Piperidinedione compound and preparation method therefor, and use

Abstract

Provided are a compound as shown in formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope marker, metabolite or prodrug thereof. The compound can be used for degrading proteins such as GSPT1, so as to prevent, alleviate or treat diseases related to protein disorders. In addition, the compound can also be used as a payload for a ligand-drug conjugate, so as to further expand the indication scope thereof.

Description

Piperidinedione compounds, preparation methods and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2023112601408, filed September 26, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of medical technology, and in particular relates to a piperidinedione compound, a preparation method thereof and an application thereof. Background Art

[0003] Protein function is tightly regulated in both space and time during cell growth and proliferation. Dysregulation of these processes can lead to uncontrolled cell growth, proliferation, and migration, potentially contributing to the development of diseases such as tumors.

[0004] Inducing protein degradation as a therapeutic strategy has been clinically validated by a class of immunomodulatory drugs (IMiDs), including lenalidomide and pomadomide. These compounds have the ability to bind to cereblon (CRBN) and promote the degradation of cullin-damaged DNA-binding-RING box-domain protein (CUL4-DDB1-RBX1-CRBN), or (CRL4) for short. CRBN ) The ability of E3 ubiquitin ligase to mediate the recruitment and ubiquitination of substrate proteins, thereby achieving the purpose of treating diseases by promoting the degradation of target proteins.

[0005] Studies have found that subtle structural changes in different immunomodulatory drugs can significantly alter the substrate specificity of E3 ligases, resulting in significant changes in drug metabolic activity and biological activity. For example, while both pomalidomide and lenalidomide mediate the ubiquitination and degradation of IKZF1 / 3, only lenalidomide can degrade CK1α, which may be a promising target for myelodysplastic syndrome with 5q deletion. CC-90009 specifically mediates the degradation of GSPT1 (also known as eRF3a, a translation termination factor) for the treatment of acute myeloid leukemia. BTX-1188 can simultaneously degrade GSPT1 and IKZF1 / 3, demonstrating promising preclinical anti-tumor efficacy in various solid tumors (breast, ovarian, and lung cancers).

[0006] As an important target for anti-tumor and immunomodulatory drugs, CRBN has been shown to be effective in treating various hematological malignancies, including multiple myeloma and chronic lymphocytic leukemia, skin diseases such as erythema nodosum leprosum, and autoimmune diseases such as systemic lupus erythematosus. However, current doxorubicin-based drugs have significant side effects. Therefore, there remains a significant clinical need and application value for the development of novel CRBN modulators that can enhance efficacy, improve safety, and expand the scope of indications.

[0007] Summary of the Invention

[0008] The present invention provides a piperidinedione compound, its preparation method, and its use. The compounds of the present invention can be used to degrade proteins such as GSPT1, thereby preventing, alleviating, or treating diseases associated with disorders of these proteins. Furthermore, the compounds of the present invention can serve as payloads in ligand-drug conjugates (e.g., antibody-drug conjugates), further expanding the range of indications for the compounds of the present invention.

[0009] In one aspect, the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof,

[0010] in,

[0011] R 1 Selected from hydrogen, deuterium, halogen, -C 1-6 Alkyl or -halogenated C 1-6 alkyl;

[0012] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0013] U is selected from -CH2- or -C(O)-;

[0014] R a are each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Cycloalkyl or 4- to 12-membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2 and oxo;

[0015] m is selected from 0, 1, 2 or 3;

[0016] R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, -OH, -CN and -NH2;

[0017] p is selected from 1 or 2;

[0018] L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-, vinylene, ethynylene, -C 3-8 Cycloalkylene-, 4 to 12 membered heterocycloalkylene; said C 1-6 Alkyl, C 1-3 Alkylene, C 3-8 Cycloalkylene, 4 to 12 membered heterocycloalkylene are each optionally substituted by one or more selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, oxo, hydroxy, -CN and -NH2 substituents;

[0019] Ring B is selected from -C 6-10 aryl, 5-10 membered heteroaryl or 4 to 14 membered heterocycloalkyl; the ring B is optionally substituted by one or more R b replace;

[0020] R b are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -COOH, -CONH2, -R d 、-P(O)(R d )2、-N(R d )2、- OR d 、-SR d 、-Si(R d )3、-(C 1-6 alkylene) m1 -(X) m2 -(C 1-6 alkylene) m3 -(Z) m4 -R d or The C 1-6 The alkylene group is optionally substituted with one or more halogens;

[0021] m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time;

[0022] X and Z are each independently selected from -O-, -S-, -NR c -、-C(O)-、-NR c C(O)-、-C(O)NR c -、-S(O)-、-S(O)2 - 、-S(O)2NR c -、-NR c S(O)2-, or -OC(O)-;

[0023] R c Selected from hydrogen, -C 1-6 Alkyl, -halogenated C 1-6 alkyl;

[0024] R d Each independently selected from hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl, 5-10 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -SH, nitro, -OC 1-6 Alkyl, -O(halogenated C 1-6 Alkyl), -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-SH, -C 1-6 Alkyl-SC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1- 6-alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6Alkyl)2, -C(O)NH2, -COOH, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl substitution;

[0025] Or, any two adjacent R b Together with the atoms it is connected to form C 5-12 Cycloalkyl, 5 to 12-membered heterocycloalkyl, 5 to 6-membered heteroaryl or phenyl; the C 5-12 Cycloalkyl, 5 to 12 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl are each optionally substituted by one or more selected from halogen, oxo, -OH, -CN, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-SH, -C 1-6 Alkyl-SC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-NH(C 1- 6 alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, -C 3-6 The substituents of the cycloalkyl and 4- to 6-membered heterocycloalkyl groups are substituted.

[0026] In some embodiments, R 1 Selected from hydrogen, deuterium or -C 1-6 Alkyl; preferably, R 1 For H.

[0027] In some embodiments, Ring A is selected from: Preferably, Ring A is: More preferably, Ring A is Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0028] In some embodiments, R aare each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl, -OC 1- 6 alkyl; preferably, R a are independently selected from hydrogen, halogen, -OH, -NH2, -C 1-6 Alkyl or -OC 1-6 Alkyl; More preferably, R a are each independently selected from hydrogen, halogen or -OC 1-6 alkyl.

[0029] In some embodiments, m is selected from 0, 1 or 2; preferably, m is 0.

[0030] In some embodiments, R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; preferably, R 2 、R 3 are each independently selected from hydrogen, deuterium or halogen; more preferably, R 2 、R 3 For hydrogen.

[0031] In some embodiments, L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-; preferably, L is a chemical bond.

[0032] In some embodiments, Ring B is selected from -C 6-10 Aryl or 5-10 membered heteroaryl; preferably, ring B is -C 6-10 Aryl; More preferably, ring B is phenyl; said ring B is optionally substituted by one or more R b replace.

[0033] In some embodiments, R b are each independently selected from hydrogen, halogen, nitro, -CN, -R d 、-N(R d )2、-OR d 、-SR d or -(C 1- 6 alkylene) m1 -(X) m2 -(C 1-6 alkylene) m3 -(Z) m4 -R d Preferably, R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2、-OR d 、-SRd or -(C 1-6 alkylene) m1 -(X) m2 -(C 1-6 alkylene) m3 -(Z) m4 -R d .

[0034] In some embodiments, X and Z are each independently selected from -O-, -S-, -NH-, -C(O)-, -NR c C(O)- or -C(O)NR c -; Preferably, X and Z are each independently selected from -O-, -S- or -NH-.

[0035] In some embodiments, R c Selected from hydrogen or -C 1-6 Alkyl; preferably H or -CH3; more preferably H.

[0036] In some embodiments, R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl substitution;

[0037] Preferably, R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -C1-6 Alkyl and -halogenated C 1-6 Alkyl substitution.

[0038] In some embodiments, any two adjacent R b Together with the atoms it is connected to form C 5-8 Cycloalkyl, 5 to 8 membered heterocycloalkyl or phenyl; the C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl or phenyl are each optionally substituted by one or more radicals selected from halogen, -OH, -NH2, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 alkyl)2 is substituted with a substituent.

[0039] In some embodiments, each halogen is fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0040] In some embodiments, each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.

[0041] In some embodiments, each -OC 1-6 Alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl; for example -O-methyl.

[0042] In some embodiments, each C 2-6 Alkenyl is independently ethenyl, propenyl, allyl, butenyl or pentenyl.

[0043] In some embodiments, each C 2-6 Alkynyl is independently ethynyl, propynyl, propargyl, butynyl or pentynyl, for example

[0044] In some embodiments, each C 3-12 Cycloalkyl is independently C 3-8 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0045] In some embodiments, the cycloalkyl group is a saturated cycloalkyl group.

[0046] In some embodiments, the cycloalkyl group is a partially saturated cycloalkyl group; the number of unsaturated bonds in the partially saturated cycloalkyl group is one or more.

[0047] In some embodiments, each 4- to 12-membered heterocycloalkyl group is independently a 5- to 8-membered heterocycloalkyl group.

[0048] In some embodiments, the heteroatom of each 4- to 12-membered heterocycloalkyl group may independently be N, O or S, and the number of heteroatoms may independently be 1, 2 or 3; preferably, the heteroatom of each 4- to 12-membered heterocycloalkyl group may independently be N or O, and the number of heteroatoms may independently be 1 or 2.

[0049] In some embodiments, each 4- to 12-membered heterocycloalkyl group is independently monocyclic or polycyclic, and the polycyclic rings may be bridged, fused, or spirocyclic; the polycyclic rings may be bicyclic or tricyclic; preferably, each 4- to 12-membered heterocycloalkyl group is independently 5- to 6-membered monocyclic heterocycloalkyl, 9- to 10-membered bicyclic heterocycloalkyl, or 11- to 12-membered tricyclic heterocycloalkyl.

[0050] In some embodiments, the cycloalkyl group is a saturated heterocycloalkyl group.

[0051] In some embodiments, the cycloalkyl group is a partially saturated heterocycloalkyl group; the number of unsaturated bonds in the partially saturated heterocycloalkyl group is one or more.

[0052] In some embodiments, each m is independently selected from 0 or 1, preferably 0.

[0053] In some embodiments, each -C 1-3 Alkylene- is independently -methylene-, -ethylene-, -n-propylene- or -isopropylene-.

[0054] In some embodiments, each -C 3-8 Cycloalkylene- is independently -C 3-6 Cycloalkylene-, for example, -cyclopropylene-, -cyclobutylene-, -cyclopentylene- or -cyclohexylene-, is preferably -cyclopropylene- or -cyclobutylene-.

[0055] In some embodiments, the cycloalkylene group is a saturated cycloalkylene group.

[0056] In some embodiments, the cycloalkyl group is a partially saturated cycloalkylene group; the number of unsaturated bonds in the partially saturated cycloalkylene group is one or more.

[0057] In some embodiments, each 4- to 12-membered heterocycloalkylene group is independently a 5- to 8-membered heterocycloalkylene group.

[0058] In some embodiments, the heteroatom of each 4- to 12-membered heterocycloalkylene group may independently be N, O or S, and the number of heteroatoms may independently be 1, 2 or 3; preferably, the heteroatom of each 4- to 12-membered heterocycloalkylene group may independently be N or O, and the number of heteroatoms may independently be 1 or 2.

[0059] In some embodiments, each 4- to 12-membered heterocycloalkylene group is independently monocyclic or polycyclic, and the polycyclic rings may be bridged, fused, or spirocyclic; the polycyclic rings may be bicyclic or tricyclic; preferably, the 4- to 12-membered heterocycloalkylene group is independently a 5- to 6-membered monocyclic heterocycloalkyl group, a 9- to 10-membered bicyclic heterocycloalkyl group, or an 11- to 12-membered tricyclic heterocycloalkyl group.

[0060] In some embodiments, the cycloalkylene group is a saturated heterocycloalkylene group.

[0061] In some embodiments, the cycloalkylene group is a partially saturated heterocycloalkylene group; the number of unsaturated bonds in the partially saturated heterocycloalkylene group is one or more.

[0062] In some embodiments, each halo is independently fluoro, chloro, bromo, or iodo.

[0063] In some embodiments, each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl.

[0064] In some embodiments, the heteroatom of each 5-10 membered heteroaryl group can independently be N, O or S, and the number of heteroatoms can independently be 1, 2 or 3.

[0065] In some embodiments, each 5-10 membered heteroaryl group is independently monocyclic or bicyclic, wherein the bicyclic rings are fused.

[0066] In some embodiments, each 4- to 14-membered heterocycloalkyl group is a 5- to 12-membered heterocycloalkyl group; preferably, a 5- to 6-membered heterocycloalkyl group.

[0067] In some embodiments, the heteroatom of each 4- to 14-membered heterocycloalkyl group is N, O, or S, and the number of heteroatoms is 1, 2, or 3; preferably, the heteroatom is N, and the number of heteroatoms is 1 or 2.

[0068] In some embodiments, each 4- to 14-membered heterocycloalkyl group is monocyclic or polycyclic (eg, bicyclic or tricyclic), and the polycyclic rings may be bridged, fused, or spirocyclic.

[0069] In some embodiments, each 4- to 14-membered heterocycloalkyl group contains 0, 1 or 2 unsaturated rings, preferably 1 unsaturated ring and at least one saturated ring; the unsaturated ring is preferably an aromatic ring, such as a benzene ring.

[0070] In some embodiments, when each 4- to 14-membered heterocycloalkyl group contains one unsaturated ring and at least one saturated ring, the heteroatom is located in the saturated ring.

[0071] In some embodiments, each 4- to 14-membered heterocycloalkyl group contains 0, 1, or 2 unsaturated bonds.

[0072] In some embodiments, each 4- to 14-membered heterocycloalkyl group may be a monocyclic heterocycloalkyl group, a bicyclic heterocycloalkyl group, or a tricyclic heterocycloalkyl group; preferably, a 5- to 6-membered monocyclic heterocycloalkyl group, a 9- to 10-membered bicyclic heterocycloalkyl group, or an 11- to 14-membered tricyclic heterocycloalkyl group; for example For example

[0073] In some embodiments, each -C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0074] In some embodiments, in Ring B, the -C 6-10 Aryl is phenyl.

[0075] In some embodiments, in ring B, the 5-10 membered heteroaryl group is thienyl, pyridyl or indolyl, for example

[0076] In some embodiments, in Ring B, the 4- to 14-membered heterocycloalkyl group is Preferably

[0077] In some embodiments, in R d In the 4- to 12-membered heterocycloalkyl group, the heteroatom is N, O or S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom is N or O, and the number of heteroatoms is 1 or 2.

[0078] In some embodiments, in R d wherein the 4- to 12-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group; preferably a morpholinyl group, a piperidinyl group, an azetidinyl group or a tetrahydropyrrolyl group; preferably

[0079] In some embodiments, in R d In the embodiment, the 5-10 membered heteroaryl group is a pyridyl group; for example

[0080] In some embodiments, when two adjacent R b Together with the atoms it is connected to form C5-12 When cycloalkyl, the C 5-12 Cycloalkyl is cyclohexyl, cyclopentyl, cyclohexenyl or cyclopentenyl.

[0081] In some embodiments, when two adjacent R b When the atoms to which it is attached form a 5- to 12-membered heterocycloalkyl group, the 5- to 12-membered heterocycloalkyl group is 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl, pyrrolyl or

[0082] In some embodiments, when two adjacent R b When the atoms to which it is attached form a 5- to 6-membered heteroaryl group, the 5- to 6-membered heteroaryl group is pyridyl.

[0083] In some embodiments, the compound of the structure shown in formula (I), wherein R a are each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -CH3 or -OCH3; preferably, R a is selected from hydrogen, -F, -OH, -NH2, -CH3 or -OCH3; more preferably, R a is selected from hydrogen, -F or -OCH3.

[0084] In some embodiments, the compound of the structure shown in formula (I), wherein R 2 、R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; preferably, R 2 、R 3 are each independently selected from hydrogen, deuterium or -F; more preferably, R 2 、R 3 For hydrogen.

[0085] In some embodiments, the compound of the structure shown in formula (I), wherein L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-; preferably, L is selected from a chemical bond, -NH- or -CH2-; more preferably, L is a chemical bond.

[0086] In some embodiments, the compound of formula (I), wherein ring B is selected from -C 6-10 Aryl, 5-6 membered heteroaryl, 5 to 6 membered heterocycloalkyl; preferably, ring B is selected from phenyl, pyridyl, Preferably, ring B is selected from phenyl and pyridyl; more preferably, ring B is phenyl; said ring B is optionally substituted by one or more R b replace.

[0087] In some embodiments, the compound of the structure shown in formula (I), wherein R b are each independently selected from hydrogen, halogen, nitro, -CN, -R d 、-N(R d )2、-OR d 、-SR d or -(C 1-3 alkylene) m1 -(X) m2 -(C 1-3 alkylene) m3 -(Z) m4 -R d Preferably, R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2、-OR d 、-SR d or -(C 1-3 alkylene) m1 -(X) m2 -(C 1-3 alkylene) m3 -(Z) m4 -R d .

[0088] In some embodiments, the compound of the structure shown in formula (I), wherein X and Z are each independently selected from -O-, -S-, -NH-, -N(CH3)-, -C(O)-, -NHC(O)- or -C(O)NH-; preferably, X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-.

[0089] In some embodiments, the compound of the structure shown in formula (I), wherein R b Each independently selected from hydrogen, -F, -Cl, nitro, -CN, -N(R d )2、-OR d 、-SR d 、-(C 1-3 alkylene) m1 -(O) m2 -(C 1-3 alkylene) m3 -(O) m4 -R d 、-(C 1-3 alkylene) m1 -(O) m2 -(C 1-3 alkylene) m3 -(NH) m4 -R d 、-(C 1-3 alkylene)m1 -(NH) m2 -(C 1-3 alkylene) m3 -(O) m4 -R d 、-(C 1-3 alkylene) m1 -(NH) m2 -(C 1-3 alkylene) m3 -(NH) m4 -R d Preferably, R b Each independently selected from -F, -Cl, -N(R d )2、-OR d 、-SR d 、-(C 1-3 alkylene) m1 -(O) m2 -(C 1-3 alkylene) m3 -(O) m4 -R d 、-(C 1-3 alkylene) m1 -(O) m2 -(C 1-3 alkylene) m3 -(NH) m4 -R d 、-(C 1-3 alkylene) m1 -(NH) m2 -(C 1- 3 alkylene) m3 -(O) m4 -R d 、-(C 1-3 alkylene) m1 -(NH) m2 -(C 1-3 alkylene) m3 -(NH) m4 -R d .

[0090] In some embodiments, the compound of the structure shown in formula (I), wherein R d are each independently selected from hydrogen, -C 1-4 Alkyl, cyclopropyl, cyclobutyl, 4 to 6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; the C 1-6 Alkyl, cyclopropyl, cyclobutyl, 4 to 6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6-alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl substitution;

[0091] Preferably, R d are each independently selected from hydrogen, -C 1-4 Alkyl, -cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thienyl, furyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, azetyl, oxetanyl, oxolanyl; the -C 1-4 Alkyl, -cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thienyl, furyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, azetyl, oxetanyl, oxolanyl, each of which is optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution;

[0092] More preferably, R d Each independently selected from hydrogen, -CH3, -CH2CH3, -iPr, -tBu, -CF3, -cyclopropyl, phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl; the -CH3, -CH2CH3, cyclopropyl, phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution;

[0093] More preferably, R d Each independently selected from hydrogen, -CH3, -CH2CH3, -iPr, -tBu, -CF3, -cyclopropyl, phenyl, pyridyl, piperidyl, morpholinyl and azetidinyl; -CH3, -CH2CH3, -cyclopropyl, phenyl, pyridyl, piperidyl, morpholinyl and azetidinyl are each optionally substituted by one or more selected from halogen, -NH2, -OC 1-6 Alkyl, -NHC1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1- 6-alkyl, -halogenated C 1-6 Alkyl substitution.

[0094] In some embodiments, any two adjacent R b Together with the atoms it is connected to form C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl, or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2;

[0095] Preferably, any two adjacent R b Together with the atoms to which it is attached, it forms a cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl, pyrrolyl, Pyridyl or phenyl; the cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl, pyrrolyl, The pyridyl or phenyl groups are each optionally substituted with one or more substituents selected from halogen, -NH2, -CH3, -CH2CH3, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0096] In some embodiments, the compound of the structure shown in formula (I), wherein R b are independently selected from hydrogen, halogen, -NH2, -C 1-4 Alkyl, -CF3, -OCF3, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2, 4-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-(5-6 membered heteroaryl), -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-(4-6 membered heterocycloalkyl), -CH2-(4-6 membered heterocycloalkyl), -CH2-O-phenyl and phenyl; the C 1-4 Alkyl, C 3-6Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by one or more radicals selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution;

[0097] Preferably, R b Each is independently selected from hydrogen, F, Cl, -NH2, methyl, ethyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridinyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azetidinyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl are each optionally substituted by one or more selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3;

[0098] More preferably, R b Each independently selected from: -NH2, methyl, chlorine, -OCF3, fluorine, tert-butyl, -CF3,

[0099] In some embodiments, the compound of the structure represented by formula (I), wherein ring B is selected from:

[0100] In some embodiments, when Ring B is replaced by one or more R b When substituted, Ring B is selected from:

[0101] In some embodiments, the compound of the structure shown in formula (I) is

[0102] R 1 is H;

[0103] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0104] R a are each independently selected from hydrogen, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl;

[0105] m is selected from 0, 1 or 2;

[0106] R 2 and R 3 is H;

[0107] P is 1;

[0108] L is a chemical bond;

[0109] Ring B is selected from a benzene ring, a 5-6 membered heteroaryl or a 5 to 6 membered heterocycloalkyl; said ring B is optionally substituted by one or more R b replace;

[0110] R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2、-OR d 、-SR d or -(C 1-6 alkylene) m1 -(X) m2 -(C 1-6 alkylene) m3 -(Z) m4 -R d ;

[0111] m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time;

[0112] X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-;

[0113] R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -OC 1-6 Alkyl, -NHC1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, and 4 to 6 membered heterocycloalkyl substitution;

[0114] Or, any two adjacent R b Together with the atoms it is connected to form C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0115] In some embodiments, the compound of the structure shown in formula (I) is

[0116] R 1 is H;

[0117] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0118] R 2 and R 3 is H;

[0119] P is 1;

[0120] L is a chemical bond;

[0121] Ring B is selected from a benzene ring, a 5-6 membered heteroaryl or a 5 to 6 membered heterocycloalkyl; said ring B is optionally substituted by one or more R b replace;

[0122] R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2、-OR d 、-SR d or -(C 1-3 alkylene) m1 -(X) m2 -(C 1-3 alkylene) m3 -(Z) m4 -R d ;

[0123] m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time;

[0124] X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-;

[0125] R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution;

[0126] Or, any two adjacent R b Together with the atoms it is connected to form C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0127] In some embodiments, the compound of the structure shown in formula (I) is

[0128] R 1 is H;

[0129] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0130] R 2 and R 3 is H;

[0131] P is 1;

[0132] L is a chemical bond;

[0133] Ring B is selected from a benzene ring or a pyridyl group; the ring B is optionally substituted by one or more R b replace;

[0134] R bEach is independently selected from hydrogen, halogen, -NH2, methyl, ethyl, tert-butyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridinyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3) , -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azetidinyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl are each optionally substituted by one or more selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3;

[0135] Or, any two adjacent R b Together with the atoms to which it is attached, it forms a cyclopentenyl, a 1,2,3,4-tetrahydropyridine, a 2,3-dihydro-1H-pyrrolyl, a pyrrolyl or The cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl or pyrrolyl are each optionally substituted by one or more substituents selected from halogen, -NH2, -CH3, -CH2CH3, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0136] In some embodiments, the compound of the structure shown in formula (I) is

[0137] R 1 is H;

[0138] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0139] R 2 and R 3 is H;

[0140] P is 1;

[0141] L is a chemical bond;

[0142] Ring B is a benzene ring;

[0143] R b are independently selected from hydrogen, halogen, NH2, -C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C3-6 Cycloalkyl, -O-phenyl; the -C 1-6 Alkyl, -C 3-6 Cycloalkyl and phenyl are each optionally substituted by one or more radicals selected from halogen, NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution.

[0144] In some embodiments, the compound of the structure shown in formula (I) is

[0145] R 1 is H;

[0146] Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione;

[0147] R 2 and R 3 is H;

[0148] P is 1;

[0149] L is a chemical bond;

[0150] Ring B is a benzene ring;

[0151] R b Each is independently selected from hydrogen, F, Cl, NH2, methyl, ethyl, propyl, tert-butyl, -CF3, -NHCH3, -N(CH3)2,

[0152] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0153] in,

[0154] R 1 , L, Ring A and Ring B are as described in any one of Formula (I) of the present invention.

[0155] In some embodiments, the compounds of formula (I) and formula (II) are compounds of formula (III), formula (IV), formula (V) and formula (VI):

[0156] in,

[0157] R 1 , L, R a , m and ring B are each independently as described in any one of formula (I) and formula (II) of the present invention.

[0158] In some embodiments, the compound represented by formula (I), formula (II), or formula (III) is a compound represented by formula (IIIa):

[0159] in,

[0160] R a 、R b , m are each independently as described in any one of formula (I), formula (II), and formula (III) of the present invention;

[0161] q is selected from 0, 1, 2, 3 or 4.

[0162] In some embodiments, the compound represented by the structure of formula (I), formula (II), or formula (III) is a compound represented by the following formula:

[0163] in,

[0164] R b Each is independently as described in any one of formula (I), formula (II) and formula (III) of the present invention.

[0165] In some embodiments, the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (IIIa) of the present invention are selected from any one of the following compounds:

[0166] Those skilled in the art will appreciate that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also included within the scope of the present invention.

[0167] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0168] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof and a pharmaceutically acceptable excipient.

[0169] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0170] The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0171] The pharmaceutical composition can be administered in any form, as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the route of administration.

[0172] In other embodiments, the administration of the compound or pharmaceutical composition of the present invention can be combined with another treatment method. The other treatment method can be selected from, but not limited to: radiation therapy, chemotherapy, immunotherapy, or a combination thereof.

[0173] The present invention also relates to a pharmaceutical preparation comprising a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0174] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. As used herein, an article of manufacture is intended to include, but is not limited to, a kit and a package. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.

[0175] The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and / or individual / bulk sales. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing, or dispensing pharmaceutical products.

[0176] The second container is a container for accommodating the first container and optional package insert. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion methods, or it can be placed inside the second container without any physical tool for adhering to the first container. Alternatively, the package insert is located outside the second container. When located outside the second container, it is preferably physically adhered to the package insert via a cable tie, glue, staples, or other adhesion methods. Alternatively, it can abut or contact the outside of the second container without physical adhesion.

[0177] The package insert is a trademark, label, or indicia that lists information about the pharmaceutical composition within the first container. The information listed is typically determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which the information contained therein or thereon can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) onto which the desired information can be formed (e.g., printed or applied).

[0178] In another aspect, the present invention provides a use of a substance Y in the preparation of a drug, wherein the substance Y is a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition thereof;

[0179] The drug meets one of the following conditions:

[0180] The medicament is used for treating and / or preventing cancer;

[0181] The medicine is used for preventing and / or treating GSPT1-related diseases.

[0182] In some embodiments, the cancer is selected from breast cancer, colorectal cancer, colon cancer, lung cancer, and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0183] In some embodiments, the GSPT1-associated disease is a disease that is sensitive or responsive to GSPT1 degradation.

[0184] In some embodiments, the GSPT1-related disease is cancer; preferably, the cancer includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0185] In another aspect, the present invention provides a use of a substance Y in the preparation of a GSPT1 degrader, wherein the substance Y is a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition thereof.

[0186] In some embodiments, the GSPT1 degrader can achieve at least one of the following technical effects:

[0187] (1) High inhibitory activity against GSPT1;

[0188] (2) excellent physicochemical properties (e.g., solubility, physical and / or chemical stability);

[0189] (3) excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action);

[0190] (4) Excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window).

[0191] In another aspect, the present invention provides a method for preventing or treating a GSPT1-related disease, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0192] In some embodiments, the GSPT1-associated disease is a disease that is sensitive or responsive to GSPT1 degradation.

[0193] In some embodiments, the GSPT1-related disease is cancer; preferably, the cancer includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0194] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.

[0195] In another aspect, the present invention provides a method for preventing or treating cancer, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled form, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention; preferably, the cancer includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0196] In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat cancer.

[0197] In another aspect, the present invention provides a substance X for treating cancer; the substance X is a compound represented by formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention. Preferably, the cancer includes but is not limited to breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, as well as leukemia (including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0198] The present invention provides a novel class of highly active GSPT1 degraders that can achieve at least one of the following technical effects: (1) high inhibitory activity against GSPT1; (2) excellent physicochemical properties (e.g., solubility, physical and / or chemical stability); (3) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (4) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0199] General Terms and Definitions

[0200] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0201] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0202] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0203] Unless otherwise indicated, concentrations are by weight and ratios (including percentages) are by molar amounts.

[0204] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0205] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form "about a to b," or equivalently, "approximately a to b," or equivalently, "about a b") should be understood to represent each value and range encompassed within the broader range.

[0206] For example, the statement "C 1-6 " should be understood to include any sub-ranges therein and each point value, such as C 2-5 、C 3-4 、C 1-2 、C 1-3 、C1-4、C1-5 etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression “C 3-10 ” should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, for example, C 3-9 、C 6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C 7-8 、C 8-9 etc. and C3, C4, C5, C6, C7, C8, C9, C 10 etc. For another example, the expression "3-10 yuan" should be understood to include any sub-ranges and point values ​​therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc. For another example, the expression "5-10 yuan" should also be understood in a similar manner, such as it can include any sub-ranges and point values ​​contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc., as well as 5, 6, 7, 8, 9, 10 yuan, etc.

[0207] The expression “(X) 0-1 "When it is 0, it means it is a connecting key, for example, "(C 1-6 Alkylene)O" is a connecting bond.

[0208] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group, alone or in combination with other groups. 1-6 "Alkyl" refers to a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms). 1-6 The "alkyl" group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl.

[0209] As used herein, the term "alkylene" refers to a saturated, linear or branched, divalent hydrocarbon group. 1-6 "Alkylene" refers to a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of "alkylene" include, but are not limited to, methylene, ethylene, propylene, or butylene.

[0210] The term "alkenyl" refers to a group having the specified number of carbon atoms (e.g., C 2-6) a linear or branched unsaturated monovalent hydrocarbon group having a carbon-carbon sp 2 Double bond.

[0211] The term "alkynyl" refers to a group having the specified number of carbon atoms (e.g., C 2-6 ) a linear or branched, unsaturated, monovalent hydrocarbon group having a carbon-carbon sp triple bond. Alkynyl groups include, but are not limited to: wait.

[0212] In this application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, "C3-12 cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.

[0213] In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic divalent cyclic group. For example, "C 3-12 "Cycloalkylene" or "3-12 membered cycloalkylene" refers to a cycloalkylene group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). Common cycloalkylene groups include, but are not limited to, monocyclic cycloalkylene groups such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylene groups including fused, bridged or spiro rings such as bicyclo[1.1.1]pentylene, bicyclo[2.2.1]heptylene, bicyclo[3.2.1]octylene, bicyclo[5.2.0]nonylene, decahydronaphthylene, etc.

[0214] The term "heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic cyclic group containing at least one ring member selected from N, O, P, and S, preferably, the number of the heteroatoms is 1, 2, 3, or 4. More preferably, the heteroatom is N, O, or S, and the number of the heteroatoms is 1, 2, or 3. The heterocycloalkyl group may be monocyclic or polycyclic, and the polycyclic ring may be a cyclic, spirocyclic, or bridged ring structure. For example, a 3-12-membered, 3-10-membered, 3-8-membered, 3-6-membered, 5-8-membered, 5-6-membered, or 4-8-membered heterocycloalkyl group. In addition, the heterocycloalkyl group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, oxiranyl, oxocyclobutane, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, pyrrolidonyl, and the like.

[0215] The term "heterocycloalkylene" refers to a saturated or partially unsaturated, non-aromatic, divalent cyclic group containing at least one ring member selected from N, O, P, and S. Preferably, the number of heteroatoms is 1, 2, 3, or 4. More preferably, the heteroatom is N, O, or S, and the number of heteroatoms is 1, 2, or 3. The heterocycloalkylene group may be monocyclic or polycyclic, and the polycyclic rings may be cyclic, spirocyclic, or bridged. Examples include 3-8 membered or 3-6 membered heterocycloalkylene groups. In addition, the heterocycloalkylene group may contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, oxiranylene, oxocyclobutanylene, pyrrolidinylene, tetrahydrofuranylene, piperidinylene, piperazinylene, tetrahydropyranylene, homopiperazinylene, and pyrrolidonylene.

[0216] The term "fused ring (fused ring system)" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbocyclic or heterocyclic rings with a common ring edge, wherein the carbocyclic ring includes a cycloalkyl group and an aryl group, and the heterocyclic ring includes a heteroaryl group and a heterocycloalkyl group. The fused ring system includes, but is not limited to, a fused ring system formed by a cycloalkyl group and a cycloalkyl group, a fused ring system formed by a cycloalkyl group and a heterocycloalkyl group, a fused ring system formed by a cycloalkyl group and an aryl group, a fused ring system formed by a cycloalkyl group and a heteroaryl group, a fused ring system formed by a heterocycloalkyl group and a heteroaryl group, a fused ring system formed by a heterocycloalkyl group and an aryl group, a fused ring system formed by a heteroaryl group and a heteroaryl group, and a fused ring system formed by a heteroaryl group and an aryl group.

[0217] In this application, the term "aryl" or "aromatic ring" refers to a monocyclic or condensed aromatic hydrocarbon group having a conjugated π electron system. For example, the term "C 6-10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms (e.g., phenyl, naphthyl, etc.).

[0218] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to monocyclic and fused heterocyclic ring systems having one or more conjugated π-electron systems, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. A heteroaryl group or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, indolyl, and the like.

[0219] In the present application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0220] In this application, the term "hydroxyl" refers to -OH.

[0221] As used herein, the term "cyano" refers to -CN.

[0222] As used herein, the term "nitro" refers to -NO2.

[0223] As used herein, the term "amino" refers to -NH2.

[0224] In the present application, "oxo" refers to C(O), ie, carbonyl.

[0225] In this application, the term "haloalkyl" when used alone or in combination with other groups refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Haloalkyl" refers to a C 1-6 Alkyl. It will be understood by those skilled in the art that when there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0226] In this application, the term "alkoxy" when used alone or in combination with other groups means an alkyl group as described above with an oxygen atom attached to the parent molecular moiety. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and the like.

[0227] The term "independently" as used in this application means that at least two groups (or fragments) with the same or similar value ranges in a structure may have the same or different meanings under specific circumstances. For example, substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When substituent A is hydrogen, substituent B can be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl. Similarly, when substituent B is hydrogen, substituent A can be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl.

[0228] The term "substituted" as used in this application and its other variant forms in this article refer to that one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded and a stable compound can be formed. If a certain atom or atomic group is described as "optionally substituted by...", it can be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein can be from any suitable position of a substituent. When the connecting bond in a substituent is shown as a chemical bond between two atoms connected to each other in a ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0229] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. This means that the corresponding group R is connected to other fragments or groups in the compound through this site. A "-" at the end of a group indicates that the group is connected to another fragment in the molecule through this site. For example, CH3-C(=O)- means that the C(=O) in the acetyl group is connected to another fragment in the molecule.

[0230] In this application, unless otherwise indicated, the structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds that are identical to the structures described herein except for the replacement of a hydrogen atom by deuterium or tritium, or a carbon atom by carbon-13 or carbon-14, are within the scope of this application.

[0231] The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0232] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0233] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0234] As used herein, the term "ester" refers to esters derived from compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention may themselves also be esters.

[0235] The compounds of the present invention may exist in the form of solvates (preferably hydrates). The amount of polar solvents, especially water, may be present in a stoichiometric or non-stoichiometric ratio.

[0236] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by assays. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by methods that contact the compounds of the present invention with a mammal for a period of time sufficient to produce their metabolites.

[0237] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0238] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0239] The present invention also encompasses methods for preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction can be carried out in a solvent or solvent mixture that is appropriate for the reagents and materials used and suitable for the transformation to be achieved.

[0240] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.

[0241] As used herein, the term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") refers to an amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the appearance of the condition or its symptoms.

[0242] As used herein, unless otherwise indicated, the terms "treat," ...

[0243] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0244] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0245] The reagents and raw materials used in the present invention are commercially available.

[0246] The positive and progressive effects of the present invention are that the compounds of the present invention can be used to degrade proteins such as GSPT1, thereby preventing, alleviating or treating diseases related to disorders of these proteins; at the same time, the compounds of the present invention can also serve as the effective load of ligand-drug conjugates (e.g., antibody-drug conjugates), further expanding the range of indications of the compounds of the present invention. DETAILED DESCRIPTION

[0247] The present invention includes all combinations of the described specific embodiments. Further embodiments of the present invention and the full scope of applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific examples indicate preferred embodiments of the present invention, these descriptions and examples are provided by way of illustration only, because various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. For all purposes, all publications, patents and patent applications cited herein, including citations, will be incorporated herein by reference in their entirety. The present invention is further illustrated below by way of example, but the present invention is not limited to the scope of the described embodiments. The experimental methods for which specific conditions are not specified in the following examples are selected according to conventional methods and conditions, or according to the product specifications.

[0248] Mass spectrometry (MS) was measured using an Agilent (ESI) mass spectrometer, manufactured by Agilent, model: Agilent 6120B.

[0249] Preparative high performance liquid chromatography (HPLC) was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 × 20 mm column).

[0250] Thin layer chromatography purification was performed using GF 254 (0.4-0.5 nm) silica gel plates produced in Yantai.

[0251] The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used include, but are not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds or by adding triethylamine.

[0252] Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. Eluent systems include, but are not limited to, dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0253] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 30°C).

[0254] Unless otherwise specified, the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, Anaiji, or Shanghai Shuya Pharmaceutical Technology.

[0255] The above embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated by reference in its entirety.

[0256] In general synthesis methods, preparation examples, examples and intermediate synthesis examples, the meanings of the abbreviations are as follows.

[0257] Synthesis of intermediates:

[0258] Intermediate Preparation Example 1: Preparation of Compound Int1

[0259] Step 1: Preparation of compound Int1-2

[0260] To a MeCN (25 mL) solution, Int1-1 (1.00 g, 3.90 mmol) and sodium diformamide (1.81 g, 19.00 mmol) were added, and the mixture was stirred at 80°C for 1 h. The solution was extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int1-2 (0.49 g, 51% yield).

[0261] Step 2: Preparation of compound Int1

[0262] A solution of compound Int1-2 (0.32 g, 1.26 mmol) in ethanol (12 mL) was mixed with concentrated HCl (4 mL, 12 N) and stirred at 80° C. for 1 h. The solution was concentrated to afford compound Int1 (0.24 g, 100% yield), which was used in the next step without purification.

[0263] Intermediate Preparation Example 2: Preparation of Compound Int7

[0264] Step 1: Preparation of compound Int7-2

[0265] A solution of In7-1 (1.28 g, 5.60 mmol) was added to acetonitrile (20 mL). NBS (1.30 g, 7.30 mmol) and p-TsOH (1.05 g, 6.1 mmol) were added under nitrogen. The mixture was stirred at 60°C for 4 h, quenched by addition of saturated NaCl solution, and extracted with EA. The organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to remove the solvent. Purification by column chromatography afforded Int7-2 (1.20 g, 70% yield).

[0266] Step 2 to Step 3: Preparation of Compound Int7

[0267] Compound In7 was synthesized by referring to the method of Intermediate Preparation Example 1.

[0268] Intermediate Preparation Example 3: Preparation of Compound Int9

[0269] Step 1: Preparation of compound Int9-2

[0270] To a DMF (30 mL) solution, Int9-1 (2.00 g, 14.70 mmol), p-fluoronitrobenzene (2.07 g, 14.7 mmol), and potassium carbonate (2.03 g, 14.70 mmol) were added and heated with stirring at 120°C for 6 h. After completion, the reaction was cooled to room temperature, and water and ethyl acetate were added. The mixture was stirred and separated. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford Int9-2 (3.21 g, 85% yield).

[0271] Step 2 to Step 4: Preparation of Compound Int9

[0272] Compound Int9 was synthesized by a similar method to that of Intermediate Preparation Example 2.

[0273] Referring to Intermediate Preparation Example 1, the following compound was synthesized using commercially available α-halogenated aryl ethyl ketone:

[0274] Example 1: Synthesis of target compound

[0275] Preparation Example 1: Synthesis of Compound 1

[0276] Step 1: Synthesis of compound 1-1

[0277] IntA (0.37 g, 1.30 mmol) was added to a DMF (20 mL) solution, followed by HATU (0.74 g, 1.95 mmol) and DIEA (0.51 g, 3.91 mmol). The mixture was stirred for 1 hour, and then compound Int1 (0.25 g, 1.30 mmol) was added and stirred for 2 hours. The solution was extracted with EA, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford compound 1-1 (0.20 g, 33% yield).

[0278] Step 2: Synthesis of compound 1

[0279] 10% Pd / C (5 mg) was added to a DMF (3 mL) solution of compound 1-1 (0.03 g, 0.05 mmol), and the mixture was stirred at room temperature for 40 min under a hydrogen atmosphere. The solution was purified by reverse HPLC to obtain compound 1 (0.07 g, yield 31%).

[0280] MS m / z(ESI):435.3[M+H] +

[0281] 1H-NMR (400MHz, DMSO-d6): δ11.03(s,1H),8.97(t,J=5.5Hz,1H),8.12(s,1H),8.04(d,J=7 .9Hz,1H),7.85(d,J=7.9Hz,1H),7.25(s,1H),7.20(d,J=7.7Hz,1H),7.10(d,J=7.8Hz,1H) ,5.24–5.08(m,3H),4.72(d,J=5.5Hz,2H),4.55(d,J=17.5Hz,1H),4.42(d,J=17.6Hz,1H) ,2.97–2.80(m,1H),2.61–2.59(m,1H),2.48–2.40(m,1H),2.13(s,3H),2.07–2.01(m,1H).

[0282] Referring to the method of Preparation Example 1, the following compounds were synthesized using different intermediates.

[0283] Example 2: In vitro proliferation inhibition test of the compound on tumor cells and normal liver cells

[0284] Purpose of the test

[0285] In order to test the efficacy and safety of the drug compounds, the proliferation inhibitory activity of BT-474, NCI-N87 tumor cells and normal liver cells THLE-2 was carried out in vitro. The cells were treated with different concentrations of the compounds in vitro and cultured for 6 days. Luminescent Cell Viability Assay (Promega, Catalog No. G7558) was used to detect cell proliferation. 50 The in vitro activity of the compound was evaluated.

[0286] The control compound CC-885 was purchased from MCE, catalog number: HY-101488

[0287] Experimental methods

[0288] The following uses the in vitro proliferation inhibition test method of NCI-N87 cells as an example to illustrate the method for testing the in vitro proliferation inhibition activity of the compounds of the present application on tumor cells. This method is also applicable to, but not limited to, testing the in vitro proliferation inhibition activity of other tumor cells.

[0289] 1. Cell culture: NCI-N87 cells were cultured in RPMI-1640 medium supplemented with 10% FBS.

[0290] 2. Cell preparation: Take NCI-N87 cells in the logarithmic growth phase, wash once with PBS, add 2-3 ml of trypsin and digest for 2-3 minutes. After the cells are completely digested, add 10-15 ml of cell culture medium to elute the digested cells, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and then add 10-20 ml of cell culture medium to resuspend the cells to make a single-cell suspension.

[0291] 3. Cell plating: Mix the NCI-N87 single cell suspension and adjust the viable cell density to 6x10 4 The cell suspension after density adjustment was mixed and added to a 96-well cell culture plate at 50 μl / well. The culture plate was cultured in an incubator (37°C, 5% CO2) for 18 hours.

[0292] 4. Compound Preparation: Dissolve the compound in DMSO and prepare a stock solution with an initial concentration of 10 mM. For small molecule compounds, a total of 9 concentrations are prepared, with a maximum concentration of 1 uM, and 3-fold dilution.

[0293] 5. Sample addition: Add different concentrations of the test sample to the culture plate, with two replicates for each sample. Incubate the culture plate in an incubator for 6 days (37°C, 5% CO2).

[0294] 6. Color development: Take out the 96-well cell culture plate, add 50ul CTG reagent to each well, and incubate at room temperature for 10 minutes.

[0295] 7. Plate reading operation: Take out the 96-well cell culture plate, place it in a microplate reader, and measure the chemiluminescence using the microplate reader.

[0296] Data analysis: Microsoft Excel and Graphpad Prism 5 were used to process and analyze the data.

[0297] Table 1 IC values ​​of the small molecule fragments in this application for inhibition of NCI-N87 cell proliferation in vitro 50 value.

[0298] ++++:<10nM,+++:10~30nM,++:30~150nM,+:>150nM

[0299] Conclusion: According to the results in Table 1, the small molecule fragments in the present application have significant proliferation inhibitory activity on NCI-N87 cells and BT-474 cells; in addition, compared with the control compound CC-885, the compounds of the present application have a weaker inhibitory effect on normal liver cell THLE-2 and are significantly safer than CC-885.

[0300] The above embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated by reference in its entirety.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, in, R 1 Selected from hydrogen, deuterium, halogen, -C 1-6 Alkyl or -halogenated C 1-6 alkyl; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; U is selected from -CH2- or -C(O)-; R a are each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4 to 12 membered heterocycloalkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl or 4 to 12 membered heterocycloalkyl are each optionally substituted with one or more substituents selected from halogen, -OH, -CN, -NH2 and oxo; m is selected from 0, 1, 2 or 3; R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen, -OH, -CN and -NH2; p is selected from 1 or 2; L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-, vinylene, ethynylene, -C 3-8 Cycloalkylene-, 4 to 12 membered heterocycloalkylene; said C 1-6 Alkyl, C 1-3 Alkylene, C 3-8 Cycloalkylene, 4 to 12 membered heterocycloalkylene, each optionally substituted by one or more selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, oxo, hydroxy, -CN and -NH2 substitution Base substitution; Ring B is selected from -C 6-10 aryl, 5-10 membered heteroaryl or 4 to 14 membered heterocycloalkyl; the ring B is optionally substituted by one or more R b replace; R b are each independently selected from hydrogen, deuterium, halogen, nitro, -CN, -COOH, -CONH2, -R d 、-P(O)(R d )2、-N(R d )2.-OR d 、-SR d 、-Si(R d )3.-(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d or The C 1-6 The alkylene group is optionally substituted with one or more halogens; m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time; X and Z are each independently selected from -O-, -S-, -NR c -、-C(O)-、-NR c C(O)-、-C(O)NR c -、-S(O)-、-S(O)2 - 、-S(O)2NR c -、-NR c S(O)2-, or -OC(O)-; R c Selected from hydrogen, -C 1-6 Alkyl, -halogenated C 1-6 alkyl; R d Each independently selected from hydrogen, deuterium, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl, 5-10 membered heteroaryl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -SH, nitro, -OC 1-6 Alkyl, -O(halogenated C 1-6 Alkyl), -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-SH, -C 1-6 Alkyl-SC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1- 6-Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, -C(O)NH2, -COOH, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHC(O)OC 1-6 Alkyl, -S(O)2C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl substitution; Or, any two adjacent R b Together with the atoms it is connected to, it forms C 5-12 Cycloalkyl, 5 to 12-membered heterocycloalkyl, 5 to 6-membered heteroaryl or phenyl; the C 5-12 Cycloalkyl, 5 to 12 membered heterocycloalkyl, 5 to 6 membered heteroaryl, phenyl are each optionally substituted with one or more selected from halogen, oxo, -OH, -CN, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-SH, -C 1-6 Alkyl-SC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-NH(C 1- 6 alkyl), -C 1-6 Alkyl-N(C 1-6 Alkyl)2, -C 3-6 The substituents of cycloalkyl and 4- to 6-membered heterocycloalkyl are substituted.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 Selected from hydrogen, deuterium or -C 1-6 Alkyl; preferably, R 1 is H; (2) Ring A is selected from: Preferably, Ring A is: More preferably, Ring A is Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; (3)R a are each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl, -OC 1-6 Alkyl; preferably, R a are each independently selected from hydrogen, halogen, -OH, -NH2, -C 1-6 Alkyl or -OC 1-6 More preferably, R a are each independently selected from hydrogen, halogen or -OC 1-6 alkyl; (4) m is selected from 0, 1 or 2; m is preferably 0; (5)R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; preferably, R 2 , R 3 are each independently selected from hydrogen, deuterium or halogen; more preferably, R 2 , R 3 is hydrogen; (6) L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-; preferably, L is a chemical bond; (7) Ring B is selected from -C 6-10 Aryl or 5-10 membered heteroaryl; preferably, ring B is -C 6-10 Aryl; More preferably, Ring B is phenyl; (8)R b are each independently selected from hydrogen, halogen, nitro, -CN, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d Preferably, R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d ; (9) X and Z are each independently selected from -O-, -S-, -NH-, -C(O)-, -NR c C(O)- or -C(O)NR c -; Preferably, X and Z are each independently selected from -O-, -S- or -NH-; (10)R c Selected from hydrogen or -C 1-6 Alkyl; preferably H or -CH3; more preferably H; (11)R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 The aryl or 5-10 membered heteroaryl groups are each optionally substituted with one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl substitution; Preferably, R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution; and (12) Any two adjacent R b Together with the atoms it is connected to, it forms C 5-8 Cycloalkyl, 5 to 8 membered heterocycloalkyl or phenyl; the C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl or phenyl are each optionally substituted by one or more selected from halogen, -OH, -NH2, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH(C 1-6 Alkyl), -C 1-6 Alkyl-N(C 1-6 alkyl)2 is substituted with a substituent.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) Each halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (2) Each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl; (3) Each -OC 1-6 Alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-tert-butyl, -O-isobutyl or -O-sec-butyl; for example -O-methyl; (4) Each C 2-6 Alkenyl is independently ethenyl, propenyl, allyl, butenyl or pentenyl; (5) Each C 2-6 Alkynyl is independently ethynyl, propynyl, propargyl, butynyl or pentynyl, for example (6) Each C 3-12 The cycloalkyl groups are independently C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) The cycloalkyl group is a saturated cycloalkyl group or a partially saturated cycloalkyl group; the number of unsaturated bonds in the partially saturated cycloalkyl group is one or more; (8) each 4- to 12-membered heterocycloalkyl group is independently a 5- to 8-membered heterocycloalkyl group; (9) The heteroatom of each 4- to 12-membered heterocycloalkyl group is independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom of each 4- to 12-membered heterocycloalkyl group is independently N or O, and the number of heteroatoms is independently 1 or 2; (10) Each 4- to 12-membered heterocycloalkyl group is independently a monocyclic or polycyclic ring, and the polycyclic ring may be a bridged ring, a fused ring or a spiro ring; the polycyclic ring may be a bicyclic ring or a tricyclic ring; preferably, each 4- to 12-membered heterocycloalkyl group is independently a 5- to 6-membered monocyclic heterocycloalkyl group, a 9- to 10-membered bicyclic heterocycloalkyl group or an 11- to 12-membered tricyclic heterocycloalkyl group; (11) The heterocycloalkyl group is a saturated heterocycloalkyl group or a partially saturated heterocycloalkyl group; the number of unsaturated bonds in the partially saturated heterocycloalkyl group is one or more; (12) each m is independently selected from 0 or 1, preferably 0; (13) Each-C 1-3 Alkylene- is independently -methylene-, -ethylene-, -n-propylene- or -isopropylene-; (14) Each-C 3-8 Cycloalkylene- is independently -C 3-6 Cycloalkylene-, for example -cyclopropylene-, -cyclobutylene-, -cyclopentylene- or -cyclohexylene-, preferably -cyclopropylene- or -cyclobutylene-; (15) The cycloalkylene group is a saturated cycloalkylene group or a partially saturated cycloalkylene group; the number of unsaturated bonds in the partially saturated cycloalkylene group is one or more; (16) each 4- to 12-membered heterocycloalkylene group is independently a 5- to 8-membered heterocycloalkylene group; (17) The heteroatom of each 4- to 12-membered heterocycloalkylene group is independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3; preferably, the heteroatom of each 4- to 12-membered heterocycloalkylene group is independently N or O, and the number of heteroatoms is independently 1 or 2; (18) Each 4- to 12-membered heterocycloalkylene group is independently a monocyclic or polycyclic ring, and the polycyclic ring may be a bridged ring, a fused ring or a spiro ring; the polycyclic ring may be a bicyclic ring or a tricyclic ring; preferably, the 4- to 12-membered heterocycloalkylene group is independently a 5- to 6-membered monocyclic heterocycloalkyl group, a 9- to 10-membered bicyclic heterocycloalkyl group or an 11- to 12-membered tricyclic heterocycloalkyl group; (19) each halo is independently fluoro, chloro, bromo or iodo; (20) Each C 6-10 Aryl is independently phenyl or naphthyl, for example phenyl; (21) The heteroatom of each 5-10 membered heteroaryl group is independently N, O or S, and the number of heteroatoms is independently 1, 2 or 3; (22) Each 5-10 membered heteroaryl group is independently a monocyclic or bicyclic ring, wherein the bicyclic ring is a paracyclic ring; (23) each 4- to 14-membered heterocycloalkyl is a 5- to 12-membered heterocycloalkyl; (24) The heteroatom of each 4- to 14-membered heterocycloalkyl group is N, O or S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom is N, and the number of heteroatoms is 1 or 2; (25) Each 4- to 14-membered heterocycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic or tricyclic), and the polycyclic rings may be bridged, fused or spirocyclic; (26) Each-C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (27) In ring B, the -C 6-10 Aryl is phenyl; (28) In ring B, the 5-10 membered heteroaryl group is thienyl, pyridyl or indolyl, for example (29) In ring B, the 4- to 14-membered heterocycloalkyl group is Preferably (30) In R d In the 4- to 12-membered heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is 1, 2 or 3; preferably, the heteroatom is N or O, and the number of the heteroatom is 1 or 2; (31) In R d wherein the 4- to 12-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group; preferably a morpholinyl group, a piperidinyl group, an azetidinyl group or a tetrahydropyrrolyl group; more preferably (32) In R d In the above, the 5-10 membered heteroaryl group is pyridyl; for example (33) When two adjacent R b Together with the atoms it is connected to, it forms C 5-12 When cycloalkyl, the C 5-12 Cycloalkyl is cyclohexyl, cyclopentyl, cyclohexenyl or cyclopentenyl; (34) When two adjacent R b When the atoms to which it is attached form a 5- to 12-membered heterocycloalkyl, the 5- to 12-membered heterocycloalkyl The radical is 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl, pyrrolyl or and (35) When two adjacent R b When the atoms to which it is attached form a 5- to 6-membered heteroaryl group together, the 5- to 6-membered heteroaryl group is pyridyl.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R a are each independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -CH3 or -OCH3; preferably, R a is selected from hydrogen, -F, -OH, -NH2, -CH3 or -OCH3; more preferably, R a Selected from hydrogen, -F or -OCH3; (2)R 2 , R 3 are each independently selected from hydrogen, deuterium, halogen, -OH or -C 1-6 Alkyl; preferably, R 2 , R 3 are each independently selected from hydrogen, deuterium or -F; more preferably, R 2 , R 3 is hydrogen; (3) L is selected from a chemical bond, -NH-, -N(C 1-6 Alkyl)-, -C 1-3 Alkylene-; preferably, L is selected from a chemical bond, -NH- or -CH2-; more preferably, L is a chemical bond; (4) Ring B is selected from -C 6-10 Aryl, 5-6 membered heteroaryl, 5 to 6 membered heterocycloalkyl; preferably, ring B is selected from phenyl, pyridyl, Preferably, ring B is selected from phenyl and pyridyl; more preferably, ring B is phenyl; said ring B is optionally substituted by one or more R b replace; (5)R b are each independently selected from hydrogen, halogen, nitro, -CN, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-3 Alkylene) m1 -(X) m2 -(C 1-3 Alkylene) m3 -(Z) m4 -R d Preferably, R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-3 Alkylene) m1 -(X) m2 -(C 1-3 Alkylene) m3 -(Z) m4 -R d ; Preferably, R b are each independently selected from hydrogen, -F, -Cl, nitro, -CN, -N(R d )2.-OR d 、-SR d 、-(C 1-3 Alkylene) m1 -(O) m2 -(C 1-3 Alkylene) m3 -(O) m4 -R d 、-(C 1-3 Alkylene) m1 -(O) m2 -(C 1-3 Alkylene) m3 -(NH) m4 -R d 、-(C 1-3 Alkylene) m1 -(NH) m2 -(C 1- 3 alkylene) m3 -(O) m4 -R d 、-(C 1-3 Alkylene) m1 -(NH) m2 -(C 1-3 Alkylene) m3 -(NH) m4 -R d ; More preferably, R b Each independently selected from -F, -Cl, -N(R d )2.-OR d 、-SR d 、-(C 1-3 Alkylene) m1 -(O) m2 -(C 1-3 Alkylene) m3 -(O) m4 -R d 、-(C 1-3 Alkylene) m1 -(O) m2 -(C 1-3 Alkylene) m3 -(NH) m4 -R d 、-(C 1-3 Alkylene) m1 -(NH) m2 -(C 1-3 Alkylene) m3 -(O) m4 -R d 、-(C 1-3 Alkylene) m1 -(NH) m2 -(C 1-3 Alkylene) m3 -(NH) m4 -R d ; (6) X and Z are each independently selected from -O-, -S-, -NH-, -N(CH3)-, -C(O)-, -NHC(O)- or -C(O)NH-; preferably, X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-; (7)R d are each independently selected from hydrogen, -C 1-4 Alkyl, cyclopropyl, cyclobutyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; the C 1-6 Alkyl, cyclopropyl, cyclobutyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl substitution; Preferably, R d are each independently selected from hydrogen, -C 1-4 Alkyl, -cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thienyl, furanyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, azetyl, oxetanyl, oxolanyl; the -C 1-4 alkyl, -cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thienyl, furanyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, azetidinyl, oxetanyl, oxolanyl, each of which is optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution; More preferably, R d Each is independently selected from hydrogen, -CH3, -CH2CH3, -iPr, -tBu, -CF3, -cyclopropyl, phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl; the -CH3, -CH2CH3, cyclopropyl, phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution; More preferably, R d Each independently selected from hydrogen, -CH3, -CH2CH3, -iPr, -tBu, -CF3, -cyclopropyl, phenyl, pyridyl, piperidyl, morpholinyl and azetidinyl; -CH3, -CH2CH3, -cyclopropyl, phenyl, pyridyl, piperidyl, morpholinyl and azetidinyl are each optionally substituted by one or more selected from halogen, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1- 6-alkyl, -halogenated C 1-6 Alkyl substitution; (8) Any two adjacent R b Together with the atoms it is connected to, it forms C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2; Preferably, any two adjacent R b Together with the atoms to which it is attached, it forms a cyclohexyl, a cyclopentyl, a cyclohexenyl, a cyclopentenyl, a 1,2,3,4-tetrahydropyridine, a 2,3-dihydro-1H-pyrrolyl, a pyrrolyl, Pyridyl or phenyl; the cyclohexyl, cyclopentyl, cyclohexenyl, cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl, pyrrolyl, Pyridyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -NH2, -CH3, -CH2CH3, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2; and (9)R b are each independently selected from hydrogen, halogen, -NH2, -C 1-4 Alkyl, -CF3, -OCF3, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, 4-6 membered heterocycloalkyl, -C 3-6 Cycloalkyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-(5-6 membered heteroaryl), -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-(4-6 membered heterocycloalkyl), -CH2-(4-6 membered heterocycloalkyl), -CH2-O-phenyl and phenyl; the C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by one or more selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution; Preferably, R b Each independently selected from hydrogen, F, Cl, -NH2, methyl, ethyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, Morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridinyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azetidinyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl are each optionally substituted by one or more selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3; More preferably, R b Each independently selected from: -NH2, methyl, chloro, -OCF 3、 fluorine, tert-butyl, -CF3, 5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one or both of the following conditions: (1) Ring B is selected from: and (2) When ring B is surrounded by one or more R b When substituted, Ring B is selected from:

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one of the following schemes: Solution 1: R 1 is H; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; R a are each independently selected from hydrogen, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl; m is selected from 0, 1 or 2; R 2 and R 3 is H; P is 1; L is a chemical bond; Ring B is selected from a benzene ring, a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more R b replace; R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d ; m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time; X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-; R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, and 4 to 6 membered heterocycloalkyl substitution; Or, any two adjacent R b Together with the atoms it is connected to, it forms C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2; Option 2: R 1 is H; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; R 2 and R 3 is H; P is 1; L is a chemical bond; Ring B is selected from a benzene ring, a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl; the ring B is optionally substituted by one or more R b replace; R b are each independently selected from hydrogen, halogen, -R d 、-N(R d )2.-OR d 、-SR d or -(C 1-3 Alkylene) m1 -(X) m2 -(C 1-3 Alkylene) m3 -(Z) m4 -R d ; m1, m2, m3 and m4 are each independently 0 or 1; and m2 and m4 are not 0 at the same time, and m1 and m3 are not 0 at the same time; X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-; R d Each independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocycloalkyl, -C 6-10 Aryl or 5-10 membered heteroaryl are each optionally substituted by one or more selected from halogen, -NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution; Or, any two adjacent R b Together with the atoms it is connected to, it forms C 5-6 Cycloalkyl, 5 to 7 membered heterocycloalkyl or phenyl; the C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2; Option 3: R 1 is H; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; R 2 and R 3 is H; P is 1; L is a chemical bond; Ring B is selected from a benzene ring or a pyridyl group; the ring B is optionally substituted by one or more R b replace; R b Each is independently selected from hydrogen, halogen, -NH2, methyl, ethyl, tert-butyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridinyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3) , -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azetidinyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl are each optionally substituted by one or more selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3; Or, any two adjacent R b Together with the atoms to which it is attached, it forms a cyclopentenyl, a 1,2,3,4-tetrahydropyridine, a 2,3-dihydro-1H-pyrrolyl, a pyrrolyl or The cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrolyl or pyrrolyl are each optionally substituted by one or more substituents selected from halogen, -NH2, -CH3, -CH2CH3, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2; Option 4: R 1 is H; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; R 2 and R 3 is H; P is 1; L is a chemical bond; Ring B is a benzene ring; R b are each independently selected from hydrogen, halogen, NH2, -C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C 3-6 Cycloalkyl, -O-phenyl; the -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -O-phenyl are each optionally substituted by one or more selected from halogen, NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution; Option 5: R 1 is H; Ring A is selected from: Among them, 1 is connected to -C(O)-, and 2 is connected to piperidinedione; R 2 and R 3 is H; P is 1; L is a chemical bond; Ring B is a benzene ring; R b Each is independently selected from hydrogen, F, Cl, NH2, methyl, ethyl, propyl, tert-butyl, -CF3, -NHCH3, -N(CH3)2, 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) satisfies one of the following schemes: Solution 1: The compound of the structure shown in formula (I) is the compound shown in formula (II): in, R 1 , L, Ring A and Ring B as described in any one of claims 1-6; Option 2: The compounds of the structures shown in formula (I) and formula (II) are compounds shown in formula (III), formula (IV), formula (V) and formula (VI): in, R 1 , L, R a , m and ring B are each independently as described in any one of claims 1 to 6; Option 3: The compounds represented by the structures of formula (I), formula (II) and formula (III) are compounds represented by formula (IIIa): in, R a , R b , m are each independently as described in any one of claims 1 to 6; q is selected from 0, 1, 2, 3 or 4; Preferably, the compound represented by the structure of formula (I), formula (II) or formula (III) is a compound represented by the following formula: in, R b Each independently as described in any one of claims 1 to 6.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, characterized in that: The compound represented by formula (I) is selected from any of the following compounds:

9. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

10. Use of a substance Y in the preparation of a drug, wherein the substance Y is a compound of formula (I) as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition as claimed in claim 9; The drug meets one of the following conditions: The medicament is used for treating and / or preventing cancer; The drug is used for preventing and / or treating GSPT1-related diseases; Preferably, the GSPT1-related disease is a disease that is sensitive or responsive to GSPT1 degradation; preferably, the GSPT1-related disease is cancer; Preferably, the cancer is selected from breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, leukemia, multiple myeloma and lymphoma.

11. Use of a substance Y in the preparation of a GSPT1 degradation agent, wherein the substance Y is a compound of formula (I) as described in any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite or prodrug thereof, or a pharmaceutical composition as described in claim 9.

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