 mmol) were added to the reaction system. The mixture was heated to 50°C and stirred for 3 h under nitrogen. TLC confirmed the completion of the reaction. The reaction solution was filtered, and the filtrate was added to water (50 mL). The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford 3-(morpholinomethyl)-5-(trifluoromethoxy)aniline (98 mg, 90% yield) as a yellow oil.

[0181] Step 5: Phenyl (3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (2-6)

[0182] 3-(Morpholinomethyl)-5-(trifluoromethoxy)aniline (55 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and pyridine (31.5 mg, 0.36 mmol) was added. Phenyl chloroformate (37.4 mg, 0.22 mmol) was added under nitrogen protection in an ice bath, and the mixture was warmed to room temperature and stirred for 3 h. LCMS monitoring confirmed the completion of the reaction. The reaction solution was added to water (30 mL) and extracted three times with ethyl acetate (20 mL). The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1 mL) and purified by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain phenyl (3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (28 mg, 36% yield) as a yellow oil. MS: m / z [M+H] + =397.1.

[0183] Step 6: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (Example 2)

[0184] Dissolve 3-(4-(Hydroxymethyl)-2-oxobenzo[cd]indol-1-(2H)-yl)piperidine-2,6-dione (19 mg, 0.09 mmol) in N,N-dimethylformamide (1.5 mL). Add sodium hydride (4.32 mg, 0.18 mmol) under nitrogen atmosphere under ice-cooling. Stir for 30 min. Add phenyl(3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (25 mg, 0.06 mmol), warm to room temperature, and stir for 3 h. LCMS (YC23046-033) monitored the reaction for completion. Under ice-cooling, hydrochloric acid and ethyl acetate solution were slowly added dropwise to adjust the pH of the reaction system to pH 6. Water (30 mL) was added and extracted twice with methyl tert-butyl ether (20 mL). The organic phases were combined and concentrated under reduced pressure. The residue was subjected to reverse-phase chromatography and lyophilized to give (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate (0.80 mg, purity = 98.90%, yield 2%) as a yellow solid. MS: m / z [M+H] + =613.2; 1 H NMR (400MHz, DMSO) δ10.17(s,1H),8.30(s,1H),8.17(s,1H),7.70(d,J=8.6Hz,1H), 7.59–7.54(m,1H),7.48(s,1H),7.42(s,1H),7.27–7.21(m,1H),7.18(d,J=7.1Hz,1H ),6.92(s,1H),5.49–5.42(m,3H),5.49-5.44(m,2H),3.58-3.55(m,4H),3.20-3.15 (m,1H),2.86-2.83(m,1H),2.69-2.66(m,1H),2.35-2.33(m,4H),2.03-1.95(m,1H).

[0185] Example 3: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)-methyl(3-chloro-5-(difluoromethoxy)phenyl)carbamate

[0186] The target compound was prepared using a method similar to that of Example 2 to obtain a yellow product (30.0 mg, HPLC purity: 99.6%, yield 42%). MS: m / z [M+1] + =530.0; 1H NMR (400MHz, DMSO) δ11.14(s,1H),10.27(s,1H),8.30(s,1H),8.17(s,1H),7.70(d,J=8.4Hz,1H),7.63–7.52(m,1H),7.44-7.43(m,1H),7.32-7. 31(m,1H),7.26-7.07(m,2H),6.96-6.95(m,1H),5.58–5.33(m,3H),3.0 0–2.89(m,1H),2.82-2.73(m,1H),2.68-2.63(m,1H),2.14–2.08(m,1H).

[0187] Example 4: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(4-fluoro-3-(trifluoromethoxy)phenyl)carbamate

[0188] The target compound was prepared using a method similar to that of Example 2 to obtain a yellow solid product (1.47 mg, HPLC purity: 96.28%, yield 6.9%). MS: m / z [M-1] - =530; 1 H NMR(400MHz,MeOD)δ8.21(s,1H),8.16(s,1H),7.70 -7.64(m,2H),7.55–7.51(m,1H),7.40–7.36(m,1H),7.22(t,J=9.5Hz,1H),7.09(d,J=7.1Hz, 1H),5.48(s,2H),5.45-5.40(m,1H),2.98–2.88(m,1H),2.86-2.80(m,2H),2.26–2.21(m,1H).

[0189] Example 5: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(3-chloro-5-(trifluoromethoxy)phenyl)carbamate

[0190] The target compound was prepared using a method similar to that of Example 2 to obtain a yellow solid product (6.0 mg, HPLC purity: 92.8%, yield 79%). MS: m / z [M-1] - =546; 1H NMR (400MHz, MeOD) δ8.22(s,1H),8.16(s,1H),7.65(d,J=8.5Hz,1H),7.56-7.52(m,2H),7.46(s,1H),7.09(d,J=7 .1Hz,1H),6.96(s,1H),5.49(s,2H),5.45-5.40(m,1H),2.98-2.89(m,1H),2.86–2.80(m,2H),2.27–2.21(m,1H).

[0191] Example 6: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(4-(trifluoromethoxy)phenyl)carbamate

[0192] The target compound was prepared using a method similar to that of Example 2 to obtain a yellow solid product (6.80 mg, HPLC purity: 99.5%, yield 72%). MS: m / z [M+1] + =514.1; 1 H NMR (400MHz, DMSO) δ11.15(s,1H),10.08(s,1H),8.30(s,1H),8.18(s,1H),7.70(d,J=8.4Hz,1H),7.60–7.55(m,3H),7.31(d, J=8.6Hz,2H),7.18(d,J=7.1Hz,1H),5.49–5.45(m,3H),3.00–2.91(m,1H),2.82–2.72(m,1H),2.64(s,1H),2.14–2.08(m,1H).

[0193] Example 7: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0194] The preparation scheme is shown in the figure below:

[0195] Step 1: (3-aminophenyl)sulfur pentafluoride

[0196] Dissolve (3-aminophenyl)sulfur pentafluoride (110 mg, 0.50 mmol) in 5 mL of tetrahydrofuran, slowly add diphosgene (342 mg, 1.73 mmol) dropwise, and reflux at 60°C for 30 min under nitrogen. Monitor with LC-MS. After completion of the reaction, cool the reaction mixture to room temperature and concentrate under reduced pressure to remove tetrahydrofuran and residual diphosgene. The residue is used directly in the next reaction (yield 100%, 123 mg). MS: m / z [M+MeOH+H] + =278.

[0197] Step 2: (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0198] Under nitrogen protection, 3-(6-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-inden-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.50 mmol) was dissolved in tetrahydrofuran (8 mL). Triethylamine (140 mg, 1.40 mmol) was added to the reaction system, stirred evenly, and pentafluoro(3-isocyanatophenyl)-λ was added dropwise. 6 -sulfane (123 mg, 0.50 mmol) (dissolved in 2 mL of tetrahydrofuran) was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure, and the residue was directly subjected to silica gel column chromatography to obtain a white solid (150 mg, yield 46%). MS: m / z [MH] - =648.2. Step 3: (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0199] (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6 Dissolve 226 mg of 1-thio)phenyl)carbamate (226 mg, 0.35 mmol) in 10 mL of dichloromethane, add 2 mL of trifluoroacetic acid at 0°C, and stir at room temperature for 2 h. After the reaction is complete, the reaction solution is concentrated to obtain a white solid (126 mg, 100% yield) after LCMS monitoring. MS: m / z [M+1] + =550.

[0200] Step 4: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6-thio)phenyl)carbamate

[0201] The crude product (2-(1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl (3-(pentafluoro-λ 6 (-sulfanyl)phenyl)carbamate (254 mg, 0.35 mmol) was dissolved in 10 mL of acetonitrile and stirred until homogeneous. 0.5 mL of aqueous ammonia was slowly added dropwise and stirred at room temperature for 30 min. After completion of the reaction as monitored by LCMS, saturated ammonium chloride solution was added to quench the reaction. The resulting mixture was then extracted with 50 mL of ethyl acetate. The aqueous phase was extracted once more with 30 mL of ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield a white powdery solid (88 mg, HPLC purity: 90.1%, yield: 73.4%). MS: m / z [M+1] + =520.1; 1 H NMR (400MHz, DMSO) δ11.01(s,1H),10.28(s,1H),8.13(s,1H),7.81(s,1H),7.73–7.63(m,3H),7.56-7.51(m,2H),5.30(s ,2H),5.15-5.11(m,1H),4.50-4.32(m,2H),2.96-2.87(m,1H),2.62-2.58(m,1H),2.46–2.33(m,1H),2.03–2.01(m,1H).

[0202] Example 8: (2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)methyl (4-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0203] The target product (126 mg, HPLC purity: 98.1%, yield: 69.6%) was obtained as a white solid using a method similar to that of Example 7. MS: m / z [M+1] + =520.1; 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.35(s,1H),7.85–7.82(m,3H),7.71-7.64(m,4H),5.31(s,2H),5.15-5 .11(m,1H),4,50-4.32(m,2H),2.97–2.86(m,1H),2.68–2.59(m,1H),2.43-2.38(m,1H),2.04-1.98(m,1H).

[0204] Example 9: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(4-(tert-butyl)-3-chlorophenyl)carbamate

[0205] The target compound (10.8 mg, HPLC purity: 99.6%, yield: 2.58%) was obtained as a yellow solid using a method similar to that of Example 1. MS: m / z [M+Na] + =542; 1 H NMR (400MHz, DMSO) δ11.16(s,1H),9.99(s,1H),8.32(s,1H),8.19(s,1H),7.72(d,J=7.7Hz,1H),7.61–7.57(m,2H),7 .42–7.36(m,2H),7.20(d,J=6.0Hz,1H),5.49(s,3H),3.03–2.66(m,4H),2.36-2.03(m,1H),1.43(s,9H),1.26(s,1H).

[0206] Example 10: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(2-fluoro-5-(trifluoromethoxy)phenyl)carbamate

[0207] The target product (4.75 mg, HPLC purity: 95.3%, yield 31.4%) was obtained as a yellow solid using a preparation method similar to that of Example 1. MS: m / z [M+H] + =532;1H NMR (400MHz, DMSO) δ11.15(s,1H),9.96(s,1H),8.32(s,1H),8.22(s,1H),7.89-7.87(m,1H),7.71(d,J=8.4Hz,1H),7.62–7.55(m,1H),7.45–7.37 (m,1H),7.20(d,J=7.2Hz,1H),7.18-7.14(m,1H),5.59–5.41(m,3H),3.0 3–2.92(m,1H),2.84-2.77(m,1H),2.71-2.69(m,1H),2.18-2.11(m,1H).

[0208] Example 11: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(3-(trifluoromethoxy)phenyl)carbamate

[0209] The target product was obtained as a yellow solid using a preparation method similar to that of Example 1 (55 mg, HPLC purity: 99.9%, yield 72%). 1 H NMR (500MHz, DMSO) δ11.21(s,1H),10.25(s,1H),8.36(s,1H),8.24(s,1H),7.75(d,J=8.4Hz,1H),7.66–7.60(m,2H),7.48–7.45(m,2H),7. 24(d,J=7.2Hz,1H),7.05-7.04(m,1H),5.58–5.46(m,3H),3.05–2.97(m,1H),2.87-2.78(m,1H),2.72(d,J=17.2Hz,1H),2.19–2.15(m,1H).

[0210] Example 12: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(3-(2-methoxyethoxy)-5-(trifluoromethoxy)phenyl)carbamate

[0211] The target compound (20 mg, HPLC purity: 96.4%, yield 47%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M-1] - =586.0; 1 H NMR(400MHz,DMSO)δ11.15(s,1H),10.14(s,1H),8.29(s,1H),8.17(s,1H),7.7 0(d,J=8.5Hz,1H),7.56(t,J=7.8Hz,1H),7.18(d,J=7.3Hz,2H),7.06(s,1H),6 .59(s,1H),5.48–5.44(m,3H),4.08–4.06(m,2H),3.64–3.62(m,2H),3.29(s,3 H),2.99–2.90(m,1H),2.82-2.74(m,1H),2.68-2.63(m,1H),2.13-2.08(m,1H).

[0212] Example 13: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)methyl(4-chloro-3-(difluoromethoxy)phenyl)carbamate

[0213] The target compound (36 mg, HPLC purity: 91.3%, yield 44%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+1] + =530.0; 1 H NMR (400MHz, DMSO) δ11.15(s,1H),10.21(s,1H),8.30(s,1H),8.17(s,1H),7. 70(d,J=8.5Hz,1H),7.63(s,1H),7.59–7.54(m,1H),7.50(d,J=8.9Hz,1H),7.3 2(dd,J=8.9,2.4Hz,1H),7.22(s,1H),7.18(d,J=7.2Hz,1H),5.47-5.44(m,3H ),3.00-2.89(m,1H),2.82-2.73(m,1H),2.68-2.66(m,1H),2.14-2.07(m,1H).

[0214] Example 14: 1-(1-(4-(2,6-dioxol-3-yl)-3,5-difluorophenyl)azetidin-3-yl)-3-(4-(pentafluoro-λ 6 -thio)phenyl)urea

[0215] The target compound (37 mg, HPLC purity: 96.0%, yield: 17.01%) was obtained as a white solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =541.0;H NMR (400MHz, DMSO) δ10.88(s,1H),9.14(s,1H),7.75(d,J=9.3Hz,2H),7.59(d,J =8.9Hz,2H),7.09(d,J=7.3Hz,1H),6.18(d,J=11.0Hz,2H),4.57(dd,J=13.0,6. 0Hz, 1H), 4.14 (t, J=7.6Hz, 2H), 4.04 (dd, J=12.9, 4.6Hz, 1H), 3.68 (t, J=7.0Hz, 2H),2.81-2.73(m,1H),2.49-2.45(m,1H),2.18-2.03(m,1H),2.00-1.87(m,1H).

[0216] Example 15: 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)-N-(4-(pentafluoro-λ 6 -thio)phenyl)acetamide

[0217] The preparation scheme is shown in the figure below:

[0218] Dissolve 2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)acetic acid (150 mg, 0.44 mmol) and 4-(pentafluorothio)aniline (97.27 mg, 0.44 mmol) in dry N,N-dimethylformamide (2 mL). Add N,N-diisopropylethylamine (227.04 mg, 1.76 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (418 mg, 1.1 mmol). Replace the atmosphere with nitrogen three times and allow to react at room temperature for 16 h. The reaction was complete as monitored by LCMS. The reaction was quenched by adding 20 mL of water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to afford the title compound as a white solid (17 mg, HPLC purity: 97.0%, yield 7.32%). MS: m / z [M+H] + =540.0; 1 H NMR (400MHz, DMSO) δ10.87(s,1H),10.45(s,1H),7.86-7.77(m,4H),6.13(d,J=11.1Hz,2H),4.03–3.98 (m,3H),3.58–3.55(m,2H),3.09–3.04(m,1H),2.82–2.71(m,4H),2.12-2.05(m,1H),1.95-1.91(m,1H).

[0219] Example 16: 1-(4-(2,6-dioxopiperazine-3-yl)-3,5-difluorophenyl)azetidin-3-yl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0220] The target compound (20 mg, HPLC purity: 90.7%, yield 52%) was obtained as a white solid using a method similar to that of Example 2. MS: m / z [M+1] + =542.0; 1H NMR(400MHz,MeOD)δ9.86(s,1H),8.07(s,1H),7.62-7.60(m,1H),7.49-7.46(m,2H),6.12(d,J=10.8Hz,2H),5.40-5.35(m,1H),4.29–4.25(m ,2H),4.08(dd,J=12.5,5.1Hz,1H),3.89(dd,J=8.7,4.0Hz,2H),2.82-2.73(m,1H),2.69–2.63(m,1H),2.30-2.19(m,1H),2.11-2.03(m,1H).

[0221] Example 17: 1-(4-(2,6-dioxopiperazine-3-yl)-3,5-difluorophenyl)azetidin-3-yl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0222] The target compound (11 mg, HPLC purity: 90.4%, yield 45%) was obtained as a white solid using a method similar to that of Example 2. MS: m / z [M+1] + =542.0; 1 H NMR (400MHz, DMSO) δ10.88(s,1H),10.44(s,1H),7.85(d,J=9.0Hz,2H),7.65(d,J=8.8Hz,2H),6.23(d,J=11.1Hz ,2H),5.32(s,1H),4.25–4.21(m,2H),4.07-4.03(m,1H),3.87-3.84m,2H),2.82-2.67(m,2H),2.09-1.98(m,2H).

[0223] Example 18: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)azetidin-3-yl (3-(pentafluoro-λ 6 -thio)phenyl)carbamate

[0224] The target compound (10.01 mg, HPLC purity: 92.8%, yield: 7.4%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+H] + =597; 1H NMR (400MHz, DMSO) δ11.12(s,1H),10.40(s,1H),8.16(s,1H),7.68-7.65(m,1H),7.59-7.54(m,2H),7.45–7.38(m,3H),7.08-7.07(m,1H) ,6.88(d,J=6.8Hz,1H),5.42-5.38(m,2H),4.44–4.40(m,2H),4.03-4.00(m,2H),3.00-2.90(m,2H),2.80-2.71(m,1H),2.11–2.05(m,1H).

[0225] Example 19: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(3-chloro-5-(trifluoromethoxy)phenyl)carbamate

[0226] The target compound (27.34 mg, HPLC purity: 97.16%, yield 23.3%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+H] + =589.0; 1 H NMR (400MHz, DMSO) δ11.12(s,1H),10.47(s,1H),7.55(d,J=1.7Hz,2H),7.45–7.38(m,3H),7.20(s,1H),7.07(d,J=1.5Hz,1H),6.88 (d,J=6.4Hz,1H),5.43–5.38(m,2H),4.43-4.39(m,2H),4.03-4.00(m,2H),2.99–2.90(m,1H),2.79-2.62(m,2H),2.11-2.06(m,1H).

[0227] Example 20: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(4-chloro-3-(trifluoromethoxy)phenyl)carbamate

[0228] The target compound (14.2 mg, HPLC purity: 95.54%, yield: 18.8%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+1] + =589.0; 1H NMR (400MHz, DMSO) δ11.12(s,1H),10.41(s,1H),7.84-7.81(m,1H),7.63(d,J=8.9Hz,1H),7.45–7.38(m,4H),7.07(d,J=1.5Hz,1H), 6.89-6.87(m,1H),5.43-5.37(m,2H),4.43–4.39(m,2H),4.02–3.99(m,2H),2.95-2.89(m,1H),2.79–2.69(m,2H),2.13–2.08(m,1H).

[0229] Example 21: 1-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-4-yl)azetidin-3-yl)urea

[0230] The target compound (21.48 mg, HPLC purity: 94.7%, yield: 16.03%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+H] + =588.0; 1 H NMR (400MHz, DMSO) δ11.12(s,1H),9.10(s,1H),7.52(d,J=1.7Hz,2H),7.44–7.36(m,3H),7.23(d,J=6.8Hz,1H),7.05-7.03(m,2H),6.87(d,J=6 .7Hz,1H),5.42-5.37(m,1H),4.69-4.64(m,1H),4.34-4.31(m,2H),3.8 4-3.81(m,2H),2.98-2.89(m,1H),2.79-2.62(m,2H),2.10-2.05(m,1H).

[0231] Example 22: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(4-fluoro-3-(trifluoromethoxy)phenyl)carbamate

[0232] The target compound (37 mg, HPLC purity: 97.0%, yield: 19.08%) was obtained as a yellow solid using a method similar to that of Example 2. MS: m / z [M+H] + =573.0; 1H NMR (400MHz, DMSO) δ11.13(s,1H),10.29(s,1H),7.77(d,J=6.8Hz,1H),7.51–7.39(m,5H),7.08(d,J=1.4Hz,1H),6.89(d,J=6.4Hz,1H) ,5.43–5.38(m,2H),4.44-4.40(m,2H),4.02-3.99(m,2H),2.99-2.90(m,1H),2.80-2.72(m,1H),2.69-2.66(m,1H),2.12-2.06(m,1H).

[0233] Example 23: 1-(1-(4-(2,6-dioxopiper-3-yl)-3,5-difluorophenyl)azetidin-3-yl)-3-(3-(pentafluoro-λ 6 -thio)phenyl)urea

[0234] The target compound (135 mg, HPLC purity: 96.0%, yield: 20.05%) was obtained as a white solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =541.0; 1 H NMR (400MHz, DMSO) δ10.87(s,1H),9.04(s,1H),8.20(s,1H),7.53–7.40(m,3H),7.04(d,J=7.2Hz,1H),6.18(d,J=11.0Hz,2H),4.60–4.55(m ,1H),4.16-4.12(m,2H),4.07-4.02(m,1H),3.70-3.67(m,2H),2.83– 2.73(m,1H),2.56-2.50(m,1H),2.13-2.03(m,1H),1.97-1.91(m,1H).

[0235] Example 24: 1-((3-(2,6-dioxol-3-yl)benzofuran-6-yl)methyl)-3-(3-(pentafluoro-λ 6 -thio)phenyl)urea

[0236] The target compound (39 mg, HPLC purity: 92.0%, yield: 15.03%) was obtained as a white solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =504.0; 1H NMR (400MHz, DMSO) δ10.91 (s, 1H), 9.09 (s, 1H), 8.21 (t, J = 2.0 Hz,1H),7.87(s,1H),7.55–7.39(m,5H),7.22-7.20(m,1H),6.88(t,J=5.9Hz,1H),4.41(d,J=5.9Hz, 2H),4.15-4.10(m,1H),2.79–2.67(m,1H),2.60–2.55(m,1H),2.37–2.27(m,1H),2.14–2.08(m,1H).

[0237] Example 25: 1-((3-(2,6-dioxol-3-yl)benzofuran-6-yl)methyl)-3-(4-(pentafluoro-λ 6 -thio)phenyl)urea

[0238] The target compound (45 mg, HPLC purity: 91.0%, yield: 16.07%) was obtained as a white solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =504.0; 1 H NMR (400MHz, DMSO) δ10.90(s,1H),9.15(s,1H),7.87(s,1H),7.74(d,J=9.2H z,2H),7.59(d,J=9.0Hz,2H),7.54(d,J=8.1Hz,1H),7.49(s,1H),7.21(d,J= 8.2Hz,1H),6.89(t,J=5.9Hz,1H),4.41(d,J=5.8Hz,2H),4.14-4.10(m,1H), 2.78–2.67(m,1H),2.60-2.58(m,1H),2.37-2.26(m,1H),2.13–2.07(m,1H).

[0239] Example 26: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl(4-fluoro-3-(morpholinomethyl)-5-(trifluoromethoxy)phenyl)carbamate

[0240] The target compound (30 mg, HPLC purity: 94.3%, yield: 16.51%) was obtained as a yellow solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =631.0; 1H NMR (400MHz, DMSO) δ11.15(s,1H),10.16(s,1H),8.30(s,1H),8.17(s,1H),7. 70(d,J=8.4Hz,1H),7.67-7.63(m,1H),7.59–7.55(m,1H),7.52-7.50(m,1H), 7.18(d,J=7.1Hz,1H),5.49-5.45(m,3H),3.58-3.53(m,6H),3.00–2.91(m,1H) ),2.82–2.75(m,1H),2.68-2.64(m,1H),2.39-2.38(m,4H),2.14–2.08(m,1H).

[0241] Example 27: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(3-(trifluoromethoxy)phenyl)carbamate

[0242] The target compound (52.25 mg, HPLC purity: 96.67%, yield: 27.5%) was obtained as a yellow solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =555.0; 1 H NMR (400MHz, DMSO) δ11.12(s,1H),10.29(s,1H),7.61(s,1H),7.47–7.37(m,5H),7.07(s,1H),7.01(s,1H),6.88(d,J=6.6Hz, 1H),5.41(s,2H),4.47-4.33(m,2H),4.00(m,2H),3.00-2.85(m,1H),2.79-2.69(m,1H),2.67-2.62(m,1H),2.14-2.03(m,1H).

[0243] Example 28: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl (3-chloro-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate

[0244] The target compound (47.74 mg, HPLC purity: 98.28%, yield 67.9%) was obtained as a yellow solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =565.1; 1H NMR(400MHz,DMSO)δ11.14(s,1H),10.02(s,1H),8.60(s,2H),8.29(s,1H),8.16(s,1 H),7.69(m,1H),7.62(m,1H),7.59-7.52(m,1H),7.34(m,2H),7.19(d,J=7.2Hz,1H), 5.57-5.35(m,3H),3.73-3.57(m,4H),3.14-3.02(m,2H),2.99-2.95(m,1H),2.91(t, J=7.0Hz,2H),2.85-2.72(m,1H),2.66-2.64(m,1H),2.53(m,3H),2.18-2.03(m,1H).

[0245] Example 29: (1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)methyl (3-(difluoromethoxy)-4-(2-(2-(methylamino)ethoxy)ethyl)phenyl)carbamate hydrochloride

[0246] The target compound (53 mg, HPLC purity: 98.98%, yield: 82.8%) was obtained as a yellow solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =597.2; 1 H NMR (400MHz, CD3OD_SPE) δ8.22(s,1H),8.16(s,1H),7.65(m,1H),7.54(m,1H),7.40(s,1H),7.22(m,2H),7.10(d,J=7.1Hz,1H),6.79(m,1H),5.47 (s,2H),5.42(m,1H),3.73–3.66(m,4H),3.17(m,2H),3.00–2.94(m,1H), 2.92(t,J=7.0Hz,2H),2.86–2.79(m,2H),2.67(s,3H),2.30–2.19(m,1H).

[0247] Example 30: 1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenz[cd]indol-4-yl)azetidin-3-yl(3-(2-(methylamino)ethoxy)-5-(trifluoromethoxy)phenyl)carbamate hydrochloride

[0248] The target compound (3.60 mg, HPLC purity: 98.49%, yield: 4.63%) was obtained as a yellow solid using a method similar to that of Example 2. ESI-MS: m / z [M+H] + =628.2; 1 H NMR (400MHz, DMSO) δ11.11(s,1H),10.30(s,1H),8.57(s,2H),7.50–7.35(m,3H),7.20(d,J=1.9Hz,2H),7.07(d,J=1.5Hz,1H),6.89(m,1H),6.68(s ,1H),5.44–5.35(m,2H),4.45–4.35(m,2H),4.26–4.20(m,2H),4.01(m,2 H),3.49–3.41(m,2H),3.00–2.70(m,3H),2.65(s,3H),2.14–2.04(m,1H).

[0249] Other compounds of the present application can be prepared by similar preparation procedures as described above, using the intermediates described above and making appropriate changes to the reactants, reaction conditions and amounts of reagents.

[0250] The positive controls CC90009 and MRT-2359 used in the following test examples are described in WO2016007848 A1 (Example 7) and WO2022152821 A1 (Example 145), respectively.

[0251] Test Example 1: Cell experiment (NCI-H1155 cell proliferation inhibition experiment)

[0252] NCI-H1155 cells were cultured in McCoys-5A (Gibco) medium (containing 10% fetal bovine serum; ExCell bio) supplemented with 1% penicillin and streptomycin in a cell culture incubator at 37°C, 5% CO2, and saturated humidity. After confluence, cells were subcultured into 96-well plates (5,000 cells / well). After overnight incubation, the compounds were added at concentrations of 0.04 nM, 0.15 nM, 0.61 nM, 2.44 nM, 9.77 nM, 39.1 nM, 156.3 nM, 625 nM, 2,500 nM, and 10,000 nM. 0.1% DMSO and culture medium were used as vehicle and negative controls, respectively. Each sample was plated in duplicate. The compounds were mixed and incubated in a 37°C, 5% CO2 incubator for 72 h. After treatment, the 96-well plate was placed at room temperature for 30 min, and 50 μL (Promega), and placed on an orbital shaker for 2 minutes, and then incubated at room temperature in the dark for 10 minutes. The 96-well plate was placed in a SpectraMax Paradigm (Molecular Devices) to test the luminance signal.

[0253] Cell activity inhibition rate (%) = 100-(RLU compound -RLU blank ) / (RLU control -RLU blank )*100%, Control is the 0.1% DMSO-treated group, and blank is the culture medium-treated group. The IC values ​​of the compounds were calculated using the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0. 50 and draw the dose-effect curve.

[0254] Table 1: Exemplary results of compound cell proliferation inhibition experiments

[0255] Experimental Example 2: PBMCs cell activity experiment

[0256] PBMCs were purchased from Miaoshun Biotechnology Co., Ltd. The PBMCs cells were resuspended in RPMI-1640 (Solarbio, 11965) cell culture medium (containing 10% FBS: Solarbio, S903), and the cells were placed in an incubator at 37°C and 5% CO2 for overnight culture. The cells were stained with AOPI and counted with a cell counter. The proportion of live cells must be above 80%. The cells after overnight culture were inoculated into a 96-well plate, 20,000 cells per well, and compounds at concentrations of 10,000 nM, 2,500 nM, 625 nM, 156.25 nM, 39 nM, 9.8 nM, 2.4 nM, 0.6 nM, and 0.15 nM were added to the cell suspension. The final DMSO concentration was 0.2%, and the test was repeated. After the 96-well plate was placed in a 37°C, 5% CO2 incubator and incubated for 72 hours, 50 μL (Promega, G7573) and mixed, incubated in the dark for 10 min, and then placed on SpectraMax Paradigm (Molecular Devices) to read the luminance signal value.

[0257] Table 2: Results of PBMC proliferation inhibition experiments with exemplary compounds

[0258] As can be seen from the above table, the compounds of the examples of the present application showed significantly higher IC 50The value means that the compounds of the examples of the present application have less toxic side effects on normal human immune cells and are safer.

[0259] Test Example 3: Liver microsome stability test

[0260] Phase I metabolic stability testing utilizes an in vitro liver microsomal incubation system to simulate the physiological conditions of liver microsomes and to incorporate the redox coenzyme NADPH for the relevant reactions. First, 445 μL of a 0.56 mg / mL mouse or human liver microsomal working solution (mouse: Xenotech, M1000; human: Corning, 452117) was added to two 96-well culture plates. These plates were designated as T60 incubation plates (with NADPH added) and non-co-factor 60 (NCF 60) incubation plates (without NADPH), respectively.

[0261] After pre-incubation of the above-mentioned incubation plate in a 37°C water bath for approximately 10 minutes, 5 μL of the test compound or control compound (testosterone, diclofenac, and propafenone) at a concentration of 100 μM was added. 50 μL of potassium phosphate buffer was added to each well of the NCF60 incubation plate to initiate the reaction. A T0 stop 96-well plate was prepared, and 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regeneration system working solution (NADPH powder dissolved in 10 mM MgCl2 solution to prepare a 10 mM NADPH solution) were pre-added. 54 μL of sample was removed from the T60 incubation plate and transferred to the T0 stop plate (T0 sample generation). The reaction was initiated by adding 44 μL of NADPH regeneration system working solution to each well of a T60 incubation plate. Blank wells were filled with only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of stop solution. Therefore, in the test or control compound samples, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively. After incubation for the appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), the reaction was terminated by adding 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) to each sample well. All sample plates were shaken and centrifuged at 3220 × g for 20 min, and then 80 μL of supernatant from each well was diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis.

[0262] Table 3: Results of liver microsomal metabolic stability experiments of exemplary compounds

[0263] Experimental Example 4: Protein degradation (In-cell Western) experiment

[0264] NCI-H1155 cells were seeded into 6-well plates at a plate size of 3 × 10 5 Cells / well were added and drug was administered 24 hours after seeding. The final drug concentration was 10 nM. The cells and drugs were co-incubated in an incubator at 37°C and 5% CO2. After 24 hours, 100 μL of trypsin working solution (0.25%) was added to each well for digestion. The cells were collected and washed once with PBS. The centrifugation conditions were 4°C, 1000 rpm, and 5 minutes. The cells were collected by quick spinning at 4°C and 13000 rpm for 10 seconds. 0.5 mL of RIPA (containing 1 mM PMSF) was added to each sample, mixed well, and lysed on ice for 5 minutes. Repeat 3 times. Centrifuge at 4°C and 13000 rpm for 30 minutes, take the supernatant, and store at 4°C for later use. BCA was used for quantification and the protein concentration of each sample was adjusted to the same level. After sample denaturation, SDS-PAGE gel electrophoresis was performed. First, a constant voltage of 80V was applied for 30 minutes. After the markers were separated, a constant voltage of 120V was applied for 60 minutes. After gel electrophoresis, cut a PVDF membrane of appropriate size and wet-transfer it at 250 mA for 90 minutes. The transferred PVDF membrane was then blocked for 1 hour with 5% milk powder, incubated with the primary antibody overnight, washed with TBST for 30 minutes, incubated with the secondary antibody for 1 hour, and finally washed with TBST for 30 minutes. Prepare ECL luminescence solution and incubate the strips with it at room temperature for approximately 5 minutes. Excess solution was drained and exposed. The strips were analyzed using Image J.

[0265] The compounds in the examples of the present application exhibited strong protein degradation capabilities against GSPT1 and MYC in NCI-H1155 cells.

[0266] Experimental Example 5: Mouse PK experiment

[0267] The clear solution of the compound of the present application example was injected into ICR mice via the tail vein (overnight fasting) or orally administered to ICR mice (fed). The intravenous and oral administration doses were 0.5 mg / kg and 1 mg / kg, respectively, and the administration solvent was 5% DMSO + 10% Solutol + 85% Saline. 50 μL of blood was collected from the cheek by intravenous injection or oral administration at 0 h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. The blood samples were placed on ice after collection and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 6000 g, 3 min, 2-8 ° C). Plasma drug concentrations were determined by LC-MS / MS internal standard method, and relevant pharmacokinetic parameters were calculated by non-compartmental linear logarithmic trapezoidal method using Phoenix WinNonlin8.2.0 pharmacokinetic software.

[0268] Test Example 6: In vivo efficacy experiment in mice

[0269] The NOD / SCID mice used in this experiment were provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. They were female, 6-8 weeks old, and weighed 18-22 grams. Upon arrival, the animals were isolated and quarantined for 7 days before the experiment began. NCI-H1155 cells (with Matrigel, Corning, BD356230, at a volume ratio of 1:1) in the logarithmic growth phase were subcutaneously inoculated on the right back of the mice. The average tumor volume reached approximately 150-200 mm. 3 The patients were given oral QD for 21 consecutive days, and the tumors were measured and weighed three times a week. The tumor volume was measured with a vernier caliper using the formula TV = 0.5a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. Tumor weight was measured after the experiment. The anti-tumor efficacy of the compound was evaluated using the TGI (%). TGI (%) reflects the rate of tumor growth inhibition: TGI (%) = [(1 - (average tumor volume of a treatment group at the end of dosing - average tumor volume of the treatment group at the start of dosing) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the start of treatment)] × 100%.

[0270] The compounds of the examples of the present application all exhibited tumor-suppressing effects in the NCI-H1155 mouse subcutaneous transplant tumor model.

[0271] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A compound represented by formula (I), its deuterated form, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof: in: Ring A is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl or C3-C 10 Carbocyclic group; Ring B is selected from 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl or C3-C 10 Carbocyclic group; Ring C is selected from represents a single bond or a double bond; X is selected from CR 10 or NR 10 ; R a , R b independently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylaminomethyl acyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; the C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C8 -C6 alkyl acyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C substituted with a substituent of C1-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R c are independently selected from H or deuterium; L is selected from a chemical bond, a 4-10 membered heterocyclic group, -CR2R3-, -O-, -S- or -NR4-; L1 is selected from chemical bonds, -CR 2’ R 3’ -, -O-, -S-, or -NR 4’ -; R1 is selected from a chemical bond, -CR5R6-, -OCR5R6-, -SCR5R6-, -NCR5R6-, -O-, -S- or -NR7-; R2, R3, R4, R 2’ , R 3’ , R 4’ R5, R6, and R7 are each independently selected from H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-8 membered heterocyclyl; the C1-C6 alkyl C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-8 membered heterocyclyl may be optionally unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, amino, hydroxyl, thiol; Alternatively, R2 and R3 together with the carbon atom to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group; Or, R2 and R a or R4 and R a Together with ring A, it forms C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group; Alternatively, R5 or R6 and R2 or R3 together with the carbon atom to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group; Alternatively, R5 and R4 or R6 and R4 together with the atoms to which they are attached form a C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group; When multiple R2, R3, R4, R 2’ , R 3’ , R 4’ , R5, R6 or R7, each R2, R3, R4, R 2’ , R 3’ , R 4’ , R5, R6 or R7 are the same or different; R8 is selected from a chemical bond, a C1-C3 alkylene group or -C(O); R9 is selected from H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkyl Acyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or substituted with substituents selected from one or more H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; R 10 Selected from H, deuterium or absent; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2, 3 or 4; q is selected from 1 or 2.

2. The compound according to claim 1, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound has a structure shown in formula (II): in: Ring A is selected from * indicates the site of connection with L; Ring B is selected from 6-12 membered aryl or 5-10 membered heteroaryl; R a , R b , X, L, L1, R1, m, n are as defined in claim 1.

3. The compound according to claim 1, its deuterated form, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound has a structure shown in formula (III): in: R b1 is selected from H, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; the C1-C6 C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, halogen, cyano, SF5, -O-(CH2) 2- O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl substituent; R b2 Selected from C1-C6 haloalkoxy or SF5; R8 is selected from a chemical bond, a C1-C3 alkylene group or -C(O); R9 is selected from H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C 1- C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; the C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl may be optionally unsubstituted or selected from one or more H, halogen, cyano, SF5, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C 1- C6 haloalkoxy, C 1- Substituted with a C6 haloalkyl, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl, C1-C6 alkylacyl, C1-C6 alkylcarbamoyl, C1-C6 alkylthiol, C1-C6 alkylsulfone, C3-C8 cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; n1 is selected from 0, 1 or 2; Ring A, Ring B, Ring C, R a , R c , L, L1, R1, m, p are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The ring C is selected from represents a single bond or a double bond, X is selected from CR 10 or NR 10 , R 10 Selected from H, deuterium or absent; preferably, ring C is selected from More preferably, the ring C is selected from More preferably, the ring C is and / or The ring A is selected from * indicates the site of connection with L; preferably, the ring A is and / or The ring B is selected from a 6-12-membered aryl group, or a 5-10-membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms, or S atoms; preferably, the ring B is selected from a 6-10-membered aryl group, or a 5-6-membered heteroaryl group containing 1-2 heteroatoms selected from N atoms, O atoms, or S atoms; more preferably, the ring B is selected from a benzene ring or pyridine, and further preferably, the ring B is a benzene ring.

5. The compound according to any one of claims 1 to 4, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: L is selected from a chemical bond, a 4-8 membered heterocyclic group containing 1-3 members selected from N atoms, O atoms or S atoms, -CR2R3-, -O-, -S- or -NR4-; preferably, L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR2R3- or -NR4-, and R2 and R3 are each independently selected from H, halogen, cyano or C1-C6 alkyl; more preferably, L is selected from -CH2-, azetidinyl; and / or R1 is selected from a chemical bond, -CR5R6-, -O-, -S- or -NR7-, R5, R6, R7 are each independently selected from H, halogen or C1-C6 alkyl; preferably, R1 is selected from -O-, -S- or -NR7-, R7 is selected from H or C1-C5 alkyl; more preferably, R1 is selected from -O-, -S- or -NH-; further preferably, R1 is -O- or -NH-; and / or L1 is selected from chemical bonds, -CR 2’ R 3’ -, or -NR 4’ -, R 2’ , R 3’ , R 4’ Each is independently selected from H, halogen, C1-C6 alkyl; preferably, L1 is selected from -NR 4’ -, R 4’ is H or C1-C6 alkyl; more preferably, L1 is -NH-.

6. The compound according to any one of claims 1 to 5, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: R b independently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkoxyalkyl, C1-C6 alkylamino, C1-C6 aminoalkyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino; R8 is selected from a chemical bond, C1-C3 alkylene or -C(O ); R9 is selected from -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C3-C8 cycloalkyl, 3-12 membered heterocyclyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 aminoalkyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl is unsubstituted or substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylamino; n is selected from 0, 1, 2, 3 or 4; Or, R b Independently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; the C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from H, halogen, C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, C1-C3 alkylene or -C(O); R9 is selected from C1-C6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C1-C6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkylamino; n is selected from 1, 2, 3 or 4; Or, R b Independently selected from H, deuterium, halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, C1-C3 alkylene; R9 is selected from C1-C6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C1-C6 alkoxy is unsubstituted or substituted by C1-C6 alkylamino, the 4-8 membered heterocyclic group is unsubstituted or substituted by C1-C6 alkyl; n is selected from 1, 2 or 3; Or, R b Independently selected from halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy is unsubstituted or substituted by one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, C1-C3 alkylene; R9 is selected from C1-C6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms or O atoms or S atoms, the C1-C6 alkoxy is unsubstituted or substituted by C1-C6 alkylamino; n is selected from 1, 2 or 3.

7. The compound according to any one of claims 1 to 6, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: R a is independently selected from H, deuterium, halogen, C1-C6 alkyl; m is selected from 0, 1, 2 or 3; and / or R c Independently selected from H or deuterium, p is selected from 0, 1 or 2, preferably, p is 0.

8. The compound according to any one of claims 1 to 7, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound is selected from: Among them, R 11 and R 12 are each independently H, deuterium, halogen or C1-C6 alkyl, or R 11 and R 12 The carbon atoms to which it is connected together form a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; L is selected from a chemical bond, a 4-6 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, -CR2R3- or -NR4-; R2 and R3 are each independently selected from H, halogen, cyano or C1-C6 alkyl; R4 is selected from H, C4-C6 cycloalkyl, or a 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; R1 is selected from -O-, -S- or -NR7-; R7 is selected from H, halogen, or C1-C6 alkyl; R b Independently selected from H, deuterium, halogen, cyano, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; the C1-C6 alkoxy is unsubstituted or substituted with one or more substituents selected from H, halogen, C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, a C1-C3 alkylene group or -C(O); R9 is selected from C1-C6 alkoxy, 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms; the C1-C6 alkoxy, 4-8 membered heterocyclic group is unsubstituted or substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkylamino; n is selected from 1, 2, 3 or 4; or, wherein R1 is selected from a chemical bond, -CR5R6-, -O-, -S- or -NR7-; R5, R6, R7 are each independently selected from H or C1-C6 alkyl; R b Selected from H, deuterium, halogen, cyano, SF5, C1-C6 alkyl; the C1-C6 alkyl is unsubstituted or substituted by halogen; or, R b Selected from H, deuterium, halogen, cyano, SF5, C1-C6 alkyl; the C1-C6 alkyl is unsubstituted or substituted by halogen.

9. The compound according to claim 8, its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: In the compound represented by formula (IV), R 11 and R 12 Each independently is H, or R 11 and R 12 Together with the carbon atom to which it is attached, it forms a phenyl group; L is selected from -CH2-, azetidinyl; R1 is selected from -O-, -S- or -NH-; R b Independently selected from H, deuterium, halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the C1-C6 alkoxy is unsubstituted or substituted with one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, a C1-C3 alkylene group; R9 is selected from C1-C6 alkoxy, a 4-8 membered heterocyclic group containing 1-3 heteroatoms selected from N atoms, O atoms or S atoms, the C1-C6 alkoxy is unsubstituted or substituted by C1-C6 alkylamino, and the 4-8 membered heterocyclic group is unsubstituted or substituted by C1-C6 alkyl; n is selected from 1, 2 or 3.

10. The compound according to claim 8 or 9, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: In the compound represented by formula (IV), R 11 and R 12 Together with the carbon atom to which it is attached, it forms a phenyl group; L is selected from -CH2-, azetidinyl; R1 is selected from -O-, or -NH-; R b Independently selected from halogen, SF5, -R8-R9, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, wherein the C1-C6 alkoxy is unsubstituted or substituted with one or more substituents selected from C1-C6 alkoxy, or C1-C6 alkylamino; R8 is selected from a chemical bond, a C1-C3 alkylene group; R9 is selected from C1-C6 alkoxy, a 5-7 membered heterocyclic group containing 1-2 heteroatoms selected from N atoms, O atoms or S atoms, wherein the C1-C6 alkoxy is unsubstituted or substituted by a C1-C6 alkylamino group; n is selected from 1, 2 or 3.

11. The compound according to any one of claims 1 to 10, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound is the following compound: Wherein, L is selected from -CH2-, azetidinyl; R1 is selected from -O-, or -NH-; R b Independently selected from fluorine, chlorine, bromine, iodine, SF5, (C1-C6 alkyl)-NH-(C1-C6 alkoxy)-(C1-C3 alkylene)-, (C1-C6 alkyl)-NH-(C1-C6 alkoxy)-, (5-7 membered heterocyclyl)-(C1-C3 alkylene)-, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 haloalkoxy, the 5-7 membered heterocyclyl contains 1-2 heteroatoms selected from N atoms or O atoms; n is selected from 1, 2 or 3.

12. The compound according to any one of claims 1 to 11, its deuterated product, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound is the following compound: or Wherein, R1 is selected from -O-, or -NH-; R b independently selected from fluorine, chlorine, bromine, SF5, CH3NH(CH2)2-O-(CH2)2-, CH3NH(CH2)2-O-, -O-(CH2)2-O-CH3, C1-C6 alkyl, C1-C6 fluoroalkoxy; n is selected from 1, 2 or 3.

13. The compound according to any one of claims 1 to 8, its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The compound is selected from:

14. The compound according to any one of claims 1 to 13, its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof for use in treating and / or preventing a disease associated with GSPT1.

15. The compound for use according to claim 14, its deuterated substance, its stereoisomer, its tautomer, its pharmaceutically acceptable salt, or a mixture thereof, wherein: The disease associated with GSPT1 is cancer; preferably, the cancer comprises a solid tumor or a hematological malignancy; more preferably, the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, upper respiratory tract cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, neuroblastoma, glioblastoma, hemangiopericytoma , multiple brain metastases, glioblastoma multiforme, brain stem glioma, malignant brain tumor with poor prognosis, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, Kapos sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion-mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, leiomyosarcoma, fallopian tube carcinoma, leiomyoma, leiomyoma, leiomyoma, leukemia, lymphoma.

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