Piperidine diketone compound, and preparation method and application thereof

Abstract

The invention discloses a piperidinedione compound as well as a preparation method and application thereof. The invention provides compounds as shown in formulas (I) and (II), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope labels, metabolites or prodrugs thereof. The compound provided by the invention can be used for degrading proteins such as GSPTl and the like, so that diseases related to protein imbalance are prevented, relieved or treated; meanwhile, the compound provided by the invention can also be used as an effective load of a ligand drug conjugate, so that the adaptation disease range of the compound provided by the invention is further expanded.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a piperidinedione compound, a preparation method thereof and application thereof. BACKGROUND

[0002] Protein function is a strictly regulated process in space and time during cell growth and proliferation. Abnormal regulation of these processes can lead to uncontrolled cell growth, proliferation and migration, leading to the occurrence of diseases such as tumors.

[0003] Inducing protein degradation as a therapeutic strategy has been clinically verified by a class of immunomodulatory drugs (IMiDs) including lenalidomide and pomalidomide. These compounds have the ability to bind to cereblon (CRBN) and promote the recruitment and ubiquitination of substrate proteins mediated by cullin-damaged DNA-binding-RING box-domain protein (CUL4-DDB1-RBX1-CRBN) or simply (CRL4 CRBN ) E3 ubiquitin ligase, by promoting the degradation of target proteins, thereby achieving the purpose of treating diseases.

[0004] Research has found that minor structural changes in different immunomodulatory drugs can significantly change the substrate specificity of E3 ligase, resulting in significant changes in drug metabolic activity and biological activity. For example: pomalidomide and lenalidomide can both mediate the ubiquitination and degradation of IKZF1 / 3, but only lenalidomide can degrade CK1a, which can be an effective target for 5q deletion myelodysplastic syndrome; CC-90009 specifically mediates the degradation of GSPT1 (also known as eRF3a, a translation termination factor) to treat acute myeloid leukemia; BTX-1188 can degrade GSPT1 and IKZF1 / 3, and preclinical studies have shown good antitumor effects in various solid tumors (breast cancer, ovarian cancer, lung cancer, etc.).

[0005] CRBN, as an important target of anti-tumor and immunomodulatory drugs, has been proven to have a clear effect on various hematological malignancies such as multiple myeloma and chronic lymphocytic leukemia, skin diseases such as leprosy nodular erythema, and autoimmune diseases such as systemic lupus erythematosus. However, the current lenalidomide drugs have many side effects, so there is still a high clinical demand and application value for developing CRBN modulator drugs with novel structures that can improve effectiveness, safety, and expand the scope of indications. SUMMARY

[0006] The present application aims to provide a piperidinedione compound, a preparation method and application thereof. The compound of the present application can be used for degrading proteins such as GSPT1, thereby playing a role in preventing, relieving or treating diseases related to disorders of these proteins; meanwhile, the compound of the present application can also be used as an effective payload of a ligand drug conjugate (for example: an antibody drug conjugate), thereby further expanding the indication range of the compound of the present application.

[0007] In one aspect, the present application provides a compound represented by formula (I) or (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically-labeled, metabolite or prodrug thereof,

[0008]

[0009] wherein R 1 is independently hydrogen, deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl;

[0010] Group A is independently:

[0011] wherein 1 is connected with L, and 2 is connected with piperidinedione;

[0012] U is -CH2- or -C(O)-;

[0013] R a is each independently 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 or 4-12 membered heterocycloalkyl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted with one or more substituents independently being halogen, -OH, -CN, -NH2 or oxo;

[0014] m is independently 0, 1, 2 or 3;

[0015] L is each independently a chemical bond, C 1-3 alkylene, C 3-8 cycloalkylene or 4-12 membered heterocycloalkylene; said C 1-6 alkyl, C 1-3 alkylene, C 3-8Cycloalkylene and 4-12 membered heterocycloalkylene are each optionally substituted with one or more substituents which are independently halogen, C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2;

[0016] C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; b C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2;

[0017] C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; b C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2;

[0018] C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; c C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2;

[0019] C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; c C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 2-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 2-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 3-12 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 2-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 2-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 3-12 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 6-10 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2; 1-6 C1-6alkyl, -OC1-6alkyl, -CN, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2;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 group 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 group, -S(O)2C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl or 4-6 membered heterocyclic alkyl groups;

[0020] And / or, any two adjacent R c Together with the atoms attached to it, they form C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl; the C 5-12 Cycloalkyl, 5-12-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl are each optionally separated by one or more R e replace;

[0021] R e Each can be independently a halogen, oxo group, -OH, -CN, -NH2, or -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 3-6cycloalkyl or 4-6 membered heterocyclic alkyl;

[0022] In the heteroaryl group, the number of heteroatoms is independently 1, 2, 3 or 4, and each heteroatomole is independently N, O or S; in the heterocyclic alkyl and heterocyclic alkyl groups, the number of heteroatoms is independently 1, 2, 3 or 4, and each heteroatomole is independently N, O, P or S.

[0023] In some implementation schemes, R 1 Independently hydrogen, deuterium, or -C 1-6 alkyl.

[0024] In some implementation schemes, R 1 H stands for H independently.

[0025] In some implementations, group A is independently:

[0026] In some implementations, group A is independently...

[0027] In some implementations, group A is independently...

[0028] In some implementation schemes, R a Each can be independently represented by hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, or -C. 1-6 Alkyl or -OC 1-6 alkyl.

[0029] In some implementation schemes, R a Each can be independently hydrogen, halogen, -OH, -NH2, or -C. 1-6 Alkyl or -OC 1-6 alkyl.

[0030] In some implementation schemes, R a Each is independently hydrogen, halogen, or -OC. 1-6 alkyl.

[0031] In some implementations, m is independently 0, 1, or 2.

[0032] In some implementations, m is independently 0.

[0033] In some implementations, L is independently a chemical bond or C. 1-3 Alkylene.

[0034] In some implementations, L is independently C 1-3 Alkylene.

[0035] In some implementations, L is independently -CH2-.

[0036] In some embodiments, group B is independently a phenyl or a 5-6-membered heteroaryl group; said phenyl and 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. b replace.

[0037] In some embodiments, group B is independently phenyl or pyridyl; said phenyl and pyridyl groups are optionally surrounded by one or two R groups. b replace.

[0038] In some implementations, group B is independently... The a-terminal is connected to the carbonyl group shown, and the b-terminal is connected to the alkynyl group or C-group shown; for example...

[0039] In some implementations, group B is independently...

[0040] In some implementation schemes, R b Each is independently hydrogen, deuterium, halogen, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl group 2; the alkyl group is optionally substituted by one or more substituents that are independently halogen, -OH, -CN, or -NH2.

[0041] In some implementation schemes, R b Each is independently hydrogen, deuterium, halogen, -OC 1-3 Alkyl, -CN, -NH2, -NHCH3 or -N(CH3)2.

[0042] In some implementation schemes, R b Each can be independently hydrogen, deuterium, F, Cl, -OCH3, or -NH2.

[0043] In some embodiments, group C is independently a phenyl or a 5-6-membered heteroaryl group; said phenyl and 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. c replace.

[0044] In some embodiments, group C is independently a phenyl group, said phenyl group optionally being surrounded by one or two R groups. c replace.

[0045] In some embodiments, group C is independently a 5-8 membered cycloalkyl or a 5-8 membered heterocycloalkyl; said 5-8 membered cycloalkyl and 5-8 membered heterocycloalkyl are optionally surrounded by one or more R c replace.

[0046] In some embodiments, group C is independently a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl; said 5-6 membered cycloalkyl and 5-6 membered heterocycloalkyl are optionally surrounded by one or more R c replace.

[0047] In some embodiments, group C is independently pyrroleyl. Piperidinyl Azaheptanyl Or 1,3-oxazine-heptanyl The pyrrolidinyl, piperidinyl, aziridine-heptyl, and 1,3-oxaziridine-heptyl groups are optionally separated by one or more R groups. c replace.

[0048] In some embodiments, group C is independently piperidinyl. (For example ); the piperidine group Optionally by one or more R c replace.

[0049] In some implementation schemes, R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-3 Alkyl, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl group; the C group mentioned above 1-3 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more independent halogens, -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 group 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 group, -S(O)2C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl or 4-6 membered heterocyclic alkyl groups.

[0050] In some implementation schemes, R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-3 Alkyl, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2.

[0051] In some implementation schemes, R c Each can be independently hydrogen, F, Cl, -CH3, -OCH3, -CN, -NH2, -NHCH3 or -N(CH3)2.

[0052] In some implementation schemes, R c Each can be independently hydrogen, F, Cl, -CH3, -OCH3, or -NH2.

[0053] In some embodiments, in formula (I), formula (I-1), formula (I-1a), formula (I-1b), or formula (I-1c), group C is independently phenyl or a 5-6-membered heteroaryl; said phenyl and 5-6-membered heteroaryl are optionally surrounded by one or more R c Replace; R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10The aryl group and the 5-10 heteroaryl group are each optionally surrounded by one or more independent halogens, -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 group 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 group, -S(O)2C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl or 4-6 membered heterocyclic alkyl groups.

[0054] In some implementations, group C is

[0055] In some implementations, any two adjacent R c Together with the atoms attached to it, they form C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl; the C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl are each optionally separated by one or more R e replace.

[0056] In some implementations, any two adjacent R c Together with the atoms attached thereto, they form a 5-6 membered heteroaryl or phenyl group; the 5-6 membered heteroaryl and phenyl group are each optionally bonded by one or more R groups. e replace.

[0057] In some implementations, any two adjacent R c Together with the atoms bonded to it, a phenyl group is formed; each of the phenyl groups is optionally bonded by one or more R atoms. e replace.

[0058] In some implementation schemes, R e Independently halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl)2.

[0059] In some implementation schemes, R e Each can be independently a halogen, -OH, -CN, -NH2, or C. 1-3 Alkyl, -C 1-3 Alkyl-OH, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2.

[0060] In some implementation schemes, R e Each can be independently hydrogen, F, Cl, -OCH3, -NH2, -NHCH3 or -N(CH3)2.

[0061] In some implementation schemes, R e Each can be independently hydrogen, F, Cl, or -NH2.

[0062] In some embodiments, in formula (II), formula (II-1), or formula (II-1a), group C is independently a 5-8 membered cycloalkyl or a 5-8 membered heterocycloalkyl; said 5-8 membered cycloalkyl and 5-8 membered heterocycloalkyl are optionally surrounded by a plurality of R c replace;

[0063] R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-3 Alkyl, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2;

[0064] And / or, any two adjacent R c Together with the atoms attached to it, they form C 5-12 Cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl; the C 5-12 Cycloalkyl, 5-12-membered heterocycloalkyl, 5-6-membered heteroaryl and phenyl are each optionally separated by one or more Re replace.

[0065] In some implementations, group C is independently... Preferably, group C is independently...

[0066] In some implementations, each halogen is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0067] In some implementations, each C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl, such as methyl.

[0068] In some implementations, each -OC 1-6 The alkyl group 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.

[0069] In some implementations, each C 2-6 The alkenyl group can be vinyl, propenyl, allyl, butenyl, or pentenyl.

[0070] In some implementations, each C 2-6 The alkynyl group can be independently ethynyl, propynyl, propynyl, butynyl, or pentylyyl, for example...

[0071] In some implementations, each C 3-12 The cycloalkyl group is independently C 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0072] In some embodiments, the cycloalkyl group is a saturated cycloalkyl group.

[0073] In some embodiments, the cycloalkyl group is a partially saturated cycloalkyl group; the partially saturated cycloalkyl group has one or more unsaturated bonds.

[0074] In some implementations, each 4-12 membered heterocyclic alkyl group is independently a 5-8 membered heterocyclic alkyl group.

[0075] In some embodiments, the number of heteroatoms in each 4-12 membered heterocyclic alkyl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S; preferably, the number of heteroatoms in each 4-12 membered heterocyclic alkyl group is independently 1 or 2, and the heteroatoms are independently N or O.

[0076] In some embodiments, each 4-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic, wherein the polycyclic group is a bridged ring, fused ring, or spirocyclic ring; the polycyclic group is bicyclic or tricyclic; preferably, each 4-12 membered heterocyclic alkyl group is independently a 5-6 membered monocyclic heterocyclic alkyl group, a 9-10 membered bicyclic heterocyclic alkyl group, or an 11-12 membered tricyclic heterocyclic alkyl group.

[0077] In some embodiments, the heterocyclic alkyl group is a saturated heterocyclic alkyl group.

[0078] In some embodiments, the heterocyclic alkyl group is a partially saturated heterocyclic alkyl group; the number of unsaturated bonds in the partially saturated heterocyclic alkyl group is one or more.

[0079] In some implementations, each m is independently 0 or 1.

[0080] In some implementations, each m is independently 0.

[0081] In some implementations, each C 1-3 The alkylene group is independently methylene, ethylene, n-propylene, or isopropylene.

[0082] In some implementations, each C 3-8 Cycloalkylene groups are independently C 3-6 Cycloalkylene compounds, such as cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, preferably cyclopropylene or cyclobutylene.

[0083] In some embodiments, the cycloalkylene group is a saturated cycloalkylene group.

[0084] In some embodiments, the cycloalkylene group is a partially saturated cycloalkylene group; the partially saturated cycloalkylene group has one or more unsaturated bonds.

[0085] In some embodiments, each 4-12 membered heterocyclic alkyl group is independently a 5-8 membered heterocyclic group.

[0086] In some embodiments, the number of heteroatoms in each 4-12-membered heterocyclic alkyl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S; preferably, the number of heteroatoms in each 4-12-membered heterocyclic alkyl group is independently 1 or 2, and the heteroatoms are independently N or O.

[0087] In some embodiments, each 4-12 membered heterocyclic alkyl group is independently monocyclic or polycyclic, wherein the polycyclic group is a bridged ring, a fused ring, or a spirocyclic ring; the polycyclic group is a bicyclic or tricyclic ring; preferably, the 4-12 membered heterocyclic alkyl group is independently a 5-6 membered monocyclic heterocyclic alkyl group, a 9-10 membered bicyclic heterocyclic alkyl group, or an 11-12 membered tricyclic heterocyclic alkyl group.

[0088] In some embodiments, the heterocyclic alkyl group is a saturated heterocyclic alkyl group.

[0089] In some embodiments, the heterocyclic alkyl group is a partially saturated heterocyclic alkyl group; the partially saturated heterocyclic alkyl group has one or more unsaturated bonds.

[0090] In some implementations, each halogenation is independently fluorinated, chlorinated, brominated, or iodinated; for example, fluorinated or chlorinated.

[0091] In some implementations, each C 6-10 The aryl group can be phenyl or naphthyl, for example, phenyl.

[0092] In some implementations, the number of heteroatoms in each 5-10 aryl group is independently 1, 2, or 3, and the heteroatoms are independently N, O, or S.

[0093] In some implementations, each 5-10 nucleotide heteroaryl group is independently a monocyclic or bicyclic ring, wherein the bicyclic ring is a fused ring.

[0094] In some embodiments, each 4-14 membered heterocyclic alkyl group is a 5-12 membered heterocyclic alkyl group; preferably a 5-8 membered heterocyclic alkyl group.

[0095] In some embodiments, each 4-14 membered heterocyclic alkyl group has one, two, or three heteroatoms, and the heteroatoms are N, O, or S; preferably, the number of heteroatoms is one or two, and the heteroatoms are N.

[0096] In some embodiments, each 4-14 membered heterocyclic alkyl group has a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring, wherein the polycyclic is a bridged ring, a fused ring, or a spirocyclic ring.

[0097] In some embodiments, each 4-14 membered heterocyclic alkyl group contains 0, 1, or 2 saturated rings, preferably 1 unsaturated ring and at least one saturated ring; the unsaturated ring is preferably aryl, such as phenyl.

[0098] In some embodiments, when each 4-14 membered heterocyclic alkyl group contains one unsaturated ring and at least one saturated ring, the heteroatom is located on the saturated ring.

[0099] In some implementations, each 4-14 membered heterocyclic alkyl group contains 0, 1, or 2 unsaturated bonds.

[0100] In some embodiments, each 4-14 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic heterocyclic alkyl group; preferably a 5-8 membered monocyclic heterocyclic alkyl group, a 9-10 membered bicyclic heterocyclic alkyl group, or an 11-14 membered tricyclic heterocyclic alkyl group; for example

[0101] For example

[0102] In some implementations, each C 3-6 The cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0103] In some embodiments, the compound with the structure shown in formula (I) is the compound shown in formula (I-1):

[0104]

[0105] in,

[0106] Group B and group C are each independently described as in any embodiment of formula (I) of the present invention.

[0107] In some embodiments, compounds with structures shown in formula (I) and formula (I-1), wherein

[0108] Group B is independently a phenyl or a 5-6-membered heteroaryl group; said phenyl and 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. b replace;

[0109] R b Each is independently hydrogen, deuterium, halogen, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl group 2; the alkyl group is optionally substituted by one or more substituents that are independently halogen, -OH, -CN or -NH2;

[0110] Group C is independently a phenyl or a 5-6-membered heteroaryl group; said phenyl and 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. c replace;

[0111] R c Each is independently hydrogen, deuterium, halogen, -C 1-3 Alkyl, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2.

[0112] In some embodiments, compounds with the structures shown in formula (I) and formula (I-1), wherein,

[0113] Group B is independently phenyl or pyridyl, wherein the phenyl and pyridyl groups are optionally surrounded by one or more R groups. b replace;

[0114] Rb Each can be independently hydrogen, F, or Cl;

[0115] Group C is independently a phenyl group, wherein the phenyl group is optionally surrounded by one or more R groups. c replace;

[0116] R c Each can be independently hydrogen, F, Cl, -OCH3, -NH2, -NHCH3 or -N(CH3)2.

[0117] In some embodiments, the compounds with structures shown in formulas (I) and (I-1) are the compounds shown in formulas (I-1a), (I-1b), and (I-1c):

[0118]

[0119]

[0120] R b R c Each is independently described in any one of formulas (I) and (II-1) of the present invention;

[0121] n and q are each independently 0, 1, 2 or 3.

[0122] In some embodiments, the compound with the structure shown in formula (II) is the compound shown in formula (II-1):

[0123]

[0124] in,

[0125] Group B and group C are each independently described as in any embodiment of the present invention.

[0126] In some embodiments, compounds with structures shown in formula (II) and formula (II-1), wherein

[0127] Group B is independently a phenyl or a 5-6-membered heteroaryl group; said phenyl and 5-6-membered heteroaryl group are optionally surrounded by one or more R groups. b replace;

[0128] R b Each is independently hydrogen, deuterium, halogen, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl group 2; the alkyl group is optionally substituted by one or more substituents that are independently halogen, -OH, -CN or -NH2;

[0129] Group C is independently a 5-8 membered cycloalkyl or a 5-8 membered heterocycloalkyl; said 5-8 membered cycloalkyl and 5-8 membered heterocycloalkyl are optionally surrounded by one or more R c replace;

[0130] R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-3 Alkyl, -OC 1-3 Alkyl, -CN, -NH2, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2;

[0131] Or, any two adjacent R c Together with the atoms attached thereto, they form a 5-6 membered heteroaryl or phenyl group; the 5-6 membered heteroaryl and phenyl group are each optionally bonded by one or more R groups. e replace;

[0132] R e Each can be independently a halogen, -OH, -CN, -NH2, or -C. 1-3 Alkyl, -C 1-3 Alkyl-OH, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2.

[0133] In some embodiments, compounds with structures shown in formula (II) and formula (II-1), wherein

[0134] Group B is independently a phenyl group; said phenyl group is optionally surrounded by one or more R groups. b replace;

[0135] R b Each can be independently hydrogen, F, or Cl;

[0136] Group C is independently pyrroleyl Piperidinyl Azaheptanyl Or 1,3-oxazine-heptanyl The pyrrolidinyl, piperidinyl, aziridine-heptyl, and 1,3-oxaziridine-heptyl groups are optionally surrounded by a plurality of R groups. c replace;

[0137] R c Each can be independently hydrogen, F, Cl, -CH3, -OCH3, or -NH2;

[0138] Any two adjacent R c Together with the atoms bonded to it, a phenyl group is formed; each of the phenyl groups is optionally bonded by one or more R atoms. e replace;

[0139] Re Each can be independently hydrogen, F, Cl, -OCH3, -NH2, -NHCH3 or -N(CH3)2.

[0140] In some embodiments, the compounds with structures shown in formulas (II) and (II-1) are the compounds shown in formulas (II-1a), (II-1b), (II-1c), (II-1d), and (II-1e):

[0141]

[0142] in,

[0143] R b R c R e Each is independently described in any one of formulas (II) and (II-1) of the present invention;

[0144] n, p, and q are each independently 0, 1, 2, or 3.

[0145] In some embodiments, the compounds of formulas (I) and (II) of the present invention are any of the following compounds:

[0146]

[0147] Those skilled in the art will understand that this invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features from one embodiment with technical features or preferred technical features from another embodiment are also included within the scope of this invention.

[0148] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0149] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug and a pharmaceutically acceptable excipient thereof.

[0150] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining the compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0151] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0152] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0153] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0154] This invention also relates to a pharmaceutical formulation comprising, as an active ingredient, a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0155] A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. The article of manufacture as used herein is intended to include, but is not limited to, medicine boxes and packaging. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition contained 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) optionally present packaging instructions stating that the pharmaceutical composition may be used to treat oncological conditions (as defined below); and (d) a second container.

[0156] The first container is a container for containing a pharmaceutical composition. This container may be used for the 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 the preparation, containment, storage, or dispensing of pharmaceutical products.

[0157] The second container is a container for holding the first container and optional instruction manuals. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic boxes), cartons, cartons, bags (e.g., paper or plastic bags), sachets, and cloth bags. The instruction manuals may be physically attached to the outside of the first container by cable ties, glue, U-staples, or other adhesive methods, or they may be placed inside the second container without any physical means of attachment to the first container. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferable that the instruction manuals are physically attached by cable ties, glue, U-staples, or other adhesive methods. Alternatively, they may be adjacent to or in contact with the outside of the second container without physical attachment.

[0158] The packaging instructions, such as trademarks, labels, or markings, list information relating to the pharmaceutical composition contained within the first container. The listed information is typically determined by the regulatory authority governing the region where the product is to be sold (e.g., the U.S. Food and Drug Administration). Preferably, the packaging instructions specifically list the approved indications for which the pharmaceutical composition is used. The packaging instructions can be made of any material from which information contained therein or on the material can be read. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic) on which the desired information can be formed (e.g., printed or coated).

[0159] In another aspect, the present invention provides the application of substance Y in the preparation of a drug, wherein substance Y is a compound of formula (I) or (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or a pharmaceutical composition thereof.

[0160] Preferably, the drug satisfies one of the following conditions:

[0161] The drug is used to treat and / or prevent cancer;

[0162] The drug is a medicine used to prevent and / or treat GSPT1-related diseases or conditions.

[0163] In some implementations, 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 cancer (e.g., stomach cancer, intestinal 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 lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0164] In some implementations, the GSPT1-related disease or condition is a disease or condition that is sensitive to or responsive to GSPT1 degradation.

[0165] In some implementations, the GSPT1-related disease or condition 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 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 lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0166] In another aspect, the present invention provides the application of substance Y in the preparation of GSPT1 degrading agent, wherein substance Y is a compound of formula (I) or (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or a pharmaceutical composition thereof.

[0167] In some embodiments, the GSPT1 degrading agent can achieve at least one of the following technical effects:

[0168] (1) High inhibitory activity against GSPT1;

[0169] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability);

[0170] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action);

[0171] (4) Excellent safety profile (lower toxicity and / or fewer side effects, wider therapeutic window).

[0172] In another aspect, the present invention provides a method for preventing or treating GSPT1-related diseases or conditions, the method comprising administering to an individual in need an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or the pharmaceutical composition of the present invention.

[0173] In some implementations, the GSPT1-related disease or condition is a disease that is sensitive to or responsive to GSPT1 degradation.

[0174] In some implementations, the GSPT1-related disease or condition 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 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 lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0175] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat cancer.

[0176] In another aspect, the present invention provides a method for preventing or treating cancer, the method comprising administering to an individual in need an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or pharmaceutical composition of the present invention; preferably, the cancers include, but are 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 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 lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0177] In a further preferred embodiment, the compounds of the present invention can be used in combination with radiotherapy, chemotherapy, or immunotherapy to prevent or treat cancer.

[0178] In another aspect, the present invention provides a substance X for treating cancer; said substance X is a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or a pharmaceutical composition of the present invention. Preferably, the cancers include, but are 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 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 lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), multiple myeloma and lymphoma.

[0179] The present invention provides a novel class of highly active GSPT1 degrading agents 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.

[0180] General Terms and Definitions

[0181] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0182] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0183] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0184] Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by moles.

[0185] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0186] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0187] For example, the expression "C" 1-6 "This should be understood as encompassing any subrange and each point value, such as C." 2-5 C 3-4 C 1-2 C 1-3 C1-4 C 1-5 And so on, as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "C 3-10 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C." 3-9 C 6-9 C 6-8 C 6-7 C 7-10 C 7-9 C 7-8 C 8-9 And C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "3-10 yuan" should be understood as encompassing any sub-range and each point value within it, 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. Similarly, the expression "5-10 yuan" should also be understood in a similar way, for example, it can encompass any sub-range and point value included within it, 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.

[0188] The expression "(X)" 0-1 When the value is 0, it indicates a connector key, for example, "(C 1-6 "(alkylene)0" is the connecting bond.

[0189] When used alone or in combination with other groups herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. As used herein, the term "C" refers to a saturated straight-chain or branched hydrocarbon group. 1-6 "Alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). "C" 1-6 "alkyl" can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0190] When used alone or in combination with other groups herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon group. As used herein, the term "C 1-6 "Alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group having 1-6 carbon atoms. 1-6 "Alkylene" includes, but is not limited to, methylene, ethylene, propylene, or butylene.

[0191] The term "alkenyl" refers to an alkenyl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C6 ...2-6 ( ) a straight-chain or branched, unsaturated monovalent hydrocarbon group, which has carbon-carbon sp 2 Double bond.

[0192] The term "alkynyl" refers to a group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C6 ... 2-6 Alkynes are straight-chain or branched, unsaturated monovalent hydrocarbon groups with a carbon-carbon sp triple bond. Alkynes include, but are not limited to: wait.

[0193] 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, "C 3-12 "Cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (e.g., 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 bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.

[0194] In this application, the term "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic dicyclic group. For example, "C 3-12 "Cycloalkylene" or "3-12-membered cycloalkylene" refers to cycloalkylene compounds having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkylene compounds include (but are not limited to) monocyclic cycloalkylene compounds, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkylene compounds, including fused rings, bridged rings, or spirocyclic compounds, such as bicyclic[1.1.1]pentylene, bicyclic[2.2.1]heptylene, bicyclic[3.2.1]octylene, bicyclic[5.2.0]nonylene, decahydronaphthylene, etc.

[0195] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated, non-aromatic cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. 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 heterocyclic alkyl group can be monocyclic or polycyclic, and the polycyclic group can be a fused ring, spirocyclic, or bridged ring structure. Examples include 3-12-membered, 3-10-membered, 3-8-membered, 3-6-membered, 5-8-membered, 5-6-membered, or 4-8-membered heterocyclic alkyl groups. Furthermore, the heterocyclic alkyl group can contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, oxocyclobutane, nitrogen-containing heterocyclic butane, pyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, pyrrolidone, etc.

[0196] The term "heterocyclic alkylene" refers to a saturated or partially unsaturated, non-aromatic divalent cyclic group containing at least one heteroatom selected from N, O, P, and S as a ring member. 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 heterocyclic alkylene can be monocyclic or polycyclic, and the polycyclic can be fused, spirocyclic, or bridged ring structures. For example, 3-8 membered or 3-6 membered heterocyclic alkylene. Furthermore, the heterocyclic alkylene can contain 0, 1, 2, or 3 oxo groups. Specific examples include, but are not limited to, ethylene oxide, cyclobutane, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazine, tetrahydropyranyl, homopiperazine, and pyrrolidone.

[0197] The term "fused ring (fused ring system)" refers to a polycyclic structure formed by two or more (e.g., 3, 4, or 5) carbon rings or heterocycles sharing a common ring edge, wherein the carbon rings include cycloalkyl and aryl groups, and the heterocycles include heteroaryl and heterocyclic alkyl groups. The fused ring systems include, but are not limited to: fused ring systems formed by cycloalkyl groups with cycloalkyl groups, fused ring systems formed by cycloalkyl and heterocyclic alkyl groups, fused ring systems formed by cycloalkyl and aryl groups, fused ring systems formed by cycloalkyl and heterocyclic aryl groups, fused ring systems formed by heterocyclic alkyl and aryl groups, fused ring systems formed by heterocyclic aryl and heterocyclic aryl groups, fused ring systems formed by heterocyclic aryl and heterocyclic aryl groups, and fused ring systems formed by heterocyclic aryl and aryl groups, etc.

[0198] In this application, the term "aryl" or "aromatic ring" refers to a monocyclic or fused-ring aromatic hydrocarbon group having a conjugated π-electron system. For example, the term "C" as used herein... 6-10 "Aryl" refers to an aryl group having 6-10 carbon atoms (such as phenyl, naphthyl, etc.).

[0199] In this application, the term "heteroaryl" or "heteroary ring" refers to a monocyclic and fused heterocyclic system 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. Heteroaryl or heteroary rings can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl may 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 thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or indoleyl, etc.

[0200] In this application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0201] In this application, the term "hydroxyl group" refers to -OH.

[0202] In this application, the term "cyano" refers to -CN.

[0203] In this application, the term "nitro" refers to -NO2.

[0204] In this application, the term "amino" refers to -NH2.

[0205] In this application, "oxo" refers to C(O), i.e., carbonyl group.

[0206] When used alone or in combination with other groups in this application, the term "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 "Halogenated alkyl" refers to a C-aryl group optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0207] When used alone or in combination with other groups in this application, the term "alkoxy" means an alkyl group to which an oxygen atom is attached as described above to the parent molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and pentoxy.

[0208] As used in this application, the term "each independently" means that at least two groups (or segments) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent A and substituent B are each independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent A is hydrogen, substituent B can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent B is hydrogen, substituent A can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0209] As used herein, the term "substitution" and its other variations refer to the replacement of one or more (e.g., 1, 2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on a specified atom with other equivalents, provided that the replacement does not exceed the normal valence of the specified atom or group of atoms in the present case and is capable of forming a stable compound. If an atom or group of atoms is described as "optionally substituted," it may or may not be substituted. Unless otherwise stated, the linking site of a substituent herein may be derived from any suitable position of the substituent. When the linking bond in a substituent is shown as a chemical bond passing through two atoms connected to each other in a ring system, it indicates that the substituent may be linked to any one of the cyclic atoms in the ring system.

[0210] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the connection of the corresponding group R to other segments or groups in the compound through this site. The "-" at the end of the group indicates that the group is connected to other segments in the molecule through this site. For example, CH3-C(=O)- means that the C(=O) in the acetyl group is connected to other segments in the molecule.

[0211] In this application, unless otherwise specified, 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 whose structures are identical to those of this application except that hydrogen atoms are replaced by deuterium or tritium, or carbon atoms are replaced by carbon-13 or carbon-14, are within the scope of this application.

[0212] This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0213] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0214] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “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.

[0215] As used herein, the term "ester" means an ester derived from the compounds described herein, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0216] The compounds of the present invention can exist as solvates (preferably hydrates). The amount of polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0217] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0218] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0219] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0220] This invention also covers methods for preparing the compounds described herein. It should be understood that the compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof understood by 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 suitable for the reagents and materials used and suitable for achieving the conversion.

[0221] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat one or more symptoms of a target condition or disease.

[0222] As used herein, the term "effective amount" (e.g., "therapeutic effective amount" or "preventive effective amount") refers to the amount of active ingredient that, when administered, will achieve the desired effect to a certain extent, such as relieving one or more symptoms of the treated condition or preventing the occurrence of the condition or its symptoms.

[0223] Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition to which such term applies, or one or more symptoms of such a disease or condition, or to prevent such a disease or condition, or one or more symptoms of such a disease or condition.

[0224] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes 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.).

[0225] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0226] The reagents and raw materials used in this invention are all commercially available.

[0227] The positive and progressive effects of this invention are as follows: the compounds of this invention can be used to degrade proteins such as GSPT1, thereby preventing, alleviating or treating diseases related to the dysregulation of these proteins; at the same time, the compounds of this invention can also serve as the effective payload of ligand drug conjugates (e.g., antibody drug conjugates), further expanding the indications of the compounds of this invention. Detailed Implementation

[0228] This invention includes all combinations of the specific embodiments described. Further embodiments of the invention and the full scope of its applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific embodiments indicate preferred embodiments of the invention, these descriptions and embodiments are provided by way of illustration only, as various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. For all purposes, all disclosures, patents, and patent applications cited herein, including in quotation marks, are incorporated herein by reference in their entirety. The invention is further illustrated below by way of examples, but this does not limit the invention to the scope of the examples described. Experimental methods in the following examples, unless specific conditions are specified, are performed according to conventional methods and conditions, or as selected according to the trade specification.

[0229] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0230] The preparative high performance liquid chromatography (HPLC) method was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm column).

[0231] Thin-layer chromatography purification was performed using GF 254 (0.4–0.5 nm) silica gel plates produced in Yantai.

[0232] The reaction was monitored using thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used included, but were 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 solvent was adjusted according to the polarity of the compound, or by adding triethylamine, etc.

[0233] Column chromatography typically uses 200-300 mesh silica gel from Qingdao Ocean 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 solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0234] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0235] 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, etc.

[0236] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the 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. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

[0237] The meanings of the abbreviations in the conventional synthesis methods, preparation examples, and intermediate synthesis examples are shown in the table below.

[0238]

[0239]

[0240] Synthesis of intermediates:

[0241] Example 1 of intermediate preparation:

[0242]

[0243] Step 1: Synthesis of compound Int1-2

[0244] Ethoxyformylmethylenetriphenylphosphine (11.4 g, 27.1 mmol) was added to a toluene (100 mL) solution of compound Int1-1 (5 g, 22.6 mmol), and the mixture was stirred at 130 °C for 16 h. After the reaction was confirmed to be complete by LMCS, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography to extract compound Int1-2 (9.0 g, 78% yield).

[0245] Step 2: Synthesis of compound Int1-3

[0246] Pd2(dba)3 (1.6 g, 1.8 mmol) was added to a DMF (50 mL) solution of compound Int1-2 (5.0 g, 17.7 mmol), Zn(CN)2 (4.16 g, 35.46 mmol), and DPPF (1.0 g, 1.8 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was confirmed to be complete by LMCS, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was column-chromatographically purified to obtain compound Int1-3 (2.5 g, yield 62%).

[0247] Step 3: Synthesis of compound Int1-4

[0248] At 0°C, tBuOK (1.3 g, 12.0 mmol) was added to a DMF (30 mL) solution of compound Int1-3 (2.5 g, 10.9 mmol), and stirring was continued for 0.5 hours after the addition was complete. Acrylamide (0.8 g, 10.9 mmol) was then slowly added to the reaction solution while maintaining this temperature. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction was confirmed to be complete by LCMS, a saturated ammonium chloride solution and ethyl acetate were added to the reaction solution. After stirring, the mixture was separated into liquid and liquid phases. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with methanol to obtain compound Int1-4 (1.8 g, 63% yield).

[0249] Step 4: Synthesis of compound Int1

[0250] Pd / C (10%, 180 mg) and hydrochloric acid (1 mL) were added to a methanol (100 mL) solution of compound Int1-4 (1.8 g, 5.5 mmol), and the mixture was stirred at room temperature for 16 h. The solution was filtered and concentrated, and purified by slurrying in methanol to give compound Int-1 (1.0 g, 55% yield).

[0251] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.37(s,3H),7.96(s,1H),7.73(s,1H),7.63(d,J=8.0Hz,1H), 7.36(dd,J=8.1,1.1Hz,1H),4.20–4.09(m,3H),2.76(m,1H),2.58(m,1H),2.34(m,1H),2.11(m,1H).

[0252] Example 1: Synthesis of Compound 15

[0253]

[0254] Step 1: Synthesis of Compound 15-2

[0255] Under nitrogen protection, compound 15-1 (1.92 g, 6.0 mmol) was dissolved in DMF (50 mL), and ethyl 4-bromo-3-chlorobenzoate (1.49 g, 6.0 mmol), Pd2(dba)3 (0.55 g, 0.6 mmol), X-Phos (0.57 g, 1.2 mmol), and K3PO4 (5.1 g, 24.0 mmol) were added sequentially. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. After the reaction was complete, the system was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography purification yielded compound 15-2 (1.1 g, 39% yield). Step 2: Synthesis of compound 15-3

[0256] Compound 15-2 (1.10 g, 2.4 mmol) was dissolved in ethyl acetate (15 mL), and palladium on carbon (0.33 g, 10%) was added. The reaction solution was reacted overnight at 25 °C under hydrogen protection. After the reaction was complete, the mixture was filtered, the residue was evaporated to dryness, and the residue was purified by column chromatography to give compound 15-3 (0.48 g, 62% yield).

[0257] Step 3: Synthesis of Compound 15-4

[0258] Compound 15-3 (370.0 mg, 0.89 mmol) was dissolved in tetrahydrofuran (10.0 mL), and saturated sodium bicarbonate aqueous solution (1.5 mL) and di-tert-butyl dicarbonate (654.0 mg, 3.0 mmol) were added sequentially. The reaction solution was reacted overnight at 25 °C. After the reaction was complete, the solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the residue was purified by column chromatography to give compound 15-4 (370.0 mg, 59% yield).

[0259] Step 4: Synthesis of Compound 15-5

[0260] Compound 15-4 (370.0 mg, 0.89 mmol) was dissolved in tetrahydrofuran and water (8 mL), and lithium hydroxide (204.7 mg, 8.9 mmol) was added. The reaction mixture was stirred overnight at 25 °C. After the reaction was complete, the solution was diluted with water, the pH was adjusted to 1 with 1 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography to give compound 15-5 (190.0 mg, yield 51.4%).

[0261] Step 5: Synthesis of Compounds 15-6

[0262] Compound 15-5 (30.0 mg, 0.07 mmol) was dissolved in DMF (2 mL), and compound Int-1 (18.1 mg, 0.07 mmol), HATU (30.4 mg, 0.08 mmol), HOAT (10.9 mg, 0.08 mmol), and TMP (33.9 mg, 0.28 mmol) were added. The reaction mixture was reacted overnight at 25 °C. After the reaction was confirmed to be complete by LCMS, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15-6 (20.0 mg, 43% yield).

[0263] Step 6: Synthesis of Compound 15

[0264] Compound 15-6 (20.0 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and HCl / dioxane (0.5 mL, 4 N) was added. The reaction mixture was stirred at 25 °C for 15 min. After the reaction was completed, the mixture was concentrated, and the residue was purified by reverse HPLC to obtain compound 15 (3.2 mg, yield 18%).

[0265] MS m / z (ESI): 543.2 [M+H] +

[0266] 1H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.13 (t, J = 5.6Hz, 1H), 8.01 (s, 1H), 7.88 (d, J = 10. 4Hz,2H),7.51(dd,J=16.7,9.2Hz,2H),7.32(dd,J=8.1,2.4Hz,2H),7.25–7.16(m,3H),4. 57(d,J=5.5Hz,2H),4.31(s,2H),4.13(dd,J=12.0,4.6Hz,1H),3.02-2.95(m,2H),2.92- 2.86(m,1H),2.80-2.67(m,2H),2.62-2.58(m,1H),2.38-2.26(m,2H),2.17–1.94(m,2H).

[0267] Example 2: Synthesis of Compound 16

[0268]

[0269] Step 1: Synthesis of Compound 16-2

[0270] At room temperature, Pd(OAc)₂ (14.62 mg, 0.065 mmol) was added to a toluene (5 mL) solution of compound 16-1 (0.20 g, 0.710 mmol), ethyl 4-iodo-3-chlorobenzoate (0.20 g, 0.650 mmol), Cs₂CO₃ (0.63 g, 1.940 mmol), and X-Phos (61.97 mmol, 0.13 mmol). The reaction mixture was reacted overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 16-2 (0.19 g, 63% yield).

[0271] Step 2: Synthesis of Compound 16-3

[0272] At room temperature, lithium hydroxide (0.12 g, 2.05 mmol) was added to a methanol / water (5 mL / 3 mL) solution of compound 16-2 (0.19 g, 0.41 mmol). The reaction mixture was reacted overnight at 25 °C. After the reaction was complete, water was added, and the pH was adjusted to 6 with 1 N hydrochloric acid solution, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 16-3 (0.12 g, 67% yield).

[0273] Step 3: Synthesis of Compound 16-4

[0274] At room temperature, Pd(OH)₂ / C (5 mg, 10%) was added to a DMF (1 mL) solution of compound 16-3 (30 mg, 68.74 μmol). The reaction was carried out in hydrogen atmosphere for 30 minutes. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, and the filtrate was concentrated to give compound 16-4 (20 mg, 96% yield).

[0275] Step 4: Synthesis of Compound 16

[0276] At room temperature, DIEA (19.25 mg, 0.15 mmol) was added to a DMF (1 mL) solution of compound 16-4 (15.00 mg, 49.65 μmol), Int1 (12.82 mg, 49.65 μmol), and HATU (22.66 mg, 59.58 μmol). The reaction mixture was reacted at 25 °C for 1 h. After the reaction was complete as detected by LCMS, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reverse HPLC to give compound 15 (5 mg, 20% yield).

[0277] MS m / z (ESI): 543.2 [M+H] +

[0278] 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 9.18 (t, J = 5.6Hz, 1H), 7.98 (s, 1H), 7.8 7(d,J=10.4Hz,2H),7.51–7.47(m,3H),7.35–7.26(m,2H),7.20–7.11(m,2H), 4.57–3.31(m,5H),4.11(d,J=4.6Hz,1H),3.03-2.96(m,2H),2.94–2.87(m,1H ),2.82–2.68(m,2H),2.64–2.57(m,1H),2.39–2.24(m,2H),2.18–1.93(m,2H).

[0279] Example 3: Synthesis of Compound 2

[0280]

[0281] Step 1: Synthesis of compounds 2-3

[0282] At room temperature, Pd(PPh3)2Cl2 (45.3 mg, 64.5 μmol) and CuI (0.1 g, 0.6 mmol) were added to a toluene (5 mL) solution of compound 2-1 (0.20 g, 0.6 mmol), compound 2-2 (0.15 g, 0.7 mmol), and TEA (0.20 g, 1.9 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give compound 2-3 (0.18 g, 70% yield).

[0283] Step 2: Synthesis of compounds 2-4

[0284] At room temperature, lithium hydroxide (0.1 g, 2.3 mmol) was added to a methanol (5 mL) and water (3 mL) solution of compound 2-3 (180.0 mg, 0.5 mmol). The mixture was reacted overnight at 25 °C. After the reaction was complete, water was added, the pH was adjusted to 6 with 1 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give compound 2-4 (100 mg, 60% yield).

[0285] Step 3: Synthesis of compounds 2-5

[0286] At room temperature, DIEA (52.2 mg, 0.4 mmol) was added to a DMF (1 mL) solution of compounds 2-4 (50.0 mg, 0.1 mmol), Int1 (34.8 mg, 0.13 mmol), and HATU (61.5 mg, 0.2 mmol). The reaction mixture was reacted at 25 °C for 1 h. After the reaction was complete as detected by LCMS, water and ethyl acetate were added to the reaction mixture, and the mixture was stirred and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reverse HPLC to give compound 2-5 (55 mg, yield 66.7%).

[0287] Step 4: Synthesis of Compound 2

[0288] At room temperature, TFA (1.0 mL) was added to a solution of compound 2-5 (35.0 mg, 57.3 μmol) in dichloromethane (1 mL). The reaction mixture was reacted at 25 °C for 30 min, the mixture was concentrated, and the residue was purified by reverse HPLC to obtain compound 2 (10.0 mg, 34%).

[0289] MS m / z (ESI): 512.2 [M+H] +

[0290] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.32(t,J=5.6Hz,1H),8.10(s,1H),7.94–7.86(m ,2H),7.79(d,J=8.0Hz,1H),7.54(d,J=8.3Hz,2H),7.35–7.30(m,1H),7.24(d,J=8.0Hz ,1H),7.16(d,J=9.2Hz,2H),7.03(d,J=7.9Hz,1H),4.59(d,J=5.7Hz,2H),4.16–4.10(m ,1H),2.77–2.72(m,1H),2.57(d,J=17.5Hz,1H),2.34–2.28(m,1H),2.14–2.08(m,1H).

[0291] Example 4: Synthesis of Compound 1

[0292]

[0293] Compound 1 was synthesized according to the synthesis method of Example 3.

[0294] MS m / z (ESI): 512.2 [M+H] +

[0295] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),9.28(t,J=5.6Hz,1H),8.11(s,1H),7.97–7 .83(m,2H),7.78(d,J=8.0Hz,1H),7.54(d,J=8.0Hz,2H),7.35–7.24(m,2H),7.15 (d,J=9.0Hz,2H),7.04(d,J=7.9Hz,1H),4.57(d,J=5.6Hz,2H),4.15–4.10(m,1H) ,2.78–2.72(m,1H),2.58(d,J=17.5Hz,1H),2.35–2.26(m,1H),2.14–2.07(m,1H).

[0296] Example 5: Synthesis of Compound 3

[0297]

[0298] Compound 3 was synthesized according to the synthesis method of Example 3.

[0299] MS m / z (ESI): 512.2 [M+H] +

[0300] 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.27 (t, 1H), 8.08 (d, J = 1.4Hz, 1H), 7.91–7.8 4(m,3H),7.54(d,J=8.3Hz,2H),7.29–7.23(m,2H),7.17-7.12(m,1H),6.77(d,J=7.7 Hz,1H),6.60-6.55(m,1H),5.32(t,1H),4.58(d,J=5.8Hz,2H),4.16–4.09(m,1H),2. 89(s,1H),2.73(d,J=0.4Hz,1H),2.61–2.54(m,1H),2.33(s,1H),2.14–2.07(m,1H).

[0301] Example 6: Synthesis of Compound 4

[0302]

[0303] Compound 3 was synthesized according to the synthesis method of Example 3.

[0304] MS m / z (ESI): 479.2 [M+H] +

[0305] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.46(t,J=6.2Hz,1H),8.80(s,1H),8.19- 8.11(m,1H),8.07(d,J=8.1Hz,1H),7.86(s,1H),7.61-7.48(m,2H),7.33-7.15( m,2H),6.95(s,2H),6.82(d,J=8.3Hz,1H),4.60(d,J=6.2Hz,2H),4.14-4.09(m, 1H),2.80-2.65(m,1H),2.58-2.54(m,1H),2.35-2.29(m,1H),2.11-2.08(m,1H).

[0306] Example 7: Synthesis of Compound 5

[0307]

[0308] Compound 5 was synthesized according to the synthesis method of Example 3.

[0309] MS m / z (ESI): 479.2 [M+H] +

[0310] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.38(t,J=5.8Hz,1H),9.07(d,J=1.8Hz,1H),8.31 -8.28(m,1H),7.88(s,1H),7.76(d,J=8.2Hz,1H),7.64-7.48(m,2H),7.32(t,J=7.8Hz,1H ),7.25(d,J=8.3Hz,1H),7.15(s,2H),7.03(d,J=7.6Hz,1H),4.61(d,J=5.7Hz,2H),4.15- 4.11(m,3H),2.74-2.70(m,1H),2.61-2.53(m,1H),2.33-2.28(m,1H),2.15-2.06(m,1H).

[0311] Example 8: Synthesis of Compound 6

[0312]

[0313] Compound 6 was synthesized according to the synthesis method of Example 3.

[0314] MS m / z(ESI): 496.2 [M+H] +

[0315] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.30(t,J=5.9Hz,1H),7.88-7.72(m,4H),7.54(d,J=8.3Hz,2H),7.27-7.23(m,2H),7.02(s,2H),6. 91(d,J=7.4Hz,1H),4.59(d,J=5.8Hz,2H),4.15-4.11(m,1H),2.79-2.67(m,1H),2.62-2.53(m,1H),2.36-2.28(m,1H),2.19-2.05(m,1H).

[0316] Example 9: Synthesis of Compound 7

[0317]

[0318] Compound 7 was synthesized according to the synthesis method of Example 3.

[0319] MS m / z (ESI): 508.2 [M+H] +

[0320] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),9.19(t,J=5.9Hz,1H),7.87(s,1H),7.61-7.47(m,5H),7.34-7.13(m,2H),6.95(s,2H),6.85(s,1 H),4.59(d,J=5.8Hz,2H),4.15-4.10(m,1H),3.92(s,3H),2.83-2.66(m,1H),2.62-2.53(m,1H),2.33-2.28(m,1H),2.15-2.06(m,1H).

[0321] Example 10: Synthesis of Compound 8

[0322]

[0323] Compound 8 was synthesized according to the synthesis method of Example 3.

[0324] MS m / z (ESI): 508.2 [M+H] +

[0325] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.18(t,J=5.9Hz,1H),7.98-7.84(m,3H),7.67-7.47(m,4H),7.25-7.23(m,1H),6.97-6.92(m,3 H),4.58(d,J=5.8Hz,2H),4.14-4.10(m,1H),3.84(s,3H),2.81-2.65(m,1H),2.61-2.53(m,1H),2.36.2.28(m,1H),2.12-1.99(m,1H).

[0326] Example 11: Synthesis of Compound 9

[0327]

[0328] Compound 9 was synthesized according to the synthesis method of Example 3.

[0329] MS m / z (ESI): 512.2 [M+H] +

[0330] 1H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.20 (t, J = 5.8Hz, 1H), 7.94 (d, J = 8. 4Hz,2H),7.87(s,1H),7.63(d,J=8.4Hz,2H),7.56-7.49(m,2H),7.24(d,J= 8.1Hz,1H),6.75-6.63(m,3H),4.58(d,J=5.8Hz,2H),4.14-4.10(m,1H),2 .74-2.70(m,1H),2.61–2.53(m,1H),2.39-2.25(m,1H),2.15-2.04(m,1H).

[0331] Example 12: Synthesis of Compound 10

[0332]

[0333] Compound 10 was synthesized according to the synthesis method of Example 3.

[0334] MS m / z (ESI): 512.2 [M+H] +

[0335] 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.22 (t, J = 5.9Hz, 1H), 7.95 (d, J = 8.5Hz, 2H),7.87(s,1H),7.64(d,J=8.5Hz,2H),7.57-7.49(m,2H),7.24(d,J=8.2Hz,2 H),6.91(s,1H),6.71(d,J=8.5Hz,1H),4.59(d,J=5.9Hz,2H),4.15-4.10(m,1H ),2.80-2.66(m,1H),2.61-2.52(m,1H),2.39-2.25(m,1H),2.14-2.06(m,1H).

[0336] Test Example 1: In vitro proliferation inhibition test of compounds on tumor cells and normal hepatocytes

[0337] Test objective

[0338] To assess the efficacy and safety of the drug compound, its inhibitory activity against BT-474 and NCI-N87 tumor cells was investigated in vitro. Cells were treated with different concentrations of the compound in vitro, and after 6 days of culture, CTG (Cellular Transmission Therapy) was used to evaluate its inhibitory activity. The Luminescent Cell Viability Assay (Promega, catalog number: G7558) uses reagents to detect cell proliferation based on IC50. 50 The value was used to evaluate the in vitro activity of the compound.

[0339] Experimental methods

[0340] The following example, using the in vitro proliferation inhibition assay method for NCI-N87 cells, illustrates the method for testing the in vitro proliferation inhibition activity of the compounds in this application against tumor cells. This method is also applicable to, but not limited to, testing the in vitro proliferation inhibition activity of other tumor cells.

[0341] 1. Cell culture: NCI-N87 cells were cultured in 10% FBS RPMI-1640 medium.

[0342] 2. Cell preparation: Take NCI-N87 cells in the logarithmic growth phase, wash them once with PBS, add 2-3 ml of trypsin to digest for 2-3 min. After the cells are completely digested, add 10-15 ml of cell culture medium to wash off the digested cells, centrifuge at 1000 rpm for 5 min, discard the supernatant, and then add 10-20 ml of cell culture medium to resuspend the cells to prepare a single-cell suspension.

[0343] 3. Cell plating: Mix the NCI-N87 single-cell suspension thoroughly, and adjust the viable cell density to 6 x 10⁻⁶ cells / mL using cell culture medium. 4 Cells / ml: Mix the density-adjusted cell suspension thoroughly and add 50 μL / well to a 96-well cell culture plate. Incubate the plate in an incubator for 18 hours (37°C, 5% CO2).

[0344] 4. Compound preparation: Dissolve the compound in DMSO to prepare a stock solution with an initial concentration of 10 mM. There are 9 concentrations of small molecule compounds, with the highest concentration being 1 μM, diluted 3 times.

[0345] 5. Sample addition procedure: Add the prepared test samples at different concentrations to the culture plate, with two replicates for each sample. Incubate the culture plate in an incubator for 6 days (37℃, 5% CO2).

[0346] 6. Color development procedure: Take out the 96-well cell culture plate, add 50 μL of CTG reagent to each well, and incubate at room temperature for 10 minutes.

[0347] 7. Plate reading procedure: Take out the 96-well cell culture plate, place it in the microplate reader, and use the microplate reader to measure the chemiluminescence.

[0348] Data analysis: The data was processed and analyzed using Microsoft Excel and Graphpad Prism 5.

[0349] Table 1. IC50 of the small molecule fragment in this application inhibiting the in vitro proliferation of BT-474 and NCI-N87 cells. 50 value.

[0350]

[0351] ++++: <10nM, +++: 10~30nM, ++: 30~150nM, +: >150nM.

[0352] Conclusion: According to the results in Table 1, the small molecule fragment in this application has significant inhibitory activity against the proliferation of NCI-N87 cells and BT-474 cells;

[0353] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to the 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. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of Formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled form, metabolite, or prodrug thereof, wherein R 1 independently hydrogen, deuterium, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl; Group A is independently: wherein 1 is attached to L and 2 is attached to the piperidinedione; U is -CH2- or -C(O)-; R a each independently is 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, or 4-12 membered heterocycloalkyl; each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, and 4-12 membered heterocycloalkyl is optionally substituted with one or more substituents independently being halogen, -OH, -CN, -NH2, or oxo; m is independently 0, 1, 2, or 3; L is each independently a chemical bond, C 1-3 alkylene, C 3-8 cycloalkylene, or 4-12 membered heterocycloalkylene; said C 1-6 alkyl, C 1-3 alkylene, C 3-8 cycloalkylene, and 4-12 membered heterocycloalkylene are each optionally substituted with one or more substituents independently being halogen, C 1-6 alkyl, -OC 1-6 alkyl, halogenated C 1-6 alkyl, oxo, hydroxyl, -CN, or -NH2; Group B is C 6-10 aryl or 5-10 membered heteroaryl; said C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more R b substituents; R b each independently is hydrogen, deuterium, halogen, -OC 1-6 alkyl, -CN, -NH2, -NHC 1-6 alkyl or -N(C 1-6 alkyl)2; said alkyl is optionally substituted with one or more substituents which are independently halogen, -OH, -CN, or -NH2; Group C is independently C 6-10 aryl, 5-10 membered heteroaryl, 4-14 membered cycloalkyl, or 4-14 membered heterocycloalkyl; said C 6-10 aryl, 5-10 membered heteroaryl, 4-14 membered cycloalkyl, and 4-14 membered heterocycloalkyl are optionally substituted with one or more R c substituents; R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally surrounded by one or more independent halogens, -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 group 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 group, -S(O)2C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substitution with cycloalkyl or 4-6 membered heterocyclic alkyl groups; and / or, any two adjacent R c with the atom to which it is attached to form C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; each of said C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl is optionally substituted with one or more R e substituents; R e each independently 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-O-C 1-6 alkyl, -C 1-6 alkyl-SH, -C 1-6 alkyl-S-C 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 cycloalkyl or 4-6 membered heterocycloalkyl; in the heteroaryl group, the number of heteroatoms is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S; in the heterocycloalkyl and heterocycloalkylene groups, the number of heteroatoms is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, P, or S.

2. The compound of claim 1, having the formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof. The compound of Formula (I), (II) satisfies one of the following schemes: Scheme One The compound of Formula (I) is a compound of Formula (I-1): wherein groups B and C are as defined in claim 1; For example, the compound of Formula (I), (I-1) is a compound of Formula (I-1a), (I-1b), (I-1c): wherein R b and R c are as defined in claim 1 ; n and q are each independently 0, 1, 2 or 3; Scheme Two The compound of Formula (II) is a compound of Formula (II-1): wherein groups B and C are as defined in claim 1; For example, the compound of Formula (II), (II-1) is a compound of Formula (II-1a), (II-1b), (II-1c), (II-1d), (II-1e): wherein R b , R c , and R e are as defined in claim 1 ; n, p, and q are each independently 0, 1, 2, or 3.

3. The compound of claim 1 or 2, of formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof, wherein, The compound of Formula (I), (II) satisfies one of the following schemes: Scheme One The compound of Formula (II), (II-1) wherein Group B is independently phenyl or 5-6 membered heteroaryl; said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more R b substituents; R b each independently is hydrogen, deuterium, halogen, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2; said alkyl is optionally substituted with one or more substituents which are independently halogen, -OH, -CN, or -NH2; Group C is independently 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl; said 5-8 membered cycloalkyl and 5-8 membered heterocycloalkyl are optionally substituted with one or more R c substituents; R c each independently hydrogen, deuterium, halogen, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; or, any two adjacent R c with the atom to which it is attached to form a 5-6 membered heteroaryl or phenyl; each of said 5-6 membered heteroaryl and phenyl is optionally substituted with one or more R e substituents; R e each independently halogen, -OH, -CN, -NH2, -C 1-3 alkyl, -C 1-3 alkyl-OH, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; Scheme Two The compound of Formula (II), (II-1) wherein Group B is independently phenyl or 5-6 membered heteroaryl; said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more R b substituents; R b each independently is hydrogen, deuterium, halogen, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2; said alkyl is optionally substituted with one or more substituents which are independently halogen, -OH, -CN, or -NH2; Group C is independently 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl; said 5-7 membered cycloalkyl and 5-7 membered heterocycloalkyl are optionally substituted with one or more R c substituents; any two adjacent R c with the atom to which it is attached to form a 5-6 membered heteroaryl or phenyl; each of said 5-6 membered heteroaryl and phenyl is optionally substituted with one or more R e substituents; R e each independently halogen, -OH, -CN, -NH2, -C 1-3 alkyl, -C 1-3 alkyl-OH, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; Scheme Three The compound of Formula (I), (I-1) wherein Group B is independently phenyl or pyridyl, said phenyl and pyridyl being optionally substituted with one or more R b substituents; R b each independently is hydrogen, F, or CI; Group C is independently phenyl, said phenyl being optionally substituted with one or more R c substituents; R c each independently is hydrogen, F, Cl, -OCH3, -NH2, -NHCH3, or -N(CH3)2; Scheme Four The compound of Formula (II), (II-1) wherein Group B is independently phenyl; said phenyl is optionally substituted with one or more R b substituents; R b each independently is hydrogen, F, or CI; Group C is independently pyrrolidinyl, piperidinyl, azepanyl, or 1,3- oxazepanyl; said pyrrolidinyl, piperidinyl, azepanyl, and 1,3-oxazepanyl are optionally substituted with one or more R c substituents; R c each independently is hydrogen, F, Cl, -CH3, -OCH3, or -NH2; any two adjacent R c together with the atom to which they are attached form a phenyl; each of said phenyl groups is optionally substituted with one or more R e substituents; R e each independently is hydrogen, F, Cl, -OCH3, -NH2, -NHCH3, or -N(CH3)2.

4. The compound of claim 1 or 2, of formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof, wherein The compound of Formula (I), (II) satisfies at least one of the following conditions: (1) R 1 independently hydrogen, deuterium, or -C 1-6 alkyl; (2) the groups A are independently: For example (3) R a each independently is hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 alkyl or -OC 1-6 alkyl; for example hydrogen, halogen, -OH, -NH2, -C 1-6 alkyl or -OC 1-6 alkyl; (4) m is independently 0, 1, or 2; (5) L is independently a bond or C 1-3 alkylene; for example, C 1-3 alkylene; (6) the group B is independently phenyl or 5-6 membered heteroaryl; said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more R b substituents; for example phenyl or pyridyl; said phenyl and pyridyl are optionally substituted with one or two R b substituents; (7) R b each independently is hydrogen, deuterium, halogen, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; said alkyl is optionally substituted with one or more substituents which are independently halogen, -OH, -CN, -NH2; for example R b each independently is hydrogen, deuterium, halogen, -OC 1-3 alkyl, -CN, -NH2, -NHCH3or -N(CH3)2; (8) Group C is independently phenyl or 5-6 membered heteroaryl; said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more R c substituents; for example phenyl, said phenyl is optionally substituted with one or two R c substituents; (9) Group C is independently 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl; said 5-8 membered cycloalkyl and 5-8 membered heterocycloalkyl are optionally substituted with one or more R c substituents; for example pyrrolidinyl, piperidinyl, azepanyl or 1,3-oxazepanyl; said pyrrolidinyl, piperidinyl, azepanyl and 1,3-oxazepanyl are optionally substituted with one or more R c substituents; for example piperidinyl; said piperidinyl is optionally substituted with one or more R c substituents. (10)R c each independently is hydrogen, deuterium, halogen, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl, -N(C 1-3 alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl; said C 1-3 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with one or more substituents independently being halogen, -OH, -CN, -NH2, -SH, nitro, -OC 1-6 alkyl, -O(haloC 1-6 alkyl), -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 1-6 alkyl, haloC 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-6 alkyl, -C 1-6 alkyl-SH, -C 1-6 alkyl-S-C 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 or 4-6 membered heterocycloalkyl; for example R c each independently is hydrogen, deuterium, halogen, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; (11) any two adjacent R c with the atom to which they are attached to form a C 5-8 cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; each of said C 5-8 cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl is optionally substituted with one or more R e ; for example, any two adjacent R c with the atom to which they are attached to form a 5-6 membered heteroaryl or phenyl; each of said 5-6 membered heteroaryl and phenyl is optionally substituted with one or more R e ; for another example, any two adjacent R c with the atom to which they are attached to form a phenyl; each of said phenyl is optionally substituted with one or more R e ; (12)R e Independently halogen, -OH, -CN, -NH2, C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -NH(C) 1-6 alkyl) or -N(C) 1-6 Alkyl groups; for example, halogens, -OH, -CN, -NH2, C 1-3 Alkyl, -C 1-3 Alkyl-OH, -NHC 1-3 Alkyl or -N(C) 1-3 Alkyl)2.

5. The compound of claim 1, of formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof. The compound of Formula (I), (II) satisfies at least one of the following conditions: (1) R 1 independently H; (2) the groups A are independently (3) m is independently 0; (4) L is independently -CH2-; (5) Group B is independently a terminal end is attached to the carbonyl group shown, and the b terminal end is attached to the alkynyl group or group C shown; for example For example, again (6) R b each independently is hydrogen, deuterium, F, Cl, -OCH3, or -NH2; (7) R c each independently is hydrogen, F, Cl, -CH3, -OCH3, -CN, -NH2, -NHCH3, or -N(CH3)2; (8) R e each independently is hydrogen, F, Cl, -OCH3, -NH2, -NHCH3, or -N(CH3)2; (9) In formula (I), formula (I-1), formula (I-1a), formula (I-1b) or formula (I-1c), group C is independently a phenyl or a 5-6 heteroaryl group; wherein the phenyl and the 5-6 heteroaryl group are optionally surrounded by one or more R groups. c Replace; R c Each is independently hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally surrounded by one or more independent halogens, -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 group 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 group, -S(O)2C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Substituents of cycloalkyl or 4-6 membered heterocyclic alkyl groups; for example, the C group is independently […]. (10) in Formula (II), Formula (II-1), or Formula (II-1a), group C is independently 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl; said 5-6 membered cycloalkyl and 5-6 membered heterocycloalkyl are optionally substituted with multiple R c substituents; R c each independently is hydrogen, deuterium, halogen, C 1-3 alkyl, -OC 1-3 alkyl, -CN, -NH2, -NHC 1-3 alkyl or -N(C 1-3 alkyl)2; and / or, any two adjacent R c together with the atoms to which they are attached form a C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl; said C 5-12 cycloalkyl, 5-12 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are each optionally substituted with one or more R e substituents; For example, group C is independently Preferably, group C is independently 6. The compound of claim 1 or 2 of formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof, wherein, The compound of Formula (I), (II) satisfies at least one of the following conditions: (1) each halo is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine; (2) each C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or s-butyl, for example methyl; (3) each -O-C 1-6 alkyl is independently -O-methyl, -O-ethyl, -O-n-propyl, -O-i-propyl, -O-n-butyl, -O-t-butyl, -O-i-butyl, or -O-s-butyl; for example, -O-methyl; (4) each C 2-6 alkenyl is independently vinyl, 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 cycloalkyl is independently C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) the cycloalkyl is a saturated cycloalkyl or a partially saturated cycloalkyl; the number of unsaturated bonds in the partially saturated cycloalkyl is one or more; (8) each 4-12 membered heterocycloalkyl is independently a 5-8 membered heterocycloalkyl; (9) the number of heteroatoms in each 4-12 membered heterocycloalkyl is independently 1, 2, or 3, and the heteroatoms are independently N, O, or S; preferably, the number of heteroatoms in each 4-12 membered heterocycloalkyl is independently 1 or 2, and the heteroatoms are independently N or O; (10) each 4-12 membered heterocycloalkyl is independently monocyclic or polycyclic, the polycyclic being bridged, fused or spiro; the polycyclic being bicyclic or tricyclic; preferably, each 4-12 membered heterocycloalkyl is independently 5-6 membered monocyclic heterocycloalkyl, 9-10 membered bicyclic heterocycloalkyl or 11-12 membered tricyclic heterocycloalkyl; (11) the heterocycloalkyl is saturated heterocycloalkyl or partially saturated heterocycloalkyl; the partially saturated heterocycloalkyl having one or more unsaturated bonds; (12) each C 1-3 alkylene is independently methylene, ethylene, n-propylene, or i-propylene; (13) each C 3-8 Cycloalkylene is independently C 3-6 Cycloalkylene is independently C Cycloalkylene is independently C (14) the cycloalkylene is saturated cycloalkylene or partially saturated cycloalkylene; the partially saturated cycloalkylene having one or more unsaturated bonds; (15) each 4-12 membered heterocycloalkylene is independently 5-8 membered heterocyclylene; (16) each 4-12 membered heterocycloalkylene has independently one, two or three heteroatoms, the heteroatoms being independently N, O or S; preferably, each 4-12 membered heterocycloalkylene has independently one or two heteroatoms, the heteroatoms being independently N or O; (17) each 4-12 membered heterocycloalkylene is independently monocyclic or polycyclic, the polycyclic being bridged, fused or spiro; the polycyclic being bicyclic or tricyclic; preferably, 4-12 membered heterocycloalkylene is independently 5-6 membered monocyclic heterocyclylene, 9-10 membered bicyclic heterocyclylene or 11-12 membered tricyclic heterocyclylene; (18) the heterocycloalkylene is saturated heterocycloalkylene or partially saturated heterocycloalkylene; the partially saturated heterocycloalkylene having one or more unsaturated bonds; (19) each halo is independently fluoro, chloro, bromo or iodo; for example, fluoro or chloro; (20) each C 6-10 aryl is independently phenyl or naphthyl, e.g., phenyl; (21) each 5-10 membered heteroaryl has independently one, two or three heteroatoms, the heteroatoms being independently N, O or S; (22) each 5-10 membered heteroaryl is independently monocyclic or bicyclic, the bicyclic being fused; (23) each 4-14 membered heterocycloalkyl is 5-12 membered heterocycloalkyl; preferably, 5-6 membered heterocycloalkyl; (24) each 4-14 membered heterocycloalkyl has one, two or three heteroatoms, the heteroatoms being N, O or S; preferably, one or two heteroatoms, the heteroatoms being N; (25) each 4-14 membered heterocycloalkyl is monocyclic or polycyclic, the polycyclic being bridged, fused or spiro; (26) each 4-14 membered heterocycloalkyl contains zero, one or two saturated rings, preferably, one unsaturated ring and at least one saturated ring; the unsaturated ring is preferably aryl, for example, phenyl; (27) when each 4-14 membered heterocycloalkyl contains one unsaturated ring and at least one saturated ring, the heteroatoms are on the saturated ring; (28) each 4-14 membered heterocycloalkyl is a monocyclic heterocycloalkyl, a bicyclic heterocycloalkyl, or a tricyclic heterocycloalkyl; preferably a 5-8 membered monocyclic heterocycloalkyl, a 9-10 membered bicyclic heterocycloalkyl, or an 11-14 membered tricyclic heterocycloalkyl; for example for example (29) each C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

7. The compound of claim 1, having the formula (I), (II), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled, metabolite, or prodrug thereof. the compound of Formula (I), (II) is selected from any one of the following compounds:

8. A pharmaceutical composition, characterized by, comprising a compound of Formula (I), (II) as described in any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically labeled form, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

9. Use of a substance Y for the manufacture of a medicament, characterized in that said substance Y is a compound of formula (I), (II) as described in any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically-labeled, metabolite or prodrug thereof, or a pharmaceutical composition as described in claim 8; Preferably, the medicament fulfils one of the following conditions: the medicament is for use in the treatment and / or prevention of cancer; the medicament is for use in the prevention and / or treatment of a GSPT1 -related disease or disorder; Preferably, the GSPT1 -related disease or disorder is a disease or disorder sensitive or responsive to GSPT1 degradation; preferably, the GSPT1 -related disease or disorder is cancer; Preferably, the cancer is selected from the group consisting of breast cancer, colorectal cancer, colon cancer, lung cancer and prostate cancer, and also cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, oesophagus cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, vulvar cancer, leukaemia, multiple myeloma and lymphoma.

10. Use of a substance Y for the preparation of a GSPT1 degrader, characterized in that, said substance Y is a compound of formula (I), (II) as described in any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopically-labeled, metabolite or prodrug thereof, or a pharmaceutical composition as described in claim 8;

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