Piperidinedione compounds, methods of making and uses thereof

Abstract

Provided are compounds represented by Formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled forms, metabolites, or prodrugs thereof. The compounds can be used to degrade proteins such as GSPT1, thereby preventing, alleviating, or treating diseases associated with disorders of these proteins. The compounds can also be used as payloads of ligand drug conjugates, further expanding the indications of the compounds.

Description

[0001] This application claims priority to Chinese patent application 2023112601408, filed on September 26, 2023. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to piperidine dione compounds, their preparation methods, and their applications. Background Technology

[0003] Protein function is a strictly regulated process both spatially and temporally during cell growth and proliferation. Abnormal regulation of these processes can lead to uncontrolled cell growth, proliferation, and migration, resulting in diseases such as tumors.

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

[0005] Studies have found that subtle structural changes in different immunomodulatory drugs can significantly alter the substrate specificity of E3 ligases, leading to substantial changes in drug metabolic and biological activity. For example, both pomalidomide and lenalidomide can mediate the ubiquitination and degradation of IKZF1 / 3, but only lenalidomide can degrade CK1α, which may be an effective target for myelodysplastic syndromes with 5q deletion; CC-90009 specifically mediates the degradation of GSPT1 (also known as eRF3a, a translation termination factor) to treat acute myeloid leukemia; BTX-1188 can simultaneously degrade GSPT1 and IKZF1 / 3, and has shown good anti-tumor effects in various solid tumors (breast cancer, ovarian cancer, lung cancer, etc.) in preclinical trials.

[0006] CRBNs, as important targets for anti-tumor and immunomodulatory drugs, have been proven to have clear efficacy in various hematological malignancies such as multiple myeloma and chronic lymphocytic leukemia, skin diseases such as erythema nodosum leprosy, and autoimmune diseases such as systemic lupus erythematosus. However, current thiamine drugs have many side effects. Therefore, there is still a high clinical demand and application value in developing CRBN modulators with novel structures that can improve efficacy, enhance safety, and expand the scope of indications. Summary of the Invention

[0007] The objective of this invention is to provide a piperidine dione compound, its preparation method, and its applications. 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; simultaneously, the compounds of this invention can also serve as payloads for ligand-drug conjugates (e.g., antibody-drug conjugates), further expanding the indications for these compounds.

[0008] On the one hand, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled compounds, metabolites, or prodrugs thereof.

[0009]

[0010] in,

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

[0012] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

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

[0014] R a Each is independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12The cycloalkyl or 4- to 12-membered heterocycloalkyl groups are each optionally substituted by one or more substituents selected from halogens, -OH, -CN, -NH2 and oxo groups;

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

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

[0017] p is selected from 1 or 2;

[0018] L is selected from chemical bonds, -NH-, -N(C) 1-6 alkyl)-, -C 1-3 alkylene, vinylene, ethynylene, -C 3-8 Cycloalkylene-, 4- to 12-membered heterocycloalkylene-; the C 1-6 Alkyl, C 1-3 Alkylene, C 3-8 The cycloalkyl group and the 4- to 12-membered heteroalkyl group are each optionally surrounded by one or more elements selected from halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Substitution of alkyl, oxo, hydroxyl, -CN and -NH2 groups;

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

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

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

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

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

[0024] R d Each element is independently selected from hydrogen, deuterium, and -C. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 Aryl, 5-10 quinone heteroaryl; the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, C 6-10 The aryl group and the 5-10 heteroaryl group are each optionally bound by one or more groups selected from halogen, -OH, -CN, -NH2, -SH, nitro, -OC. 1-6 Alkyl, -O (halogenated C) 1-6 alkyl), -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -SC 1-6 Alkyl, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-SH, -C 1-6 Alkyl-SC 1-6 Alkyl, -C 1-6 Alkyl-NH2, -C 1-6 Alkyl-NH(C) 1-6 Alkyl), -C 1-6 Alkyl-N(C) 1-6Alkyl 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 Cycloalkyl and 4- to 6-membered heterocyclic alkyl substitutions;

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

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

[0027] In some implementation schemes, ring A is selected from: Preferably, ring A is: More preferably, ring A is In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0028] In some implementation schemes, R a Each is independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C1-6 Alkyl, -OC 1-6 Alkyl; preferably, R a Each is independently selected from hydrogen, halogen, -OH, -NH2, -C 1-6 Alkyl or -OC 1-6 Alkyl; more preferably, R a Each is independently selected from hydrogen, halogen, or -OC. 1-6 alkyl.

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

[0030] In some implementation schemes, R 2 R 3 Each is independently selected from hydrogen, deuterium, halogen, -OH, or -C. 1-6 Alkyl; preferably, R 2 R 3 Each is independently selected from hydrogen, deuterium, or halogen; more preferably, R 2 R 3 It is hydrogen.

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

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

[0033] In some implementation schemes, R b Each is independently selected from hydrogen, halogen, nitro, -CN, -R d -N(R) d )2、-OR d -SR d or -(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d Preferably, R b Each is independently selected from hydrogen, halogen, -R d -N(R) d )2、-OR d -SR d or -(C 1-6 Alkylene)m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d .

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

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

[0036] In some implementation schemes, R d Each is independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 Aryl or 5-10 heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 The aryl group or 5-10 heteroaryl group is optionally bounded by one or more elements selected from halogen, -OH, -CN, -NH2, -OC. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 Cycloalkyl and 4- to 6-membered heterocyclic alkyl substitutions;

[0037] Preferably, R d Each is independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 Aryl or 5-10 heteroaryl; the C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 The aryl group or 5-10 heteroaryl group is optionally bounded by one or more elements selected from halogen, -NH2, -C 1-6 Alkyl and -halogenated C 1-6Alkyl substitution.

[0038] In some implementations, any two adjacent R b Together with the atoms attached to it, they form C 5-8 Cycloalkyl, 5- to 8-membered heterocyclic alkyl or phenyl; the C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl or phenyl groups are each optionally separated by one or more elements selected from halogen, -OH, -NH2, -C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH(C) 1-6 Alkyl), -C 1-6 Alkyl-N(C) 1-6 Alkyl)2 substituents.

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

[0040] 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.

[0041] 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.

[0042] In some implementations, each C 2-6 The alkenyl group can be vinyl, propenyl, allyl, butenyl, or pentenyl.

[0043] In some implementations, each C 2-6 The alkynyl group can be independently ethynyl, propynyl, propynyl, butynyl, or pentylyyl, for example...

[0044] In some implementations, each C 3-12 The cycloalkyl group is independently C 3-8 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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

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

[0047] In some implementations, each 4- to 12-membered heterocyclic alkyl group is independently a 5- to 8-membered heterocyclic alkyl group.

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

[0049] In some embodiments, each 4- to 12-membered heterocyclic alkyl group may be independently monocyclic or polycyclic, the polycyclic being a bridged ring, fused ring, or spirocyclic; the polycyclic being a bicyclic or tricyclic; preferably, each 4- to 12-membered heterocyclic alkyl group is independently a 5- to 6-membered monocyclic heterocyclic alkyl group, a 9- to 10-membered bicyclic heterocyclic alkyl group, or an 11- to 12-membered tricyclic heterocyclic alkyl group.

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

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

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

[0053] In some implementations, each -C 1-3 The alkylene group is independently methylene, ethylene, n-propylene, or isopropylene.

[0054] In some implementations, each -C 3-8 Cycloalkylene - independently -C 3-6 Cycloalkylene, such as cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, preferably cyclopropylene or cyclobutylene.

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

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

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

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

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

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

[0061] In some embodiments, the cycloalkylene group is a partially saturated heteroalkylene group; the partially saturated heteroalkylene group has one or more unsaturated bonds.

[0062] In some implementations, each halogenation is independently fluorinated, chlorinated, brominated, or iodinated.

[0063] In some implementations, each C 6-10 The aryl group can be phenyl or naphthyl, for example, phenyl.

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

[0065] In some implementations, each 5-10 nucleotide heteroaryl group may independently be a monocyclic or bicyclic ring, wherein the bicyclic ring is a fused ring.

[0066] In some embodiments, each of the 4 to 14-membered heterocyclic alkyl groups is a 5 to 12-membered heterocyclic alkyl group; preferably a 5 to 6-membered heterocyclic alkyl group.

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

[0068] In some embodiments, each of the 4 to 14-membered heterocyclic alkyl groups is a monocyclic or polycyclic (e.g., bicyclic or tricyclic), and the polycyclic group may be a bridged ring, a fused ring, or a spirocyclic ring.

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

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

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

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

[0073] In some implementations, each -C 3-6 The cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0074] In some implementations, in ring B, the -C 6-10 The aryl group is phenyl.

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

[0076] In some embodiments, in ring B, the 4- to 14-membered heterocyclic alkyl group is Preferred

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

[0078] In some implementations, in R d In this context, the 4- to 12-membered heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group; preferably morpholino, piperidinyl, azacyclic butyl, or tetrahydropyrroleyl; preferably...

[0079] In some implementations, in R d In this context, the 5-10 heteroaryl group is pyridyl; for example...

[0080] In some implementations, when two adjacent R b Together with the atoms attached to it, they form C 5-12When cycloalkyl, the C 5-12 The cycloalkyl group is cyclohexyl, cyclopentyl, cyclohexenyl, or cyclopentenyl.

[0081] In some implementations, when two adjacent R b When the atoms attached to it form a 5- to 12-membered heterocyclic alkyl group, the 5- to 12-membered heterocyclic alkyl group is 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrrole, pyrrole, or...

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

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

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

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

[0086] In some embodiments, the compound with the structure shown in formula (I) wherein ring B is selected from -C 6-10 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl; preferably, ring B is selected from phenyl, pyridyl, Preferably, ring B is selected from phenyl or pyridyl; more preferably, ring B is phenyl; said ring B is optionally surrounded by one or more R b replace.

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

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

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

[0090] In some embodiments, the compound with the structure shown in formula (I), wherein R d Each is independently selected from hydrogen and -C 1-4 Alkyl, cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl; the C 1-6 Alkyl, cyclopropyl, cyclobutyl, 4- to 6-membered heterocyclic alkyl, phenyl, 5- to 6-membered heteroaryl, each optionally separated by one or more elements selected from halogen, -OH, -CN, -NH2, -OC 1-6 Alkyl, -NHC 1-6Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl -OH, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 3-6 Cycloalkyl and 4- to 6-membered heterocyclic alkyl substitutions;

[0091] Preferably, R d Each is independently selected from hydrogen and -C 1-4 Alkyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thiophene, furanyl, piperidinyl, piperazinyl, morpholinyl, aziridine, aziridinepentyl, oxacyclobutyl, oxacyclopentyl; the -C 1-4 Alkyl, cyclopropyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, thiophene, furanyl, piperidinyl, piperazinyl, morpholinyl, aziridine, aziridine, oxacyclobutyl, and oxacyclopentyl are each optionally separated by one or more elements selected from halogen, -OH, -CN, -NH2, and -OC. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution;

[0092] More preferably, R d Each of the following is independently selected from hydrogen, -CH3, -CH2CH3, -iPr, -tBu, -CF3, -cyclopropyl, phenyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, aziridine, and oxacyclobutyl; wherein -CH3, -CH2CH3, cyclopropyl, phenyl, pyridyl, piperidinyl, piperazinyl, morpholinyl, aziridine, and oxacyclobutyl are each optionally separated from one or more of halogen, -OH, -CN, -NH2, and -OC. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl substitution;

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

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

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

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

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

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

[0099] In some embodiments, the compound with the structure shown in formula (I) wherein ring B is selected from:

[0100] In some implementations, when ring B is surrounded by one or more R b When replacing, ring B is selected from:

[0101]

[0102]

[0103]

[0104] In some embodiments, the compound with the structure shown in formula (I), wherein

[0105] R 1 For H;

[0106] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0107] R a Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl or -OC 1-6 alkyl;

[0108] m is selected from 0, 1, or 2;

[0109] R 2 and R 3 For H;

[0110] P is 1;

[0111] L represents a chemical bond;

[0112] Ring B is selected from a benzene ring, a 5-6 membered heteroaryl group, or a 5-6 membered heterocyclic alkyl group; said ring B is optionally separated by one or more R groups. b replace;

[0113] R b Each is independently selected from hydrogen, halogen, -R d -N(R) d )2、-OR d -SR d or -(C 1-6 Alkylene) m1 -(X) m2 -(C 1-6 Alkylene) m3 -(Z) m4 -R d ;

[0114] m1, m2, m3, and m4 are each independently 0 or 1; and m2 and m4 are not both 0 at the same time, and m1 and m3 are both 0 at the same time;

[0115] X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-;

[0116] R d Each is independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 Aryl or 5-10 heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10The aryl group or 5-10 heteroaryl group is optionally bounded by one or more elements selected from halogen, -NH2, -OC. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl groups, and 4- to 6-membered heterocyclic alkyl groups;

[0117] Or, any two adjacent R b Together with the atoms attached to it, they form C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl; the C 5-6 The cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl groups are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0118] In some embodiments, the compound with the structure shown in formula (I), wherein

[0119] R 1 For H;

[0120] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0121] R 2 and R 3 For H;

[0122] P is 1;

[0123] L represents a chemical bond;

[0124] Ring B is selected from a benzene ring, a 5-6 membered heteroaryl group, or a 5-6 membered heterocyclic alkyl group; said ring B is optionally separated by one or more R groups. b replace;

[0125] R b Each is independently selected from hydrogen, halogen, -R d -N(R) d )2、-OR d -SR d or -(C 1-3 Alkylene) m1 -(X) m2 -(C 1-3 Alkylene) m3 -(Z) m4 -R d;

[0126] m1, m2, m3, and m4 are each independently 0 or 1; and m2 and m4 are not both 0 at the same time, and m1 and m3 are both 0 at the same time;

[0127] X and Z are each independently selected from -O-, -S-, -N(CH3)- or -NH-;

[0128] R d Each is independently selected from hydrogen, -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 Aryl or 5-10 heteroaryl; the -C 1-6 Alkyl, -C 3-12 Cycloalkyl, 4- to 12-membered heterocyclic alkyl, -C 6-10 The aryl group or 5-10 heteroaryl group is optionally bounded by one or more elements selected from halogen, -NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution;

[0129] Or, any two adjacent R b Together with the atoms attached to it, they form C 5-6 Cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl; the C 5-6 The cycloalkyl, 5- to 7-membered heterocycloalkyl or phenyl groups are each optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CH3, -CH2CH3, -CH2-OH, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0130] In some embodiments, the compound with the structure shown in formula (I), wherein

[0131] R 1 For H;

[0132] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0133] R 2 and R 3 For H;

[0134] P is 1;

[0135] L represents a chemical bond;

[0136] Ring B is selected from benzene rings or pyridyl groups; said ring B is optionally surrounded by one or more R groups. b replace;

[0137] R bEach is independently selected from hydrogen, halogen, -NH2, methyl, ethyl, tert-butyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3) -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azacyclobutyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; wherein the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl groups are each optionally selected by one or more groups selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3;

[0138] Or, any two adjacent R b Together with the atoms attached to it, it forms cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrroleyl, pyrroleyl, or... The cyclopentenyl, 1,2,3,4-tetrahydropyridine, 2,3-dihydro-1H-pyrroleyl or pyrroleyl group is optionally substituted by one or more substituents selected from halogen, -NH2, -CH3, -CH2CH3, -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)2.

[0139] In some embodiments, the compound with the structure shown in formula (I), wherein

[0140] R 1 For H;

[0141] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0142] R 2 and R 3 For H;

[0143] P is 1;

[0144] L represents a chemical bond;

[0145] Ring B is a benzene ring;

[0146] R b Each is independently selected from hydrogen, halogen, NH2, -C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C 3-6Cycloalkyl, -O-phenyl; the -C 1-6 Alkyl, -C 3-6 The cycloalkyl group and the phenyl group are each optionally separated by one or more elements selected from halogens, NH2, and -C. 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution.

[0147] In some embodiments, the compound with the structure shown in formula (I), wherein

[0148] R 1 For H;

[0149] Ring A is selected from: In this configuration, 1 is connected to -C(O)-, and 2 is connected to piperidinedione.

[0150] R 2 and R 3 For H;

[0151] P is 1;

[0152] L represents a chemical bond;

[0153] Ring B is a benzene ring;

[0154] R b Each is independently selected from hydrogen, F, Cl, NH2, methyl, ethyl, propyl, tert-butyl, -CF3, -NHCH3, -N(CH3)2,

[0155] In some embodiments, the compound with the structure shown in formula (I) is the compound shown in formula (II):

[0156]

[0157] in,

[0158] R 1 L, ring A and ring B are as described in any one of the formula (I) of this invention.

[0159] In some embodiments, the compounds with structures shown in formulas (I) and (II) are the compounds shown in formulas (III), (IV), (V), and (VI):

[0160]

[0161]

[0162] in,

[0163] R 1 L, R a m and ring B are each independently described as in any one of formulas (I) and (II) of the present invention.

[0164] In some embodiments, the compounds with structures shown in formulas (I), (II), and (III) are compounds shown in formula (IIIa):

[0165]

[0166] in,

[0167] R a R b Each of m is independently described by any one of formulas (I), (II), and (III) of the present invention;

[0168] q is selected from 0, 1, 2, 3 or 4.

[0169] In some embodiments, the compounds with structures shown in formulas (I), (II), and (III) are compounds represented by the following formulas:

[0170]

[0171]

[0172] in,

[0173] R b Each is independently described in any one of formulas (I), (II), and (III) of the present invention.

[0174] In some embodiments, the compounds of formulas (I), (II), (III), (IV), (V), (VI), and (IIIa) of the present invention are selected from any of the following compounds:

[0175]

[0176]

[0177]

[0178] 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.

[0179] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0180] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite, or prodrug and a pharmaceutically acceptable excipient thereof.

[0181] 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.

[0182] The 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).

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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).

[0190] 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 a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or a pharmaceutical composition thereof.

[0191] The drug meets one of the following conditions:

[0192] The drug is used to treat and / or prevent cancer;

[0193] The drug is used to prevent and / or treat GSPT1-related diseases.

[0194] 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, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer, and vulvar cancer, and leukemia (including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML)), multiple myeloma, and lymphoma.

[0195] In some implementations, the GSPT1-related disease is a disease that is sensitive to or responsive to GSPT1 degradation.

[0196] In some implementations, the GSPT1-related disease is cancer; preferably, the cancer includes, but is not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer, and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal 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.

[0197] 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 a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope label, metabolite or prodrug, or a pharmaceutical composition thereof.

[0198] In some embodiments, the GSPT1 degrading agent can achieve at least one of the following technical effects:

[0199] (1) High inhibitory activity against GSPT1;

[0200] (2) Excellent physicochemical properties (e.g., solubility, physical and / or chemical stability);

[0201] (3) Excellent pharmacokinetic properties (e.g., good bioavailability, appropriate half-life and duration of action);

[0202] (4) Excellent safety profile (lower toxicity and / or fewer side effects, wider therapeutic window).

[0203] In another aspect, the present invention provides a method for preventing or treating GSPT1-related diseases, 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.

[0204] In some implementations, the GSPT1-related disease is a disease that is sensitive to or responsive to GSPT1 degradation.

[0205] In some implementations, the GSPT1-related disease is cancer; preferably, the cancer includes, but is not limited to, breast cancer, colorectal cancer, colon cancer, lung cancer, and prostate cancer, as well as bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal 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.

[0206] 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.

[0207] 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 as described herein in 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] General terms and definitions

[0212] 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.

[0213] 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.”

[0214] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0215] Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by moles.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] In this application, the term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. For example, "C3-12 cycloalkyl" or "3-12 membered cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.).

[0230] 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, indole, etc.

[0231] In this application, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0232] In this application, the term "hydroxyl group" refers to -OH.

[0233] In this application, the term "cyano" refers to -CN.

[0234] In this application, the term "nitro" refers to -NO2.

[0235] In this application, the term "amino" refers to -NH2.

[0236] In this application, "oxo" refers to C(O), i.e., carbonyl group.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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)).

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.).

[0256] 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.

[0257] The reagents and raw materials used in this invention are all commercially available.

[0258] 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

[0259] 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.

[0260] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0261] The preparative high performance liquid chromatography (HPLC) method was performed using a Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm column).

[0262] Thin-layer chromatography purification was performed using GF 254 (0.4–0.5 nm) silica gel plates produced in Yantai.

[0263] 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.

[0264] 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.

[0265] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0266] 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.

[0267] 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.

[0268] In the conventional synthesis methods, preparation examples, and examples and intermediate synthesis examples, the meanings of each abbreviation are as follows.

[0269]

[0270] Synthesis of intermediates:

[0271] Example 1: Preparation of intermediate 1

[0272]

[0273] Step 1: Preparation of compound Int1-2

[0274] Int1-1 (1.00 g, 3.90 mmol) was added to a MeCN (25 mL) solution, followed by sodium dimethamide (1.81 g, 19.00 mmol). The mixture was heated and stirred at 80 °C for 1 h. The solution was extracted with EA, washed with water and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int1-2 (0.49 g, 51% yield).

[0275] Step 2: Preparation of compound Int1

[0276] A 12 mL ethanol solution of compound Int1-2 (0.32 g, 1.26 mmol) was mixed with concentrated HCl (4 mL, 12 N) and stirred at 80 °C for 1 h. The solution was concentrated to obtain compound Int1 (0.24 g, 100% yield), which did not require purification and was used in the next step.

[0277] Example 2: Preparation of intermediate 7

[0278]

[0279] Step 1: Preparation of compound Int7-2

[0280] A solution of In7-1 (1.28 g, 5.60 mmol) was added to acetonitrile (20 mL). Under nitrogen protection, NBS (1.30 g, 7.30 mmol) and p-TsOH (1.05 g, 6.1 mmol) were added, and the mixture was stirred at 60 °C for 4 h. The mixture was quenched with saturated NaCl solution and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and concentrated by filtration under reduced pressure to remove the solvent. Column chromatography purification yielded Int7-2 (1.20 g, 70% yield).

[0281] Steps 2 to 3: Preparation of compound Int7

[0282] Compound In7 was synthesized following the method described in Example 1 for preparing intermediates.

[0283] Example 3: Preparation of intermediate: Int9

[0284]

[0285] Step 1: Preparation of compound Int9-2

[0286] Int9-1 (2.00 g, 14.70 mmol), p-fluoronitrobenzene (2.07 g, 14.7 mmol), and potassium carbonate (2.03 g, 14.70 mmol) were added to a 30 mL DMF solution, and the mixture was heated and stirred at 120 °C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred and separated. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain Int9-2 (3.21 g, 85% yield).

[0287] Steps 2 to 4: Preparation of compound Int9

[0288] Compound Int9 was synthesized using a method similar to that used in Example 2 for preparing intermediates.

[0289] Referring to Example 1 for the preparation of intermediates, the following compounds were synthesized using commercially available α-haloaryl ethyl ketones:

[0290]

[0291]

[0292] Example 1: Synthesis of the target compound

[0293] Preparation Example 1: Synthesis of Compound 1

[0294]

[0295] Step 1: Synthesis of Compound 1-1

[0296] IntA (0.37 g, 1.30 mmol) was added to DMF (20 mL), followed by HATU (0.74 g, 1.95 mmol) and DIEA (0.51 g, 3.91 mmol). The mixture was allowed to stand and stir for 1 h, then compound Int1 (0.25 g, 1.30 mmol) was added and the mixture was allowed to stand and stir for 2 h. The solution was extracted with EA, washed with water and brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 1-1 (0.20 g, 33% yield).

[0297] Step 2: Synthesis of Compound 1

[0298] 10% Pd / C (5 mg) was added to a DMF (3 mL) solution of compound 1-1 (0.03 g, 0.05 mmol), and the mixture was stirred at room temperature for 40 min under a hydrogen atmosphere. The solution was purified by reverse HPLC to give compound 1 (0.07 g, yield 31%).

[0299] MS m / z (ESI): 435.3 [M+H] +

[0300] 1 H-NMR (400MHz, DMSO-d6): δ11.03(s,1H),8.97(t,J=5.5Hz,1H),8.12(s,1H),8.04(d,J=7 .9Hz,1H),7.85(d,J=7.9Hz,1H),7.25(s,1H),7.20(d,J=7.7Hz,1H),7.10(d,J=7.8Hz,1H) ,5.24–5.08(m,3H),4.72(d,J=5.5Hz,2H),4.55(d,J=17.5Hz,1H),4.42(d,J=17.6Hz,1H) ,2.97–2.80(m,1H),2.61–2.59(m,1H),2.48–2.40(m,1H),2.13(s,3H),2.07–2.01(m,1H).

[0301] Following the method of Preparation Example 1, the following compounds were synthesized using different intermediates.

[0302]

[0303]

[0304]

[0305] Example 2: In vitro proliferation inhibition test of the compound on tumor cells and normal hepatocytes

[0306] Test objective

[0307] To assess the efficacy and safety of the drug compounds, their inhibitory activity against BT-474 and NCI-N87 tumor cells and normal THLE-2 hepatocytes was investigated in vitro. Cells were treated with different concentrations of the compound in vitro, and after 6 days of culture, CTG (Cellular Transplantation Therapy) was used to evaluate their inhibitory activity. The Luminescent Cell Viability Assay (Promega, catalog number: G7558) uses reagents to detect cell proliferation based on IC50. 50 The value is used to evaluate the in vitro activity of the compound.

[0308] The control compound CC-885 was purchased from MCE, catalog number: HY-101488

[0309]

[0310] Experimental methods

[0311] 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.

[0312] 1. Cell culture: NCI-N87 cells were cultured in 10% FBS RPMI-1640 medium.

[0313] 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.

[0314] 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: After adjusting the cell density, mix the 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).

[0315] 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.

[0316] 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).

[0317] 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.

[0318] 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.

[0319] Data analysis: The data was processed and analyzed using Microsoft Excel and Graphpad Prism 5.

[0320] Table 1. IC50 of the small molecule fragment in this application on the in vitro proliferation inhibition of NCI-N87 cells. 50 value.

[0321]

[0322] ++++:<10nM,+++:10~30nM,++:30~150nM,+:>150nM

[0323] 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. In addition, compared with the control compound CC-885, the compound in this application has a weaker inhibitory effect on normal hepatocytes THLE-2 and its safety is significantly better than that of CC-885.

[0324] 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), or a pharmaceutically acceptable salt thereof, ； Formula I; in, R 1 Selected from hydrogen, deuterium, halogens, -C 1-6 Alkyl or -halogenated C 1-6 alkyl; Ring A is selected from: ; where 1 is connected to -C(O)- and 2 is connected to piperidinedione; R a Each is independently selected from hydrogen, deuterium, halogen, -OH, -CN, -NH2, nitro, -C 1-6 Alkyl and -OC 1-6 alkyl; m is selected from 0, 1, 2, or 3; R 2 R 3 It is hydrogen; p is 1; L represents a chemical bond; Ring B is phenyl; said ring B is optionally separated by one or more R b replace; R b Each is independently selected from hydrogen, halogen, -NH2, -C 1-4 Alkyl, -CF3, -OCF3, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl) 2, 4-6 membered heterocyclic alkyl, -C 3-6 Cycloalkyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-(5-6-membered heteroaryl), -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), -CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-(4-6-membered heterocycloalkyl), -CH2-(4-6-membered heterocycloalkyl), -CH2-O-phenyl and phenyl; the C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl groups are each optionally separated by one or more elements selected from halogen, -OH, -CN, -NH2, -OC. 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution.

2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 Selected from hydrogen, deuterium, or -C 1-6 alkyl.

3. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 For H.

4. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Ring A is ; where 1 is connected to -C(O)- and 2 is connected to piperidinedione.

5. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R a Each is independently selected from hydrogen, halogen, -OH, -NH2, -C 1-6 Alkyl or -OC 1-6 alkyl.

6. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R a Each is independently selected from hydrogen, halogen, or -OC. 1-6 alkyl.

7. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, m is selected from 0, 1, or 2.

8. The compound of formula (I) as claimed in claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, m is 0.

9. The compound of formula (I) as claimed in claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, R a Selected from hydrogen, -F, -OH, -NH2, -CH3 or -OCH3.

10. The compound of formula (I) as claimed in claim 9, or a pharmaceutically acceptable salt thereof, characterized in that, R a Selected from hydrogen, -F, or -OCH3.

11. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R b Each is independently selected from hydrogen, F, Cl, -NH2, methyl, ethyl, -CF3, -OCF3, -NHCH3, -N(CH3)2, morpholinyl, piperidinyl, cyclopropyl, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -O-CH2-phenyl, -O-CH2-pyridyl, -O-phenyl, -S-phenyl, -NH-phenyl, -CH2CH2N(CH3)2, -CH2CH2NH(CH3), - CH2CH2OCH2CH2NHCH3, -CH2CH2OCH2CH2OCH3, -CH2-O-piperidinyl, -CH2-O-azacyclobutyl, -CH2-morpholinyl, -CH2-O-phenyl and phenyl; wherein the methyl, ethyl, cyclopropyl, phenyl, piperidinyl, morpholinyl and pyridinyl groups are each optionally substituted by one or more groups selected from halogen, -NH2, -OCH3, -NHCH3, -N(CH3)2, methyl, -CF3.

12. The compound of formula (I) as claimed in claim 11, or a pharmaceutically acceptable salt thereof, characterized in that, R b Each is independently selected from: -NH2, methyl, chlorine, -OCF 3、 fluorine, tert-butyl, -CF3 , , , , , , , , , , , , , , , , , , , , , , or .

13. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When ring B is surrounded by one or more R b When replacing, ring B is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

14. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 For H; Ring A is selected from: ; where 1 is connected to -C(O)- and 2 is connected to piperidinedione; R 2 and R 3 For H; P is 1; L represents a chemical bond; Ring B is a benzene ring; R b Each is independently selected from hydrogen, halogen, NH2, -C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, -C 3-6 Cycloalkyl, -O-phenyl; the -C 1-6 Alkyl, -C 3-6 The cycloalkyl group and -O-phenyl group are each optionally separated by one or more elements selected from halogen, NH2, -C 1-6 Alkyl and -halogenated C 1-6 Alkyl substitution.

15. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 For H; Ring A is selected from: ; where 1 is connected to -C(O)- and 2 is connected to piperidinedione; R 2 and R 3 For H; P is 1; L represents a chemical bond; Ring B is a benzene ring; R b Each is independently selected from hydrogen, F, Cl, NH2, methyl, ethyl, propyl, tert-butyl, -CF3, -NHCH3, -N(CH3)2, , and .

16. The compound of formula (I) as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound with the structure shown in formula (I) is the same as the compound shown in formula (II): ； Formula II; in, R 1 L, ring A, and ring B are as described in any one of claims 1-15.

17. The compound of formula (I) as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound with the structure shown in formula (I) is the same as the compound shown in formula (III): ； in, R 1 L, R a m and ring B are each independently as described in any one of claims 1-15.

18. The compound of formula (I) as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound with the structure shown in formula (I) is the same as the compound shown in formula (IIIa): ； Formula IIIa; in, R a R b Each of m is independently described in any one of claims 1-15; q is selected from 0, 1, 2, 3 or 4.

19. The compound of formula (I) as claimed in any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound with the structure shown in formula (I) is the compound shown in the following formula: 、 、 、 、 、 、 、 、 in, R b Each is independently described in any one of claims 1-15.

20. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is selected from any of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 21. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

22. The use of a substance Y in the preparation of a medicament, wherein the substance Y is a compound of formula (I) as described in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21; The drug meets one of the following conditions: The drug is used to treat cancer; The drug is used to treat GSPT1-related diseases.

23. The application of substance Y according to claim 22 in the preparation of a pharmaceutical product, characterized in that, The GSPT1-related diseases are those that are sensitive to or respond to GSPT1 degradation.

24. The application of substance Y according to claim 22 in the preparation of a pharmaceutical product, characterized in that, The GSPT1-related disease is cancer.

25. The use of substance Y according to claim 24 in the preparation of a pharmaceutical product, characterized in that, The cancers mentioned are selected from breast cancer, colorectal 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, vulvar cancer, leukemia, multiple myeloma, and lymphoma.

26. The application of substance Y according to claim 24 in the preparation of a pharmaceutical product, characterized in that, The cancer in question is colon cancer.

27. The use of a substance Y in the preparation of a GSPT1 degrading agent, wherein the substance Y is a compound of formula (I) as described in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 21.

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