Protein degradation agent, pharmaceutical composition comprising same, use thereof, and method

Abstract

The present invention relates to the field of medical chemistry, and provides a protein degradation agent, a pharmaceutical composition comprising same, a use thereof, and a method. Specifically, provided are a compound as shown in formula (I), or a stereoisomer, tautomer, polymorph, solvate, N-oxide, and isotopically labeled compound thereof, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof. The compound of the present invention can be used for prevention and / or treatment of tumor or cancer.

Description

Protein degrading agents, their pharmaceutical compositions, and their uses and methods Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to protein degrading agents, their pharmaceutical compositions, preparation methods, and their uses and methods. Background Technology

[0002] The ubiquitin-proteasome system (UPS) is one of the two naturally occurring protein degradation pathways in eukaryotic cells, mediating 80-90% of protein degradation and is the most important protein degradation system in eukaryotes. Ubiquitin-mediated protein degradation mainly utilizes ubiquitin activator E1, ubiquitin conjugate E2, and ubiquitin-protein ligase E3 to load ubiquitin onto target proteins for labeling and then deliver it to the 26S proteasome for degradation.

[0003] Currently, protein degraders developed using the ubiquitin-proteasome system mainly include two types: PROTACs and molecular gels. These protein degraders induce or stabilize protein-protein interactions between E3 ubiquitinase and target proteins, forming ternary complexes that lead to ubiquitination and degradation of the target protein. The earliest approved molecular gel drug was thalidomide. One part of the thalidomide molecule interacts with the E3 ubiquitin ligase CRBN, while another part links to IKZF1 / 3 proteins, inducing CRBN and IKZF1 / 3 proteins to approach each other. Subsequently, IKZF1 / 3 proteins are ubiquitinated and ultimately degraded by the proteasome. Building upon thalidomide, researchers have obtained molecular gels with different degradation properties through reasonable structural optimization, and these gels can recruit different novel substrates to lead to their degradation, such as CK1α and GSPT1.

[0004] G1-to-S phase transition protein 1 (GSPT1) belongs to the eukaryotic peptide chain releasing factor (eRF3a) class and is a GTPase primarily located in the cytoplasm, widely expressed in various organs and tissues of the human body. GSPT1 is a translation termination factor that recognizes stop codons by forming a translation termination complex (eRF1 / eRF3 / GTP complex), forcing the protein to dissociate from the ribosome after translation. GSPT1 protein is highly expressed in various tumors, and downregulation of its expression can inhibit tumor cell proliferation, migration, and invasion. Summary of the Invention

[0005] The present invention aims to provide a novel protein degrader that can be used to degrade GSPT1 protein, and also relates to pharmaceutical compositions of the protein degrader, methods of preparation, and applications in the prevention and / or treatment of diseases related to GSPT1 protein dysregulation, such as tumors.

[0006] On the one hand, the present invention provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound has a structure as shown in formula (I):

[0007] in,

[0008] X 1 Selected from CH2 and -C(=O)-;

[0009] Ring A is selected from phenyl and 5-6-membered heteroaryl groups;

[0010] Y is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 4 replace;

[0011] Z is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 3 replace;

[0012] R 1 Selected from H and C 1-6 alkyl;

[0013] R 2 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 alkyl;

[0014] R 3 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1- 6-alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -ORa -OC 1-6 Alkylene-OR a -OC 1-6 Alkylene-N(R) a )R b -C(=O)-N(R) a )-C 1-6 Alkylene-OR a -C(=O)-N(R) a )-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 6 replace;

[0015] R 4 Each is independently selected from H, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1-6 Alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -OC 1- 6-alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 5 replace;

[0016] R 5 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ;

[0017] R 6 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ;

[0018] L is selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups, and divalent structures composed of one or more of the above structural units;

[0019] R a Each is independently selected from H and C. 1-6 alkyl;

[0020] R b Each is independently selected from H and C. 1-6 alkyl;

[0021] m is selected from 1, 2, and 3;

[0022] p is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0023] q is selected independently from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0024] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

[0025] Another aspect of the present invention provides the use of the compounds described herein, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or metabolites or prodrugs or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions described herein, in the preparation of medicaments, for example, for the prevention and / or treatment of diseases, particularly diseases related to GSPT1 protein dysregulation, preferably, said diseases being tumors or cancer.

[0026] Another aspect of the present invention provides the compounds described herein, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or metabolites or prodrugs or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions described herein, for the prevention and / or treatment of diseases, particularly diseases related to GSPT1 protein dysregulation, preferably tumors or cancer.

[0027] Another aspect of the invention provides a method for preventing and / or treating diseases, particularly those related to GSPT1 protein dysregulation, the method comprising administering to an individual in need an effective amount of the compound of the invention, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention.

[0028] Another aspect of the present invention provides a method for degrading GSPT1 protein in cells, comprising contacting the cells with the compound of the present invention, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, or their metabolites or prodrugs or pharmaceutically acceptable salts or esters, or the pharmaceutical composition of the present invention.

[0029] The diseases associated with GSPT1 protein dysregulation described in this invention are tumors or cancer.

[0030] Another aspect of the present invention provides a method for preparing compound of formula I.

[0031] Another aspect of the present invention provides intermediate compounds for preparing the compounds of the present invention. Detailed Implementation

[0032] Terminology Definition

[0033] 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.

[0034] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other forms herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0035] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 6 carbon atoms (e.g., C14). 1-6 Alkyl groups and alkyl groups containing 1 to 4 carbon atoms (e.g., C14) 1-4 Alkyl). C 1-6 Alkyl (e.g., C10) 1-4 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point, preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, etc.

[0036] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon group. Unless otherwise specified, alkylene groups preferably contain 1-6 carbon atoms, for example, C64. 1-6 Alkylene group. In other embodiments, the alkylene group contains 1-4 carbon atoms, for example, C1... 1-4 Alkylene group. In other embodiments, the alkylene group contains 1-2 carbon atoms, for example, C10. 1-2 Alkylene. C 1-6 Alkylene (e.g., C16) 1-4Examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), etc., wherein the alkylene group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0037] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group, including but not limited to monocycloalkyl and bicycloalkyl groups (such as spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl). The term "C" 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 (e.g., 3-8, 3-6, 3-4) cyclic carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl group may be substituted or unsubstituted, wherein the cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0038] The term "heterocyclic group" refers to a 3- to 12-membered non-aromatic cyclic group consisting of 2 to 11 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples include 3-12-membered heterocyclic groups, 3-10-membered heterocyclic groups, 3-8-membered heterocyclic groups, 3-6-membered heterocyclic groups, and 4-6-membered heterocyclic groups. Heterocyclic groups can be saturated or partially unsaturated. Unless otherwise specifically indicated in this specification, heterocyclic groups can be monocyclic, bicyclic, tricyclic, or more ring systems, which may include fused ring systems, fused ring systems, bridged ring systems, or spirocyclic systems. For the purposes of this application, the heterocyclic group is preferably a 3- to 12-membered or 3- to 10-membered non-aromatic monocyclic or bicyclic group containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, such as a 3- to 8-membered non-aromatic monocyclic group containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 3- to 6-membered non-aromatic monocyclic group containing 1 to 2 heteroatoms selected from nitrogen and oxygen; or a 3- to 12-membered non-aromatic bicyclic group, including fused bicyclic, fused bicyclic, bridged bicyclic, or spirocyclic. The nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially unsaturated or fully saturated. The heterocyclic group may be a nitrogen-containing heterocyclic group, an oxygen-containing heterocyclic group, a sulfur-containing heterocyclic group, etc. Therefore, 3-12 membered heterocyclic groups can be 3-12 membered nitrogen-containing heterocyclic groups, 3-12 membered oxygen-containing heterocyclic groups, 3-12 membered sulfur-containing heterocyclic groups, etc., and 3-10 membered heterocyclic groups can be 3-10 membered nitrogen-containing heterocyclic groups, 3-10 membered oxygen-containing heterocyclic groups, 3-10 membered sulfur-containing heterocyclic groups, etc., and so on. Heterocyclic groups can be connected to the rest of the molecule via carbon atoms or heteroatoms and through single bonds. Examples of 3-12 membered heterocyclic groups (e.g., 3-10 membered heterocyclic groups) include, but are not limited to: ethylene oxide, aziridinyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolyl, hexahydro-1H-pyrrolinyl, pyrrolidone, imidazoalkyl, pyrazolyl, dihydropyrrolyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazineyl, etc.; or may include, but is not limited to, Where n1, n2, n3, and n4 are each independently 1, 2, or 3. This indicates a single or double bond. Among them, 3-12 member nitrogen-containing heterocyclic groups (e.g., 3-10 member nitrogen-containing heterocyclic groups) refer to heterocyclic groups containing a nitrogen atom, such as aziridinyl, azetidinyl, dihydropyrrolyl, pyrrolylalkyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, etc. etc., or for example wait.

[0039] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0040] The term "halogenated alkyl" refers to the aforementioned alkyl group that has been substituted with a halogen. For example, "C 1-6 "Halogenated alkyl" refers to a C-shaped alkyl group that is substituted with one or more (e.g., 1, 2, or 3) halogens. 1-6 Alkyl; "C" 1-4 "Halogenated alkyl" refers to a C-shaped alkyl group that is substituted with one or more (e.g., 1, 2, or 3) halogens. 1-4 alkyl.

[0041] The term "halogenated alkylene" refers to the aforementioned alkylene group that has been substituted with a halogen, such as C2. 1-6 Halogenated alkylene or C 1-4 Alkyl halides.

[0042] The term "alkoxy" refers to an alkyl group, as defined above, that is attached to a parent molecule via an oxygen atom. C 1-6 Alkoxy groups (e.g., C) 1-4 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy.

[0043] The term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and in which one hydrogen atom is replaced by a bond. The alkenyl group can be straight-chain or branched and contains about 2 to about 15 carbon atoms. In some embodiments, the alkenyl group contains about 2 to about 12 carbon atoms. In some embodiments, the alkenyl group contains about 2 to about 6 carbon atoms. In some embodiments, the alkenyl group contains about 2 to about 4 carbon atoms. The term "C 2-6 "Alkenyl" refers to an alkenyl group with 2 to 6 carbon atoms. The term "C"... 2-4 "Alkenyl" refers to an alkenyl group with 2 to 4 carbon atoms. C 2-6 alkenyl (e.g., C) 2-4 Non-limiting examples of alkenyl groups include vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, and n-pentenyl. An alkenyl group can be unsubstituted or substituted with one or more of the same or different substituents.

[0044] Term "C" 2-6 "Alynyl" refers to a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 to 4 carbon atoms (i.e., C64). 2-4 alkynyl group), for example, 2 or 3 carbon atoms (“C 2-3 The C group ("alkynyl group"). 2-6 alkynyl groups (e.g., C)2-4 The alkynyl group (e.g., ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl -Alynyl, 1-methylpentan-4-ynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbutan-3-ynyl, 1-ethylbutan-3-ynyl, 1-ethylbutan-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the ynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0045] The term "aryl" refers to a C group with a conjugated π-electron system. 6-14 All-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups, preferably C 6-10 Aryl groups, such as phenyl and naphthyl, more preferably phenyl. The aryl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0046] The term "5-10-membered heteroaryl" refers to an aromatic monocyclic or polycyclic system containing about 5 to about 10 ring atoms, wherein 1 to 4 ring atoms are independently O, N, S, or Se, and the remaining ring atoms are carbon atoms. In some embodiments, the heteroaryl is a monocyclic heteroaryl and has 5 or 6 ring atoms (i.e., a 5-6-membered heteroaryl). In some embodiments, the heteroaryl is a bicyclic heteroaryl. The heteroaryl may optionally be substituted by one or more "cyclic substituents," which may be the same or different, and are defined herein. The heteroaryl is linked by ring carbon atoms, and any nitrogen atom of the heteroaryl may optionally be oxidized to the corresponding N-oxide. Any C atom of the heteroaryl may optionally be oxidized or thiolated. The term "heteroaryl" also includes heteroaryls as defined above fused with heterocyclic groups or cycloalkyl groups. Non-limiting examples of 5-10 membered heteroaryl groups (e.g., 5-6 membered heteroaryl groups) include: pyridyl, pyrazinyl, furanyl, thiopheneyl, selenophenolyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furanyl, pyrroleyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindoyl lyl), imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, azaindolyl, benzimidazolyl, benzothiophene, quinolinyl, imidazolyl, benzimidazolyl, thiophene-pyridyl, quinazolinyl, thiophene-pyrimidinyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, etc., and all their isomers. In some embodiments, the heteroaryl is a 5-membered heteroaryl, such as a 5-membered oxygen-containing heteroaryl, a 5-membered sulfur-containing heteroaryl, or a 5-membered selenium-containing heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl, such as a 6-membered nitrogen-containing heteroaryl.

[0047] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a specified group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and the substitution forms a substantially stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a substantially stable compound.

[0048] The term “optionally” means that the groups or substituents described herein may be unsubstituted or substituted by specific groups or radicals.

[0049] The term "one or more" means one or more under reasonable conditions, such as two, three, four, five or ten.

[0050] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0051] If a compound, group or substituent described herein is described as being "optionally" substituted with a specified group or radical, it means that the compound, group or substituent may be (1) unsubstituted or (2) substituted with the specified group or radical.

[0052] If a substituent or number is described as being “independently selected” from a set of groups or numbers, then each substituent or number is selected independently of the others. Therefore, each substituent or number may be the same as or different from another (other) substituent or number.

[0053] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0054] As used herein, the term "substituent" or "suitable substituent" refers to modifications of a compound that can be made by those skilled in the art to suit the needs of the compound's substituents. "Substituent" or "suitable substituent" includes oxo (=O), halogen, cyano, NR... 9 R 10 Carboxyl, thiol, hydroxyl, ester group (e.g., -C) 1-6 Alkylene-C(=O)-OC 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, benzyl, hydroxy-substituted benzyl, indolylmethylene and C 1-6 Haloalkoxy, R 9 R 10 Each is independently selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, halogens, hydroxyl groups, carboxyl groups, and ester groups (e.g., -C) 1-6 Alkylene-C(=O)-OC 1-6 Alkyl group). The term "cyclic substituent" refers to a substituent that can replace a hydrogen atom on a ring atom, such as the aforementioned "suitable substituent".

[0055] Whether explicitly stated or not, all numerical values ​​in this application are modified by the term “about”. The term “about” means within ±20%, ±10%, ±5%, or ±2% of the stated numerical value.

[0056] The term "stereoisomer" refers to isomers formed due to the presence of at least one asymmetric center in a compound. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0057] This invention 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.

[0058] It should also be understood that certain compounds of the present invention may exist in a free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, isotope-labeled substances, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

[0059] 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 in Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0060] The term "ester" refers to esters derived from the various general formula compounds of this application, including physiologically hydrolyzable esters that can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acids or alcohols. The compounds of the present invention may themselves also be esters.

[0061] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0062] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0063] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. 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.

[0064] 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, and 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) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). 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)).

[0065] In any process of preparing the compounds of the present 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 present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0066] compound

[0067] In some embodiments, the present invention provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein said compound has a structure as shown in formula (I):

[0068] in,

[0069] X 1 Selected from CH2 and -C(=O)-;

[0070] Ring A is selected from phenyl and 5-6-membered heteroaryl groups;

[0071] Y is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 4 replace;

[0072] Z is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 3 replace;

[0073] R 1 Selected from H and C 1-6 alkyl;

[0074] R 2 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 alkyl;

[0075] R 3 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1- 6-alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -OC 1-6 Alkylene-N(R) a )R b -C(=O)-N(R) a )-C1-6 Alkylene-OR a -C(=O)-N(R) a )-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 6 replace;

[0076] R 4 Each is independently selected from H, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1-6 Alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -OC 1- 6-alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 5replace;

[0077] R 5 Each is independently selected from H, halogen, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ;

[0078] R 6 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ;

[0079] L is selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups, and divalent structures composed of one or more of the above structural units;

[0080] R a Each is independently selected from H and C. 1-6 alkyl;

[0081] R b Each is independently selected from H and C. 1-6 alkyl;

[0082] m is selected from 1, 2, and 3;

[0083] p is independently selected from 0, 1, 2, 3, 4, 5, and 6;

[0084] q is selected independently from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0085] In some implementation schemes, X 1 It is CH2.

[0086] In some embodiments, ring A is phenyl, furanyl, thiophene, or selenophenol.

[0087] In some embodiments, the compounds of the present invention have the structure of formula (II-A), formula (II-B), formula (II-C), or formula (II-D):

[0088] Among them, X 2 X 3 X 4 Each is independently selected from O, S, and Se; Y, Z, L, and R. 1 R 2 And m are as defined above.

[0089] In some embodiments, the compound has a structure of formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), or formula (III-F):

[0090] Among them, X 2 X 3 X 4 Each is independently selected from O, S, and Se; Y, Z, L, and R. 1 R 2 And m are as defined above.

[0091] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), and / or formula (III-F), R 1 For H.

[0092] In some embodiments, m is 1 in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E) and / or formula (III-F).

[0093] In some embodiments, the compounds of the present invention have the structures of formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), or (IV-K):

[0094] Among them, R 2 Y, Z, and L are as defined above.

[0095] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), and / or formula (IV-A), R 2 Selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl.

[0096] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), and / or formula (IV-A), R 2 It is H or a halogen (e.g., fluorine).

[0097] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Y is selected from C. 6-10 Aryl and 5-6-membered heteroaryl, said aryl and heteroaryl optionally being separated by one or more R 4 replace.

[0098] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), Y is selected from phenyl and pyridyl groups, wherein the phenyl and pyridyl groups are optionally separated by one or more R groups. 4 replace.

[0099] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from C. 6-10 Aryl and 5-6-membered heteroaryl, said aryl and heteroaryl optionally being separated by one or more R 3 replace.

[0100] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from phenyl and pyridinyl, said phenyl and pyridinyl groups optionally being converted by one or more R groups. 3 replace.

[0101] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from C. 6-10 aryl, said aryl group optionally surrounded by one or more R 3 replace.

[0102] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from phenyl, said phenyl optionally being reacted with one or more R 3 replace.

[0103] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R3 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -N(R) a )-C 1- 4-alkylene-OR a -N(R) a )-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -OC 1-4 Alkylene-N(R) a )R b -C(=O)-N(R) a )-C 1-4 Alkylene-OR a -C(=O)-N(R) a )-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a -C 1-4 Alkylene-N(R) a )R b C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 6 replace.

[0104] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 3 Each is independently selected from H, halogen, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxyl, -OC 1-4 alkylene -OH, -C 1-4 alkylene -OH, -C 1-4 Alkylene-NH-C 1-4 Alkyl, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace.

[0105] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 3 Each is independently selected from H, -N(R) a )R b and -C 1-4 Alkylene-OR a .

[0106] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 3Each is independently selected from H, amino, and -CH2-OH.

[0107] In some embodiments, in some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 4 Each is independently selected from H, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -N(R) a )-C 1-4 Alkylene-OR a -N(R) a )-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -OC 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a -C 1-4 Alkylene-N(R) a )R b C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 5 replace.

[0108] In some embodiments, in some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 4 Each is independently selected from H, halogen, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 alkylene -OH, -C 1-4 alkylene-OH, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace.

[0109] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 4 Each is independently selected from H and halogens (e.g., chlorine).

[0110] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 5 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a and -C 1-4 Alkylene-N(R) a )R b .

[0111] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 5 Each is independently selected from H, halogen, hydroxyl, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkylene -OH, -C(=O)-C 1-4 alkylene -OH, -C 1-6 Alkylene -OH and -OC 1-6 alkyl.

[0112] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 6 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a and -C 1-4 Alkylene-N(R) a )R b .

[0113] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R 6 Each is independently selected from H, halogen, hydroxyl, amino, C 1-4 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-NH-C 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene-NH-C 1-4 Alkyl and -OC 1-4 alkyl.

[0114] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R a Each is independently selected from H and C. 1-4 alkyl.

[0115] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), R b Each is independently selected from H and C. 1-4 alkyl.

[0116] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), Y is C. 6-10Aryl (e.g., phenyl) and 5-10 heteroaryl (e.g., pyridyl, etc.) ), the C 6- 10 Aryl (e.g., phenyl) and 5-10 heteroaryl (e.g., pyridyl, etc.) )Optionally by one or more R 4 Replace, R 4 Each is independently selected from H and halogens (e.g., chlorine).

[0117] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from C. 6-10 Aryl (e.g., phenyl) and 5-10 heteroaryl (e.g., pyridyl), wherein the aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl) are optionally surrounded by one or more R 3 Instead, the R 3 Each is independently selected from H, -N(R) a )R b and -C 1-6 Alkylene-OR a R a Each is independently selected from H and C. 1-6 Alkyl, R b Each is independently selected from H and C. 1-6 alkyl.

[0118] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), Z is selected from C. 6-10 Aryl (e.g., phenyl), said aryl (e.g., phenyl) optionally surrounded by one or more R 3 Instead, the R 3 Each is independently selected from H, -N(R) a )R b and -C1-6 Alkylene-OR a R a Each is independently selected from H and C. 1-6 Alkyl, R b Each is independently selected from H and C. 1-6 alkyl.

[0119] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), L is selected from C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C 1-4 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups (e.g., 3-12 membered nitrogen-containing heterocyclic groups, 3-10 membered heterocyclic groups or 3-10 membered nitrogen-containing heterocyclic groups), and divalent structures composed of one or more of the above structural units.

[0120] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), L is selected from C 1-4 Alkylene, -C 1-4 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q- 3-12 membered heterocyclic groups (e.g., 3-12 membered nitrogen-containing heterocyclic groups, 3-10 membered heterocyclic groups or 3-10 membered nitrogen-containing heterocyclic groups) and divalent structures composed of one or more of the above structural units.

[0121] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), L is selected from -O-(CH2). p -、 Where n1, n2, n3, and n4 are each independently 1, 2, or 3. Indicates a single bond or a double bond.

[0122] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), L is selected from C 1-4 Alkylene, -O-(CH2) p - 3-12 membered heterocyclic groups (e.g., 3-12 membered nitrogen-containing heterocyclic groups, 3-10 membered heterocyclic groups or 3-10 membered nitrogen-containing heterocyclic groups) and divalent structures composed of one or more of the above structural units.

[0123] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), L contains a 3-12 membered heterocyclic group (e.g., a 3-12 membered nitrogen-containing heterocyclic group), such as aziridine, tetrahydropyridyl, piperidinyl, etc.

[0124] In some embodiments, in the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K), L contains a 3-10 membered heterocyclic group (e.g., a 3-10 membered nitrogen-containing heterocyclic group), such as aziridine, tetrahydropyridinyl, or piperidinyl.

[0125] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), L is selected from 3-12-membered heterocyclic groups (e.g., 3-12-membered nitrogen-containing heterocyclic groups, 3-10-membered heterocyclic groups, or 3-10-membered nitrogen-containing heterocyclic groups), or is composed of a 3-12-membered heterocyclic group (e.g., 3-12-membered nitrogen-containing heterocyclic group, 3-10-membered heterocyclic group, or 3-10-membered nitrogen-containing heterocyclic group) and a compound selected from C... 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C 1-4 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-8 A divalent structure consisting of one or more structural units of a cycloalkyl group.

[0126] In some embodiments, in the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), L is selected from 3-12-membered heterocyclic groups (e.g., 3-12-membered nitrogen-containing heterocyclic groups, 3-10-membered heterocyclic groups, or 3-10-membered nitrogen-containing heterocyclic groups), or is composed of a 3-12-membered heterocyclic group (e.g., 3-12-membered nitrogen-containing heterocyclic group, 3-10-membered heterocyclic group, or 3-10-membered nitrogen-containing heterocyclic group) and a compound selected from C... 1-4 Alkylene, -O-(CH2) p - A bivalent structure consisting of one or more structural units.

[0127] In some embodiments, L is selected from the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K).

[0128] Position 1 is connected to Y, and position 2 is connected to Z.

[0129] In some embodiments, L is selected from the compounds represented by formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (IV-I), formula (IV-J), and / or formula (IV-K).

[0130] Position 1 is connected to Y, and position 2 is connected to Z.

[0131] In some embodiments, the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), Selected from

[0132] In some embodiments, the compounds represented by formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K), Selected from

[0133] In some embodiments, the compound is selected from:

[0134] In some embodiments, the compound of the present invention may optionally be substituted at a suitable position with one or more suitable substituents.

[0135] In the compounds of formulas (I), (II-A), (II-B), (II-C), (II-D), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), and / or (IV-K) of the present invention, the groups in all embodiments can be suitably selected and combined in any way to obtain different general formula ranges or specific embodiments. These ranges and embodiments are all within the scope of the present invention. The present invention covers compounds obtained by arbitrary combinations of the various embodiments.

[0136] Preparation method

[0137] On the other hand, the present invention provides a method for preparing a compound of formula (I), which includes one or more of the following steps:

[0138] Among them, X 1 Y, Z, L, R 1 R 2 Rings A and m are as defined above;

[0139] Step A: Compound I-1 undergoes an oxidation reaction to give compound I-2;

[0140] Preferably, the oxidation reaction is carried out in the presence of a suitable solvent, oxidant, and base; the solvent may be selected from 1,4-dioxane, water, pyridine, ethanol, and tert-butanol, or any combination thereof, preferably selected from pyridine; the oxidant may be selected from selenium dioxide, potassium permanganate, and sodium dichromate, preferably selected from selenium dioxide; the base may be selected from pyridine, sodium hydroxide, and potassium carbonate, preferably selected from pyridine; preferably, the reaction is carried out at a suitable temperature, which may be 80-120°C, preferably 110°C; the oxidation reaction is carried out for a suitable time, which may be 10-20 hours, for example, 18 hours.

[0141] Step B: Compound I-2 and compound I-3 undergo a condensation reaction to obtain compound I;

[0142] Preferably, the condensation reaction is carried out in the presence of a suitable solvent, condensing agent, and base; the solvent may be selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and 1,4-dioxane, or any combination thereof, preferably selected from N,N-dimethylformamide; the condensing agent may be selected from 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, and 1-ethyl-(3-dimethylaminopropyl)carbamate. The amine hydrochloride, preferably, is selected from 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; the base is selected from pyridine, N,N-diisopropylethylamine, triethylamine and N-methylmorpholine, preferably, the base is selected from N,N-diisopropylethylamine; preferably, the reaction is carried out at a suitable temperature, the temperature can be 0-40°C, preferably, the temperature is room temperature; the condensation reaction is carried out for a suitable time, the time can be 1-6 hours, for example, the time is 2 hours.

[0143] intermediate

[0144] In some embodiments, the present invention provides intermediate compounds or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotope-labeled compounds as shown below.

[0145] Among them, X 1 Y, Z, L, R 1 R 2 Rings A and m are as defined above;

[0146] Q is a halogen, such as fluorine;

[0147] PG 1 The protecting group is a hydrogen or carboxyl group, and the carboxyl protecting group is, for example, C. 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl;

[0148] PG 2 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); or an acyl amino group, for example, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), oro(p) Nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn);

[0149] PG 3 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl or p-nitrobenzoyl.

[0150] In some embodiments, the intermediate compound shown above, or its salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, or isotopically labeled compound, can be used to prepare the compound of the general formula shown herein, or its stereoisomer, tautomer, polymorph, solvate, N-oxide, or isotopically labeled compound, or its metabolite, prodrug, or pharmaceutically acceptable salt or ester.

[0151] Pharmaceutical compositions and therapeutic uses and methods

[0152] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

[0153] In another embodiment, the pharmaceutical composition may also contain one or more other therapeutic agents.

[0154] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0155] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0156] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations, or inhalation administration.

[0157] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0158] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0159] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

[0160] In some embodiments, the compounds of the present invention, or their stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or their metabolites, prodrugs, or pharmaceutically acceptable salts or esters, or the pharmaceutical compositions described in the present invention, satisfy one or more of the following:

[0161] (1) It can efficiently degrade GSPT1;

[0162] (2) It can selectively degrade GSPT1;

[0163] (3) Inhibits tumor cell proliferation;

[0164] (4) Inhibit tumor growth.

[0165] Another aspect of the present invention provides a method for degrading GSPT1 protein in cells, comprising contacting the cells with the compound of the present invention, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, or their metabolites or prodrugs or pharmaceutically acceptable salts or esters, or the pharmaceutical composition of the present invention.

[0166] Another aspect of the present invention provides the use of the compounds described herein, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or metabolites or prodrugs or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions described herein, in the preparation of medicaments, such as medicaments for the prevention and / or treatment of diseases, particularly diseases related to GSPT1 protein dysregulation, preferably, said diseases being tumors or cancer.

[0167] Another aspect of the present invention provides the use of the compounds described herein, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or metabolites or prodrugs or pharmaceutically acceptable salts or esters thereof, or pharmaceutical compositions described herein, in the context of the prevention and / or treatment of diseases, particularly those related to GSPT1 protein dysregulation, preferably tumors or cancer.

[0168] Another aspect of the invention provides a method for preventing and / or treating diseases, particularly those related to GSPT1 protein dysregulation, the method comprising administering to an individual in need an effective amount of the compound of the invention, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the invention.

[0169] The diseases associated with GSPT1 protein dysregulation described in this invention include tumors or cancer.

[0170] In some embodiments, the tumor or cancer includes non-Hodgkin's lymphoma, leukemia, and / or solid tumors. In some embodiments, the non-Hodgkin's lymphoma includes one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and T-cell lymphoma. In some embodiments, the leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia. In some embodiments, the solid tumor includes one or more of lung cancer (e.g., small cell lung cancer), liver cancer, breast cancer, and glioma.

[0171] In some implementations, the tumor or cancer is breast cancer or lung cancer (e.g., small cell lung cancer).

[0172] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0173] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0174] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician.

[0175] Unless otherwise stated, as used herein, the term “treating” means reversing, alleviating, or suppressing the progression of one or more symptoms of the condition or illness to which the term applies.

[0176] As used herein, the term "prevention" refers to the prior administration of medication to avoid or prevent the onset of one or more symptoms of a disease or condition. Those skilled in the medical field recognize that the term "prevention" is not an absolute term. In the medical field, it should be understood as the preventive administration of medication to substantially reduce the likelihood or severity of a condition or its symptoms, which is the intended meaning of this disclosure. The Physician's Desk Reference, the standard text in the field, uses the term "prevention" hundreds of times. As used therein, the term "prevention" regarding a condition or disease refers to the avoidance of the cause, effect, symptoms, or progression of a disease or condition before it has fully manifested.

[0177] 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.).

[0178] Example

[0179] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0180] The following examples are merely illustrative; other compounds in this application can also be synthesized similarly with reference to the following examples.

[0181] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 It was determined by 1H NMR or mass spectrometry (MS). 1The 1H NMR was performed using a JEOL Eclipse 400 NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS). Chemical shifts (δ) were given in parts per million (ppm).

[0182] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0183] Preparation method of high performance liquid chromatograph:

[0184] Instrument model: Agilent 1260; Column: Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); Column temperature: 25℃; Flow rate: 20.0mL / min; Detection wavelength: 214nm; Elution gradient: (0min: 10%A, 90%B; 16.0min: 90%A, 10%B); Mobile phase A: Acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution.

[0185] The thin-layer chromatography silica gel plates (TLC) used were Merck aluminum plates (20×20cm), and the TLC separation and purification used Yantai-made GF 254 (1mm) plates.

[0186] The reaction was monitored using thin-layer chromatography (TLC) or LC-MS. The developing solvent systems used included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound or by adding triethylamine, etc.

[0187] Preparation method of reverse column chromatography:

[0188] Preparation method A:

[0189] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reverse-flow column (Spherical; 20-35 μm; 100A); Column temperature: 25℃; Flow rate: 28.0 mL / min; Detection wavelength: 220 nm; Mobile phase A: acetonitrile; Mobile phase B: water;

[0190] Preparation method B:

[0191] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reverse-flow column (Spherical; 20-35μm; 100A); Column temperature: 25℃; Flow rate: 28.0mL / min; Detection wavelength: 220nm; Mobile phase A: acetonitrile; Mobile phase B: 0.05% formic acid aqueous solution;

[0192] Preparation method C:

[0193] Instrument model: Biotage rapid medium-pressure preparative chromatography; Column: Agela C18 reverse-flow column (Spherical; 20-35 μm; 100A); Column temperature: 25℃; Flow rate: 28.0 mL / min; Detection wavelength: 220 nm; Mobile phase A: acetonitrile; Mobile phase B: 0.05% NH4HCO3 aqueous solution;

[0194] The microwave reaction was performed using a Biotage Initiator+ (400W, RT~300℃) microwave reactor.

[0195] Column chromatography typically uses 200-300 mesh silica gel as the support. Eluent systems include dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine can also be added for adjustment.

[0196] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~35℃).

[0197] The reagents used in this invention were purchased from Acros Organics, Aldrich Chemical Company, and TEB Chemicals, among others.

[0198] In the conventional synthesis methods and examples, as well as intermediate synthesis examples, the meanings of the abbreviations are as follows.

[0199] Preparation Example 1: Preparation of 2-(4-(benzyloxy)phenyl)-2-oxoacetic acid (Int1)

[0200] 1-(4-benzyloxyphenyl)ethyl ketone (300 mg, 1.33 mmol) and selenium dioxide (324 mg, 2.92 mmol) were added to dry pyridine (6 mL), purged three times with nitrogen, and reacted at 110 °C for 18 hours. The reaction mixture was cooled to room temperature, acidified with 1 N hydrochloric acid, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to give the title compound (260 mg, yield: 72.7%).

[0201] MS m / z(ESI): 257.0 [M+H] + .

[0202] Preparation Example 2: Preparation of 2-(4-(benzyloxy)-3-chlorophenyl)-2-oxoacetic acid (Int2)

[0203] Step 1: Preparation of 1-(4-benzyloxy-3-chlorophenyl)ethyl ketone

[0204] 1-(3-chloro-4-hydroxyphenyl)ethyl ketone (300 mg, 1.76 mmol) and potassium carbonate (486 mg, 3.52 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), followed by benzyl bromide (361 mg, 2.11 mmol). The mixture was reacted at 60 °C for 3 hours. The reaction solution was cooled to room temperature, and the mixture was extracted three times with saturated brine and ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrates were concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (402 mg, yield: 86.8%).

[0205] MS m / z(ESI): 261.0 [M+H] + .

[0206] Step 2: Preparation of 2-(4-benzyloxy-3-chlorophenyl)-2-oxoacetic acid

[0207] Following the synthetic route of compound Int1, 1-(4-benzyloxyphenyl)ethyl ketone was replaced with 1-(4-benzyloxy-3-chlorophenyl)ethyl ketone to obtain the title compound of this step (360 mg, yield: 76.7%).

[0208] MS m / z(ESI): 291.0 [M+H] + .

[0209] Preparation Example 3: Preparation of 2-(3-chloro-4-(phenoxymethyl)phenyl)-2-oxoacetic acid (Int3)

[0210] Step 1: Preparation of methyl 3-chloro-4-phenoxymethylbenzoate

[0211] Methyl 4-(bromomethyl)-3-chlorobenzoate (300 mg, 1.14 mmol), phenol (129 mg, 1.37 mmol), and anhydrous potassium carbonate (315 mg, 2.28 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), and the mixture was reacted at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, extracted three times with water and ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1 (v / v)) to give the title compound of this step (288 mg, yield: 90.5%).

[0212] MS m / z(ESI): 277.0 [M+H] + .

[0213] Step 2: Preparation of 3-chloro-4-(phenoxymethyl)benzoic acid

[0214] Methyl 3-chloro-4-phenoxymethylbenzoate (270 mg, 0.98 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (215 mg, 4.88 mmol) was added. The reaction mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated, and the pH was adjusted to 4–5 with 1 N hydrochloric acid. The solution was filtered to obtain the title compound of this step (250 mg, yield: 96.6%).

[0215] MS m / z(ESI): 263.2 [M+H] + .

[0216] Step 3: Preparation of 3-chloro-N-methoxy-N-methyl-4-(phenoxymethyl)benzamide

[0217] 3-Chloro-4-(phenoxymethyl)benzoic acid (245 mg, 0.93 mmol), dimethylhydroxylamine hydrochloride (118 mg, 284.75 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (390 mg, 1.03 mmol), and N,N-diisopropylethylamine (362 mg, 2.80 mmol) were added to anhydrous N,N-dimethylformamide (4 mL), and the reaction was carried out under nitrogen protection at room temperature for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 30%-75%) to give the title compound of this step (282 mg, yield: 94.0%).

[0218] MS m / z (ESI): 306.1 [M+H] + .

[0219] Step 4: Preparation of 1-(3-chloro-4-(phenoxymethyl)phenyl)ethyl-1-one

[0220] Under a nitrogen atmosphere, 250 mg (0.82 mmol) of 3-chloro-N-methoxy-N-methyl-4-(phenoxymethyl)benzamide was dissolved in 3 mL of anhydrous tetrahydrofuran. Magnesium methyl bromide (1 M, 8.18 mL, 8.18 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 4 hours. The reaction mixture was quenched with 1 N hydrochloric acid, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 1 (v / v)) to give the title compound of this step (195 mg, yield: 91.5%).

[0221] MS m / z(ESI):261.0[M+H]+.

[0222] Step 5: Preparation of 2-(3-chloro-4-(phenoxymethyl)phenyl)-2-oxoacetic acid

[0223] Following the synthetic route of intermediate Int1, 1-(4-benzyloxyphenyl)ethyl ketone was replaced with 1-(3-chloro-4-(phenoxymethyl)phenyl)ethyl-1-ketone to obtain the title compound of this step (200 mg, yield: 85.2%).

[0224] MS m / z(ESI): 291.0 [M+H] + .

[0225] Preparation Example 4: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-2-oxoacetate (Int4)

[0226] Step 1: Preparation of 2-(3-chloro-4-fluorophenyl)-2-oxoacetic acid

[0227] Following the synthetic route of intermediate Int1, 1-(4-benzyloxyphenyl)ethyl ketone was replaced with 1-(3-chloro-4-fluorophenyl)ethyl-1-ketone to obtain the title compound of this step (1.0 g, yield: 80.9%).

[0228] MS m / z(ESI): 203.0 [M+H] + .

[0229] Step 2: Preparation of methyl 2-(3-chloro-4-fluorophenyl)-2-oxoacetate

[0230] 2-(3-chloro-4-fluorophenyl)-2-oxoacetic acid (1.0 g, 4.69 mmol) was dissolved in anhydrous methanol (5 mL), and thionyl chloride (2.23 g, 18.76 mmol) was slowly added. The reaction mixture was reacted at room temperature for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 (v / v)) to give the title compound of this step (850 mg, yield: 79.5%).

[0231] MS m / z(ESI): 217.0 [M+H] + .

[0232] Preparation Example 5: Preparation of 2-(3-chloro-4-(4-(4-nitrophenyl)piperidin-1-yl)phenyl)-2-oxoacetic acid (Int5)

[0233] 2-(3-chloro-4-fluorophenyl)-2-oxoacetic acid methyl ester (115 mg, 0.53 mmol), 4-(4-nitrophenyl)piperidine (109.5 mg, 0.53 mmol), and potassium carbonate (220 mg, 1.59 mmol) were added to anhydrous N,N-dimethylformamide (0.5 mL), and the reaction was carried out at 90 °C for 4 hours. The reaction solution was cooled, concentrated, and the pH was adjusted to 1 with hydrochloric acid. The solution was filtered to give the title compound (75 mg, yield: 37.2%).

[0234] MS m / z(ESI): 389.0 [M+H] + .

[0235] Preparation Example 6: Preparation of 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetic acid (Int6)

[0236] Step 1: Preparation of methyl 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetate

[0237] 4-(4-nitrophenoxy)piperidine (250 mg, 0.97 mmol), methyl 2-(3-chloro-4-fluorophenyl)-2-oxoacetate (209 mg, 0.97 mmol), and potassium carbonate (401 mg, 2.90 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), and reacted at 100 °C for 1 hour. The reaction solution was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (v / v)) to give the title compound of this step (210 mg, yield: 49.3%).

[0238] MS m / z (ESI): 419.2 [M+H] + .

[0239] Step 2: Preparation of 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetic acid

[0240] 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetate methyl ester (195 mg, 442 μmol) and lithium hydroxide monohydrate (92.8 mg, 2.21 mmol) were dissolved in a mixture of tetrahydrofuran (4 mL) and water (2 mL), and reacted at room temperature for 4 hours. The reaction solution was concentrated, and the pH was adjusted to 4–5 with 1 N hydrochloric acid. The solution was filtered to give the title compound of this step (147 mg, yield: 78.0%).

[0241] MS m / z(ESI): 405.0 [M+H] + .

[0242] Preparation Example 7: Preparation of 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid (Int7)

[0243] Following the synthetic route of intermediate Int6, the starting material 4-(4-nitrophenoxy)piperidine was replaced with 3-(4-nitrophenyl)azacyclobutane to obtain the title compound (255 mg).

[0244] MS m / z(ESI): 361.0 [M+H] + .

[0245] Preparation Example 8: Preparation of 2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetic acid (Int8)

[0246] Step 1: Preparation of 1-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)ethyl-1-one

[0247] 2-Chloro-5-acetylpyridine (170 mg, 1.08 mmol), 3-(4-nitrophenyl)-azacyclobutane (194.70 mg, 1.08 mmol), and N,N-diisopropylethylamine (281.91 mg, 2.16 mmol) were added to N,N-dimethylformamide (2 mL), and the mixture was reacted at 90 °C for 2 hours. The reaction solution was diluted with ethyl acetate, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (180 mg, yield: 50.4%).

[0248] MS m / z(ESI): 298.1 [M+H] + .

[0249] Step 2: Preparation of 2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetic acid

[0250] 1-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)ethyl-1-one (180 mg, 544.89 μmol) and selenium dioxide (152.68 mg, 1.36 mmol) were added to 1,4-dioxane (3 mL), and the reaction was carried out overnight at 110 °C. The reaction solution was cooled, diluted with ethyl acetate, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (150 mg, yield: 67.3%).

[0251] MS m / z (ESI): 326.1 [MH] － .

[0252] 1 H NMR (400MHz, DMSO-d6): δ8.61(s,1H),8.23(d,J=8.0Hz,2H),7.97(d,J=8.0Hz,1H),7 .45(d,J=8.0Hz,2H),6.53(d,J=8.0Hz,1H),4.59(t,J=8.0Hz,2H),4.24-4.15(m,3H).

[0253] Preparation Example 9: Preparation of 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-2-oxoacetic acid (Int9)

[0254] Step 1: Preparation of tert-butyl 3-(4-(hydroxymethyl)phenyl)azacyclobutane-1-carboxylate

[0255] Under ice-salt bath cooling, tert-butyl 3-(4-(methoxycarbonyl)phenyl)azacyclobutane-1-carboxylate (140 mg, 432.48 μmol) and diisobutylaluminum hydride (1 M, 10 mL) were added to tetrahydrofuran (5 mL), and the reaction was maintained at this temperature for 1 hour. The reaction was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated to give the title compound of this step (95 mg, yield: 75.1%).

[0256] MS m / z(ESI): 208.1 [M+H-56] + .

[0257] Step 2: Preparation of tert-butyl 3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-carboxylate

[0258] 3-(4-(hydroxymethyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (105.56 mg, 360.76 μmol), tert-butyldiphenylchlorosilane (62.50 mg, 541.14 μmol), and imidazole (37.17 mg, 541.14 μmol) were added to N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (100 mg, yield: 49.7%).

[0259] MS m / z (ESI): 446.1 [M+H-56] + .

[0260] Step 3: Preparation of 3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane

[0261] 3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (100 mg, 179.38 μmol) and anhydrous zinc bromide (163.22 mg, 717.52 μmol) were added to dichloromethane (3 mL) and reacted at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (75 mg, yield: 93.7%).

[0262] MS m / z(ESI): 402.2 [M+H] + .

[0263] Step 4: Preparation of methyl 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-2-oxoacetate

[0264] Methyl 2-(3-chloro-4-fluorophenyl)-2-oxoacetate (37.75 mg, 156.87 μmol), 3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane (70 mg, 156.87 μmol), and N,N-diisopropylethylamine (40.88 mg, 313.73 μmol) were added to N,N-dimethylformamide (2 mL), and the reaction was carried out at 65 °C for 3 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 95%-100%) to give the title compound of this step (87 mg, yield: 83.4%).

[0265] MS m / z (ESI): 598.3 [M+H] + .

[0266] Step 5: Preparation of 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-2-oxoacetic acid

[0267] Methyl 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-2-oxoacetate (87 mg, 130.89 μmol) was dissolved in tetrahydrofuran (2 mL) under ice-water bath cooling. The pH was adjusted to approximately 9-10 with 1 N lithium hydroxide aqueous solution, and the reaction was carried out at 0 °C for 2 hours. The reaction solution was adjusted to pH 4 with 1 N hydrochloric acid, concentrated to remove tetrahydrofuran, and filtered to obtain the title compound of this step (75 mg, yield: 88.3%).

[0268] MS m / z (ESI): 584.2 [M+H] + .

[0269] Preparation Example 10: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-2-oxoacetic acid (Int10)

[0270] Step 1: Preparation of tert-butyl 4-(4-acetyl-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0271] 3-Chloro-4-bromoacetophenone (1.0 g, 4.28 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.59 g, 5.14 mmol), potassium carbonate (1.78 g, 12.85 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (349 mg, 428 μmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and reacted at 60 °C for 6 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 (volume ratio)) to give the title compound of this step (1.4 g, yield: 92.5%).

[0272] MS m / z (ESI): 336.1 [M+H] + .

[0273] Step 2: Preparation of tert-butyl 4-(2-chloro-4-(1,1-dimethoxyethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0274] 4-(4-acetyl-2-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (800 mg, 2.38 mmol), trimethyl orthoformate (1.52 g, 14.29 mmol), and p-toluenesulfonic acid (123 mg, 714 μmol) were dissolved in anhydrous methanol (10 mL) and reacted at 60 °C for 2 h. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7 / 3 (v / v)) to give the title compound of this step (590 mg, yield: 61.6%).

[0275] MS m / z(ESI): 382.1 [M+H] + .

[0276] Step 3: Preparation of tert-butyl 4-(2-chloro-4-(1,1-dimethoxyethyl)phenyl)piperidine-1-carboxylic acid

[0277] 1.2 g (3.14 mmol) of tert-butyl 4-(2-chloro-4-(1,1-dimethoxyethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in anhydrous tetrahydrofuran (10 mL), and platinum dioxide (146 mg, 628 μmol) was added. The mixture was then purged with hydrogen and reacted at room temperature for 4 hours. The reaction solution was filtered through a diatomaceous earth sieve, and the filtrate was concentrated to give the title compound of this step (1.2 g, yield: 94.5%).

[0278] MS m / z(ESI): 284.1 [M+H-100] + .

[0279] Step 4: Preparation of 1-(3-chloro-4-(piperidin-4-yl)phenyl)ethyl-1-one

[0280] 1.3 g (3.39 mmol) of tert-butyl 4-(2-chloro-4-(1,1-dimethoxyethyl)phenyl)piperidine-1-carboxylate was dissolved in a mixture of 3 mL tetrahydrofuran and 2 mL water. Concentrated hydrochloric acid (2 mL) was added, and the reaction was carried out at 80 °C for 2 hours. The reaction solution was directly concentrated to give the title compound of this step (900 mg, yield: 98.4%).

[0281] MS m / z(ESI): 238.1 [M+H] + .

[0282] Step 5: Preparation of 1-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)ethyl-1-one

[0283] 1-(3-chloro-4-(piperidin-4-yl)phenyl)ethyl-1-one (400 mg, 1.39 mmol), 1-fluoro-4-nitrobenzene (235 mg, 1.66 mmol), and anhydrous potassium carbonate (766 mg, 5.54 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), and the mixture was reacted at 80 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (200 mg, yield: 39.8%).

[0284] MS m / z (ESI): 359.1 [M+H] + .

[0285] Step 6: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-2-oxoacetic acid

[0286] 1-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)ethyl-1-one (194 mg, 541 μmol) and selenium dioxide (180 mg, 1.62 mmol) were added to dry pyridine (5 mL), purged three times with nitrogen, and reacted at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, adjusted to acidity with 1 N hydrochloric acid, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (200 mg, yield: 90.4%).

[0287] MS m / z(ESI): 389.1 [M+H] + .

[0288] Preparation Example 11: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetic acid (Int11)

[0289] Step 1: Preparation of 2-(3-chloro-4-bromophenyl)-2-oxoacetic acid

[0290] 1-(3-chloro-4-bromophenyl)ethyl-1-one (1.2 g, 5.14 mmol) and selenium dioxide (1.25 g, 11.31 mmol) were added to pyridine (10 mL), purged three times with nitrogen, and reacted at 110 °C for 18 hours. The reaction solution was cooled to room temperature, adjusted to acidity with 1 N hydrochloric acid, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (1.1 g, yield: 77.2%).

[0291] MS m / z(ESI): 264.9 [M+H] + .

[0292] Step 2: Preparation of methyl 2-(3-chloro-4-bromophenyl)-2-oxoacetate

[0293] 2-(3-chloro-4-bromophenyl)-2-oxoacetic acid (1.1 g, 3.97 mmol) was dissolved in anhydrous methanol (5 mL), and thionyl chloride (1.89 g, 15.87 mmol) was slowly added. The reaction mixture was reacted at room temperature for 2 hours. The crude product obtained by concentration of the reaction solution was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 (v / v)) to give the title compound of this step (1.1 g, yield: 87.0%).

[0294] MS m / z(ESI): 277.0 [M+H] + .

[0295] Step 3: Preparation of tert-butyl 4-(2-chloro-4-(2-methoxy-2-oxoacetyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid

[0296] 2-(3-chloro-4-bromophenyl)-2-oxoacetic acid (400 mg, 1.44 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (535 mg, 1.73 mmol), anhydrous potassium carbonate (398 mg, 2.88 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (118 mg, 1.44 μmol) were added to 1,4-dioxane (8 mL), followed by 2 drops of water. The mixture was reacted at 60 °C for 6 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 (volume ratio)) to give the title compound of this step (460 mg, yield: 79.8%).

[0297] MS m / z (ESI): 325.1 [M+H-56] + .

[0298] Step 4: Preparation of methyl 2-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetate

[0299] 4-(2-chloro-4-(2-methoxy-2-oxoacetyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (460 mg, 1.21 mmol) was added to a solution of 1,4-dioxane in hydrogen chloride (4 M, 8 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the title compound of this step (380 mg, yield: 98.2%).

[0300] MS m / z (ESI): 280.1 [M+H] + .

[0301] Step 5: Preparation of methyl 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetate

[0302] 2-(3-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetate methyl ester (380 mg, 1.36 mmol), 1-fluoro-4-nitrobenzene (192 mg, 1.36 mmol), and anhydrous potassium carbonate (1.13 g, 8.15 mmol) were added to anhydrous N,N-dimethylformamide (8 mL), and the mixture was reacted at 60 °C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give the title compound of this step (90 mg, yield: 16.4%).

[0303] MS m / z (ESI): 401.1 [M+H] + .

[0304] Step 6: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetic acid

[0305] Methyl 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetate (90 mg, 213 μmol) and lithium hydroxide monohydrate (44.8 mg, 1.07 mmol) were dissolved in a mixture of tetrahydrofuran (2 mL) and water (1 mL), and reacted at room temperature for 2 hours. The reaction solution was concentrated to remove tetrahydrofuran, and the pH was adjusted to 4–5 with 1 N hydrochloric acid. The solution was then filtered to give the title compound of this step (82 mg, yield: 94.4%).

[0306] MS m / z(ESI): 387.0 [M+H] + .

[0307] Preparation Example 12: Preparation of 3-(5-(aminomethyl)-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (Int12)

[0308] Step 1: Preparation of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)methyl)carbamate

[0309] 3-(5-bromo-6-fluoro-1-oxoisoindololin-2-yl)piperidine-2,6-dione (120 mg, 351 μmol), potassium N-aminomethyltrifluoroborate (500 mg, 2.11 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (59.6 mg, 70.4 μmol), and N,N-diisopropylethylamine (159 mg, 1.23 mmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (0.5 mL), purged three times with nitrogen, and reacted at 80 °C for 18 hours. The crude product obtained by concentrating the reaction solution was then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1 (volume ratio)) to give the title compound of this step (120 mg, yield: 61.0%).

[0310] MS m / z(ESI): 392.2 [M+H] + .

[0311] Step 2: Preparation of 3-(5-(aminomethyl)-6-fluoro-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrochloride

[0312] 120 mg (216 μmol) of tert-butyl carbamate ((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)methyl)carbamate was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL) and reacted at room temperature for 2 hours. The reaction solution was filtered to give the title compound of this step (48 mg, yield: 56.5%).

[0313] MS m / z(ESI): 292.1 [M+H] + .

[0314] Preparation Example 13: Preparation of 3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione hydrochloride (Int13)

[0315] Following the synthetic route of intermediate Int12, 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione was replaced with 3-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione to obtain the title compound (26.4 mg).

[0316] MS m / z (ESI): 280.1 [M+H] + .

[0317] Preparation Example 14: Preparation of 3-(2-(aminomethyl)-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrolo-5-yl)piperidine-2,6-dione hydrochloride (Int14)

[0318] Following the synthetic route of intermediate Int12, 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione was replaced with 3-(2-bromo-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione to obtain the title compound (10 mg).

[0319] MS m / z (ESI): 280.1 [M+H] + .

[0320] Preparation Example 15: Preparation of 3-(2-(aminomethyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrolo-5-yl)piperidine-2,6-dione hydrochloride (Int15)

[0321] Following the synthetic route of intermediate Int12, 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione was replaced with 3-(2-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione to obtain the title compound (109.3 mg).

[0322] MS m / z(ESI): 280.0 [M+H] + .

[0323] Preparation Example 16: Preparation of 3-(3-(aminomethyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrolo-5-yl)piperidine-2,6-dione hydrochloride (Int16)

[0324] Following the synthetic route of intermediate Int12, 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione was replaced with 3-(3-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione to obtain the title compound (30.1 mg).

[0325] MS m / z(ESI): 280.0 [M+H] + .

[0326] Preparation Example 17: Preparation of 3-(2-(aminomethyl)-4-oxo-4,6-dihydro-5H-furano[2,3-c]pyrrolo-5-yl)piperidine-2,6-dione hydrochloride (Int17)

[0327] Following the synthetic route of intermediate Int12, 3-(5-bromo-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione was replaced with 3-(2-bromo-4-oxo-4,6-dihydro-5H-furano[2,3-c]pyrrole-5-yl)piperidine-2,6-dione to obtain the title compound (33 mg).

[0328] MS m / z(ESI): 264.1 [M+H] + .

[0329] Preparation Example 18: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)azacyclobutane-3-yl)phenyl)-2-oxoacetic acid (Int18)

[0330] Step 1: Preparation of tert-butyl 3-(4-acetyl-2-chlorophenyl)azacyclobutane-1-carboxylate

[0331] Zinc powder (420.08 mg, 6.42 mmol), 1,2-dibromoethane (241.37 mg, 1.28 mmol), and trimethylchlorosilane (139.59 mg, 1.28 mmol) were added to anhydrous N,N-dimethylformamide (5 mL) and reacted at 45 °C for 30 minutes. Then, tert-butyl 3-iodozacyclobutane-1-carboxylate (1.82 g, 6.42 mmol) was added and reacted at 45 °C for 30 minutes. Next, cuprous iodide (163.13 mg, 856.57 μmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (349.75 mg, 428.28 μmol), and 1-(4-bromo-3-chlorophenyl)ethyl-1-one (1 g, 4.28 mmol) were added and reacted at 65 °C for 2 hours. The reaction solution was cooled to room temperature, poured into water, and ethyl acetate was added. The mixture was filtered through diatomaceous earth to remove the flocculent matter. The filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 (volume ratio)) to give the title compound of this step (600 mg, yield: 44.6%).

[0332] MS m / z(ESI): 254.1 [M+H-56] + .

[0333] Step 2: Preparation of 1-(4-(azacyclobutan-3-yl)-3-chlorophenyl)ethyl-1-one

[0334] 3-(4-acetyl-2-chlorophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (288 mg, 929.67 μmol) was added to a 1,4-dioxane solution of hydrogen chloride (4 M, 4 mL) and reacted at room temperature for 4 hours. The reaction solution was concentrated to give the title compound of this step (229 mg, yield: 92.3%).

[0335] MS m / z(ESI): 210.1 [M+H] + .

[0336] Step 3: Preparation of 1-(3-chloro-4-(1-(4-nitrophenyl)azacyclobutane-3-yl)phenyl)ethyl-1-one

[0337] 1-(4-(azacyclobutan-3-yl)-3-chlorophenyl)ethyl-1-one (228.8 mg, 929.58 μmol), p-fluoronitrobenzene (138.07 mg, 929.58 μmol), and potassium carbonate (385.42 mg, 2.79 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), and the mixture was reacted at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, and water (15 mL) was added to precipitate a solid. The solid was filtered, and the filter cake was dried to give the title compound of this step (150 mg, yield: 46.4%).

[0338] MS m / z(ESI): 331.1 [M+H] + .

[0339] Step 4: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)azacyclobutane-3-yl)phenyl)-2-oxoacetic acid

[0340] 1-(3-chloro-4-(1-(4-nitrophenyl)azacyclobutane-3-yl)phenyl)ethyl-1-one (108 mg, 326.52 μmol) and selenium dioxide (108.69 mg, 979.55 μmol) were added to pyridine (4 mL) and reacted at 100 °C for 2.5 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 1 with 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (110 mg, yield: 88.7%).

[0341] MS m / z(ESI): 361.0 [M+H] + .

[0342] Preparation Example 19: Preparation of 2-(3-chloro-4-(3-(3-nitrophenyl)azacyclobutan-1-yl)phenyl)-2-oxoacetic acid (Int19)

[0343] Step 1: Preparation of tert-butyl 3-(2-toluenesulfonylhydrazino)azacyclobutane-1-carboxylate

[0344] p-Toluenesulfonylhydrazide (1.09 g, 5.78 mmol) and tert-butyl 3-oxoazacyclobutane-1-carboxylate (1 g, 5.78 mmol) were added to 1,4-dioxane (30 mL), the mixture was purged with nitrogen, and the reaction was carried out at 80 °C for 4 hours. The reaction solution was used directly for the next step.

[0345] MS m / z(ESI): 284.1 [M+H-56] + .

[0346] Step 2: Preparation of tert-butyl 3-(3-nitrophenyl)azacyclobutane-1-carboxylate

[0347] 3-(2-Toluenesulfonylhydrazino)azacyclobutane-1-carboxylic acid tert-butyl ester (1.8 g, 4.77 mmol), 3-nitrophenylboronic acid (1.33 g, 7.16 mmol), and cesium carbonate (2.36 g, 7.16 mmol) were added to 1,4-dioxane (30 mL) and reacted overnight at 110 °C. The reaction system was cooled to room temperature, filtered, and the crude product obtained by concentration of the filtrate was purified by reverse-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 60%-65%) to obtain the title compound of this step (160 mg, yield: 10.8%).

[0348] MS m / z(ESI): 279.0 [M+H] + .

[0349] Step 3: Preparation of 3-(3-nitrophenyl)azacyclobutane

[0350] 160 mg of tert-butyl 3-(3-nitrophenyl)azacyclobutane-1-carboxylate (517.42 μmol) was added to a 4 M, 2 mL solution of hydrogen chloride in 1,4-dioxane and reacted at room temperature for 2 hours. The reaction solution was then concentrated to obtain the title compound of this step (100 mg, crude product).

[0351] MS m / z (ESI): 179.1 [M+H] + .

[0352] Step 4: Preparation of methyl 2-(3-chloro-4-(3-(3-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetate

[0353] Methyl (3-chloro-4-fluorophenyl)-oxoacetate (60.78 mg, 252.54 μmol), 3-(3-nitrophenyl)azacyclobutane (50 mg, 252.54 μmol), and N,N-diisopropylethylamine (65.81 mg, 505.09 μmol) were added to N,N-dimethylformamide (1.5 mL), and the reaction was carried out at 65 °C for 4 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 60%-70%) to give the title compound of this step (55 mg, yield: 52.3%).

[0354] MS m / z (ESI): 375.1 [M+H] + .

[0355] Step 5: Preparation of 2-(3-chloro-4-(3-(3-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid

[0356] Methyl 2-(3-chloro-4-(3-(3-nitrophenyl)azacyclobutan-1-yl)phenyl)-2-oxoacetate (55 mg, 132.08 μmol) was added to tetrahydrofuran (1 mL), cooled to 0 °C, and the pH was adjusted to 9-10 with 1 N lithium hydroxide aqueous solution. The reaction mixture was then reacted at 0 °C for 2 hours. The pH of the reaction solution was adjusted to 4 with 1 N hydrochloric acid, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (42 mg, yield: 79.3%).

[0357] MS m / z(ESI): 361.0 [M+H] + .

[0358] 1 H NMR (400MHz, DMSO-d6): δ8.30(s,1H),8.15(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.74-7.66 (m,3H),6.71(d,J=8.0Hz,1H),4.71(t,J=8.0Hz,2H),4.31(t,J=8.0Hz,2H),4.21-4.13(m,1H).

[0359] Preparation Example 20: Preparation of 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutan-1-yl)phenyl)-2-oxoacetic acid (Int20)

[0360] Step 1: Preparation of tert-butyl 3-(4-nitrophenoxy)azacyclobutane-1-carboxylate

[0361] 3-Iodozacyclobutane-1-carboxylic acid tert-butyl ester (500 mg, 2.89 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (192.45 mg, 4.81 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. Then p-fluoronitrobenzene (339.43 mg, 2.41 mmol) was added, and the reaction was carried out at room temperature for 4 h. The reaction solution was poured into water (30 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound of this step (700 mg, yield: 88.0%).

[0362] MS m / z(ESI): 239.2 [M+H-56] + .

[0363] Step 2: Preparation of 3-(4-nitrophenoxy)azacyclobutane

[0364] 3-(4-nitrophenoxy)azacyclobutane-1-carboxylic acid tert-butyl ester (455 mg, 1.55 mmol) was added to a 1,4-dioxane solution of hydrogen chloride (5 mL) and reacted at room temperature for 4 hours. The reaction solution was concentrated to give the title compound of this step (300 mg, yield: 94.9%).

[0365] MS m / z (ESI): 195.1 [M+H] + .

[0366] Step 3: Preparation of methyl 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutane-1-yl)phenyl)-2-oxoacetate

[0367] 3-(4-nitrophenoxy)azacyclobutane (150 mg, 650.34 μmol), methyl 2-(3-chloro-4-fluorophenyl)-2-oxoacetate (140.86 mg, 650.34 μmol), and potassium carbonate (269.64 mg, 1.95 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), and the mixture was reacted at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, and water (15 mL) was added to precipitate a solid. The solid was filtered, and the filter cake was dried to give the title compound of this step (254 mg, yield: 95.0%).

[0368] MS m / z(ESI): 391.1 [M+H] + .

[0369] Step 4: Preparation of 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid

[0370] Methyl 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutan-1-yl)phenyl)-2-oxoacetate (254 mg, 649.99 μmol) and lithium hydroxide monohydrate (136.38 mg, 3.25 mmol) were added to water (3 mL) and tetrahydrofuran (6 mL), and reacted at room temperature for 4 hours. The reaction solution was concentrated to remove tetrahydrofuran, the pH was adjusted to 1 with 1N hydrochloric acid, filtered, and the filter cake was dried to give the title compound of this step (130 mg, yield: 53.1%).

[0371] MS m / z(ESI): 377.0 [M+H] + .

[0372] Example 1: Preparation of 2-(4-(benzyloxy)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-1)

[0373] 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (30.0 mg, 94.92 μmol), 2-(4-(benzyloxy)phenyl)-2-oxoacetic acid (81.8 mg, 284.75 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (39.70 mg, 104.41 mol), and N,N-diisopropylethylamine (49.07 g, 379.66 μmol) were added to anhydrous N,N-dimethylformamide (1.5 mL), and the reaction was carried out under nitrogen protection at room temperature for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 40%-60%) to give the title compound (3.1 mg, yield: 6.1%).

[0374] MS m / z (ESI): 512.2 [M+H] + .

[0375] 1H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 9.61-9.33 (m, 1H), 8.00 (d, J = 8.0Hz, 2H), 7.72(d,J=8.0Hz,1H),7.55(s,1H),7.54-7.29(m,6H),7.19(d,J=8.0Hz,2H),5. 24(s,2H),5.11(dd,J=12.0Hz,4.0Hz,1H),4.56(d,J=8.0Hz,2H),4.51-4.25(m, 2H),2.96-2.87(m,1H),2.67-2.62(m,1H),2.37-2.33(m,1H),2.01-1.99(m,1H).

[0376] Example 2: Preparation of 2-(4-(benzyloxy)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-2)

[0377] Following the synthetic route of compound C-1, 2-(4-(benzyloxy)phenyl)-2-oxoacetic acid was replaced with 2-(4-benzyloxy-3-chlorophenyl)-2-oxoacetic acid to obtain the title compound (17.3 mg, yield: 31.6%).

[0378] MS m / z (ESI): 546.2 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 9.56-9.53 (m, 1H), 8.08 (d, J = 4.0Hz, 1H), 8 .02(dd,J=8.0Hz,4.0Hz,1H)7.72(d,J=8.0Hz,1H),7.56(s,1H),7.49-7.34(m,7H) ,5.36(s,2H),5.11(dd,J=12.0Hz,4.0Hz,1H),4.56(d,J=8.0Hz,2H),4.49-4.31(m ,2H),2.96-2.87(m,1H),2.62-2.58(m,1H),2.41-2.32(m,1H),2.03-1.97(m,1H).

[0380] Example 3: Preparation of 2-(3-chloro-4-(phenoxymethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-3)

[0381] Following the synthetic route of compound C-1, 2-(4-(benzyloxy)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(phenoxymethyl)phenyl)-2-oxoacetic acid to obtain the title compound (50.0 mg, yield: 45.8%).

[0382] MS m / z (ESI): 546.2 [M+H] + .

[0383] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.66-9.61(m,1H),8.08(d,J=4.0Hz,1H),8.01(dd,J=8.0Hz ,4.0Hz,1H),7.79(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.57(s,1H),7.49(d,J=8.0Hz,1H),7.35 -7.30(m,2H),7.06-6.96(m,3H),5.26(s,2H),5.11(dd,J=12.0Hz,4.0Hz,1H),4.57(d,J=8.0Hz,2 H),4.48-4.30(m,2H),2.96-2.91(m,1H),2.67-2.57(m,1H),2.41-2.31(m,1H),2.03-1.96(m,1H).

[0384] Example 4: Preparation of 2-(4-(4-(4-aminophenyl)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-10)

[0385] Step 1: Preparation of 2-(3-chloro-4-(4-(4-nitrophenyl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0386] Following the synthetic route of compound C-1, 2-(4-(benzyloxy)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(4-(4-nitrophenyl)piperidin-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (53.0 mg, yield: 37.2%).

[0387] MS m / z (ESI): 644.2 [M+H] + .

[0388] Step 2: Preparation of 2-(4-(4-(4-aminophenyl)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0389] 2-(3-chloro-4-(4-(4-nitrophenyl)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (55 mg, 0.085 mmol) was added to ethanol (6.0 mL), followed by the addition of tin dichloride dihydrate (192.69 mg, 0.85 mmol). The reaction mixture was reacted at 60 °C for 12 hours. The crude product obtained by concentration was purified by high-performance liquid chromatography to give the title compound of this step (5 mg, yield: 9%).

[0390] MS m / z (ESI): 614.2 [M+H] + .

[0391] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.54(t,J=8.0Hz,1H),8.00(d,J=2.0Hz,1H),7.96(dd,J=8.0Hz,2.0H z,1H),7.73(d,J=8.0Hz,1H),7.56(s,1H),7.48(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,2 H),6.58(d,J=8.0Hz,2H),5.12(dd,J=12.0Hz,4.0Hz,1H),4.56(d,J=8.0Hz,2H),4.40(dd,J=56.0Hz,16.0H z, 2H), 3.61 (d, J = 12.0Hz, 2H), 3.01-2.78 (m, 3H), 2.73-2.25 (m, 4H), 2.14-1.94 (m, 1H), 1.92-1.63 (m, 5H).

[0392] Example 5: Preparation of 2-(4-(4-(4-aminophenoxy)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-11)

[0393] Step 1: Preparation of 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0394] 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (105 mg, 338 μmol), 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetic acid (137 mg, 338 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (154 mg, 406 μmol), and N,N-diisopropylethylamine (131 mg, 1.02 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 45%-90%) to give the title compound of this step (120 mg, yield: 51.0%).

[0395] MS m / z (ESI): 660.2 [M+H] + .

[0396] Step 2: Preparation of 2-(4-(4-(4-aminophenoxy)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0397] 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (40.0 mg, 60.6 μmol) was added to ethanol (4.0 mL), followed by the addition of tin dichloride dihydrate (137 mg, 0.85 mmol). The reaction mixture was reacted at 60 °C for 10 hours. The crude product obtained by concentration was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-90%) to give the title compound of this step (6.0 mg, yield: 15.0%).

[0398] MS m / z (ESI): 630.2 [M+H] + .

[0399] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.55(t,J=6.0Hz,1H),8.00(d,J=2.0Hz,1H),7.95(dd,J=8.0Hz,2.0Hz,1H) ,7.72(d,J=8.0Hz,1H),7.55(s,1H),7.48(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),6.76-6.67(m,2H),6.55-6.47(m ,2H),5.12(dd,J=12.0,6.0Hz,1H),4.56(d,J=4.0Hz,2H),4.47(d,J=16.0Hz,1H),4.38-4.27(m,2H),3.40(m,4H), 3.07-3.02(m,2H),2.96-2.87(m,1H),2.66-2.58(m,1H),2.43-2.33(m,1H),2.08-1.95(m,3H),1.78-1.71(m,2H).

[0400] Example 6: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-13)

[0401] Step 1: Preparation of 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0402] 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (208 mg, 762 μmol), 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid (250 mg, 693 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (316 mg, 832 μmol), and N,N-diisopropylethylamine (269 mg, 2.08 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), and the reaction was carried out under nitrogen protection at room temperature for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 45%-90%) to give the title compound of this step (280 mg, yield: 62.3%).

[0403] MS m / z (ESI): 616.2 [M+H] +.

[0404] Step 2: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0405] 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (50.0 mg, 81.1 μmol) and tetrahydroxydiboron (21.8 mg, 244 μmol) were added to anhydrous N,N-dimethylformamide (1.5 mL), followed by 4,4'-bipyridine (0.63 mg, 4.06 μmol). The reaction mixture was reacted at room temperature for 5 minutes. The crude product obtained by concentration was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-90%) to give the title compound of this step (16.0 mg, yield: 32.0%).

[0406] MS m / z (ESI): 586.2 [M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.47(t,J=6.0Hz,1H),7.88(d,J=2.0Hz,1H),7.84(dd,J=8.0Hz,2.0Hz,1H),7.72( d,J=8.0Hz,1H),7.54(s,1H),7.47(d,J=8.0Hz,1H),7.09-7.01(m,2H),6.65(d,J=8.0Hz,1H),6.58-6.51(m,2H),5.11(dd ,J=14.0,6.0Hz,1H),5.00(s,2H),4.61(t,J=8.0Hz,2H),4.54(d,J=8.0Hz,2H),4.46(d,J=20.0Hz,1H),4.33(d,J=20.0H z,1H),4.12-4.10(m,2H),3.82-3.75(m,1H),2.97-2.85(m,1H),2.64-2.56(m,1H),2.41-2.34(m,1H),2.04-1.96(m,1H).

[0408] Example 7: Preparation of 2-(6-(3-(4-aminophenyl)azacyclobutane-1-yl)pyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-4)

[0409] Step 1: Preparation of N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetamide

[0410] 2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetic acid (50 mg, 122.22 μmol), 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (37.11 mg, 122.22 μmol), N,N-diisopropylethylamine (31.85 mg, 244.43 μmol), 1-hydroxybenzotriazole (18.33 mg, 134.44 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.37 mg, 183.32 μmol) were added to N,N-dimethylformamide (1 mL), and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 35%-40%) to obtain the title compound of this step (18 mg, yield: 22.8%).

[0411] MS m / z (ESI): 583.2 [M+H] + .

[0412] Step 2: Preparation of 2-(6-(3-(4-aminophenyl)azacyclobutane-1-yl)pyridin-3-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0413] N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetamide (16 mg, 24.72 μmol) and tin dichloride dihydrate (16.93 mg, 74.16 μmol) were added to anhydrous ethanol (1 mL) and reacted at 70 °C for 3 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 30%-35%) to give the title compound of this step (3 mg, yield: 19.3%).

[0414] MS m / z (ESI): 553.2 [M+H] + .

[0415] 1 H NMR (400MHz, DMSO-d6): δ11.00(br,1H),9.45(t,J=8.0Hz,1H),8.82(d,J=4.0Hz,1H),8.06(dd,J=8.0,4.0Hz,1H ),7.72(d,J=8.0Hz,1H),7.54(s,1H),7.47(d,J=8.0Hz,1H),7.04(d,J=8.0Hz,2H),6.55(d,J=8.0Hz,2H),6.48( d,J=8.0Hz,1H),5.14-5.09(m,1H),5.01(s,2H),4.54(d,J=4.0Hz,2H),4.49-4.44(m,3H),4.36-4.28(m,1H),4. 02-3.98(m,2H),3.89-3.81(m,1H),2.97-2.62(m,1H),2.62-2.57(m,1H),2.45-2.37(m,1H),2.01-1.99(m,1H).

[0416] Example 8: Preparation of 2-(3-chloro-4-(3-(4-(hydroxymethyl)phenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-6)

[0417] Step 1: Preparation of 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0418] 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-2-oxoacetic acid (35 mg, 53.92 μmol), 3-(5-(aminomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (14.89 mg, 53.92 μmol), N,N-diisopropylethylamine (14.05 mg, 107.84 μmol), 1-hydroxybenzotriazole (8.10 mg, 59.31 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.60 mg, 80.88 μmol) were added to N,N-dimethylformamide (1 mL), and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 90%-95%) to obtain the title compound of this step (23 mg, yield: 45.7%).

[0419] MS m / z (ESI): 839.3 [M+H] + .

[0420] Step 2: Preparation of 2-(3-chloro-4-(3-(4-(hydroxymethyl)phenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0421] Under ice-water bath cooling, 2-(4-(3-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (23 mg, 24.66 μmol) was added to pyridine hydrogen fluoride (1 mL) and tetrahydrofuran (3 mL), and the reaction was carried out at 0 °C for 2 hours. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 30%-45%) to give the title compound of this step (6.20 mg, yield: 39.7%).

[0422] MS m / z (ESI): 601.3 [M+H] + .

[0423] 1H NMR (400MHz, DMSO-d6): δ10.99(br,1H),9.48(t,J=8.0Hz,1H),7.89-7.84(m,2H),7.72(d,J=8 .0Hz,1H),7.54(s,1H),7.47(d,J=8.0Hz,1H),7.38-7.30(m,4H),6.68(d,J=8.0Hz,1H),5.18- 5.09(m,2H),4.54(d,J=8.0Hz,2H),4.49-4.44(m,3H),4.35-4.31(m,1H),4.24-4.20(m,2H),4 .00-3.93(m,1H),2.98-2.85(m,2H),2.62-2.58(m,2H),2.45-2.35(m,1H),2.02-1.99(m,1H).

[0424] Example 9: Preparation of 2-(4-(1-(4-aminophenyl)piperidin-4-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-8)

[0425] Step 1: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0426] 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (46.0 mg, 170 μmol), 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-2-oxoacetic acid (60.0 mg, 154 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (64 mg, 170 μmol), and N,N-diisopropylethylamine (60.0 mg, 463 μmol) were added to anhydrous N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The reaction solution was then purified directly by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 15%-70%) to give the title compound of this step (60.0 mg, yield: 57.4%).

[0427] MS m / z (ESI): 644.2 [M+H] + .

[0428] Step 2: Preparation of 2-(4-(1-(4-aminophenyl)piperidin-4-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0429] 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (30 mg, 46.58 μmol) and tin dichloride (264.96 mg, 1.40 mmol) were added to ethanol (4 mL) and tetrahydrofuran (1 mL), and reacted at 80 °C for 9 hours. The reaction solution was directly purified by high performance liquid chromatography to obtain the title compound of this step (10.07 mg, yield: 33.5%).

[0430] MS m / z (ESI): 614.3 [M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.63(t,J=4.0Hz,1H),8.05(d,J=4.0Hz,1H),8.01-7.97(m,1H), 7.73(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.57(s,1H),7.51-7.47(m,1H),7.15(s,2H),7.04(s,2H) ,5.12(dd,J=12.0,4.0Hz,1H),4.57(d,J=4.0Hz,2H),4.47(d,J=16.0Hz,1H),4.33(d,J=16.0Hz,1H),3 .79(s,2H),2.97-2.87(m,2H),2.60(d,J=16.0Hz,3H),2.40(dd,J=12.0,4.0Hz,1H),2.07-1.81(m,7H).

[0432] Example 10: Preparation of 2-(4-(1-(4-aminophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-9)

[0433] Step 1: Preparation of 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindole-5-yl)methyl)-2-oxoacetamide

[0434] 3-(5-(aminomethyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (62 mg, 227 μmol), 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxoacetic acid (80 mg, 207 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (94 mg, 248 μmol), and N,N-diisopropylethylamine (80 mg, 620 μmol) were added to anhydrous N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 15%-70%) to obtain the title compound of this step (59 mg, yield: 42.2%).

[0435] MS m / z (ESI): 642.2 [M+H] + .

[0436] Step 2: Preparation of 2-(4-(1-(4-aminophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0437] 2-(3-chloro-4-(1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisodihydroindol-5-yl)methyl)-2-oxoacetamide (20.0 mg, 31.2 μmol) was dissolved in ethanol (4.0 mL), and tin dichloride (177 mg, 935 μmol) was added. The reaction mixture was reacted at 80 °C for 9 hours. The crude product obtained by concentration of the reaction solution was purified by reverse-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-90%) to give the title compound of this step (3.43 mg, yield: 17.1%).

[0438] MS m / z (ESI): 612.2 [M+H] + .

[0439] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.64(t,J=8.0Hz,1H),9.50(s,2H),8.06(d,J=4.0Hz,1H),7.98(dd,J=8.0,4. 0Hz,1H),7.73(d,J=8.0Hz,1H),7.57(s,1H),7.54(d,J=8.0Hz,1H),7.51-7.47(m,1H),7.17(s,2H),7.07(d,J=8.0H z,2H),5.99(d,J=4.0Hz,1H),5.12(dd,J=12.0,4.0Hz,1H),4.58(d,J=8.0Hz,2H),4.47(d,J=16.0Hz,1H),4.35(s,1 H), 3.94-3.86 (m, 2H), 3.52 (s, 3H), 2.96-2.87 (m, 1H), 2.60 (d, J = 16.0Hz, 2H), 2.42-2.38 (m, 1H), 2.02-1.97 (m, 1H).

[0440] Example 11: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-14)

[0441] Step 1: Preparation of 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0442] 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride (30 mg, 91.5 μmol), 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid (30 mg, 83.2 μmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (34.8 mg, 170 μmol), and N,N-diisopropylethylamine (32.2 mg, 249 μmol) were added to anhydrous N,N-dimethylformamide (2 mL), and the mixture was reacted at room temperature for 2 hours under nitrogen protection. The reaction solution was directly purified by reversed-phase column chromatography (Preparation method B, elution gradient: mobile phase A% = 10%-70%) to obtain the title compound of this step (36.0 mg, yield: 64.9%).

[0443] MS m / z (ESI): 634.2 [M+H] + .

[0444] Step 2: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide

[0445] 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (34 mg, 53.63 μmol) and tin dichloride (305.06 mg, 1.61 mmol) were added to ethanol (4 mL) and tetrahydrofuran (1 mL), and reacted at 80 °C for 2 hours. The crude product obtained after concentration was purified by high performance liquid chromatography to obtain the title compound of this step (15 mg, yield: 44.0%).

[0446] MS m / z (ESI): 604.2 [M+H] + .

[0447] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.48(t,J=8.0Hz,1H),7.86(d,J=4.0Hz,1H),7.83(dd,J=8.0,4.0Hz ,1H),7.61(d,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.30-7.24(m,2H),6.94-6.84(m,2H),6.66(d,J=8.0Hz, 1H),5.13(dd,J=12.0,4.0Hz,1H),4.75-4.51(m,6H),4.41(d,J=16.0Hz,1H),4.17(dd,J=8.0,4.0Hz,2H),3 .93-3.85(m,1H),3.45(s,1H),2.97-2.87(m,1H),2.64-2.56(m,1H),2.46-2.38(m,1H),2.09-1.98(m,1H).

[0448] Example 12: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-15)

[0449] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(5-(aminomethyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride to obtain the title compound (8.51 mg).

[0450] MS m / z (ESI): 604.2 [M+H] + .

[0451] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.44(t,J=8.0Hz,1H),7.87(d,J=4.0Hz,1H),7.84(dd,J=8.0,4.0Hz,1H),7.61(d,J =8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,2H),6.65(d,J=8.0Hz,1H),6.55(d,J=8.0Hz,2H),5.12(dd,J=12.0,4 .0Hz,1H),5.01(s,2H),4.61(t,J=8.0Hz,2H),4.56(d,J=8.0Hz,2H),4.46(d,J=16.0Hz,1H),4.32(d,J=16.0Hz,1H),4.12 (dd,J=8.0,4.0Hz,2H),3.83-3.75(m,1H),2.95-2.86(m,1H),2.61(d,J=4.0Hz,1H),2.41-2.33(m,1H),2.04-1.98(m,1H).

[0452] Example 13: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((5-(2,6-dioxoperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrolo-1-yl)methyl)-2-oxoacetamide (C-16)

[0453] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrole-5(6H)-yl)piperidine-2,6-dione hydrochloride to obtain the title compound of this step (3.25 mg).

[0454] MS m / z(ESI): 592.1 [M+H] + .

[0455] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.51(d,J=8.0Hz,1H),7.93(s,2H),7.86-7.79(m,1H),7.05( d,J=8.0Hz,2H),6.64(d,J=8.0Hz,1H),6.55(d,J=8.0Hz,2H),5.03(dd,J=12.0,4.0Hz,2H),4.62(d, J=8.0Hz,2H),4.56(d,J=8.0Hz,2H),4.34(d,J=16.0Hz,1H),4.22(d,J=16.0Hz,1H),4.16-4.09(m, 1H),3.85-3.73(m,1H),3.05-2.78(m,1H),2.37-2.23(m,2H),2.10-1.94(m,2H),1.29-1.13(m,1H).

[0456] Example 14: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((5-(2,6-dioxoperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)methyl)-2-oxoacetamide (C-17)

[0457] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(2-(aminomethyl)-4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione hydrochloride to obtain the title compound of this step (6.64 mg).

[0458] MS m / z(ESI): 592.2 [M+H] + .

[0459] 1H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 9.54 (d, J = 8.0Hz, 1H), 7.93-7.85 (m, 1H), 7.85 (s, 1H), 7.12 (s,1H),7.05(d,J=8.0Hz,2H),6.65(d,J=8.0Hz,1H),6.55(d,J=8.0Hz,2H),5.17-4.85(m,3H),4. 62(d,J=8.0Hz,4H),4.49(d,J=16.0Hz,1H),4.36(d,J=16.0Hz,1H),4.20-4.07(m,2H),3.85-3.73 (m,1H),2.88(dd,J=12.0,4.0Hz,1H),2.40-2.26(m,1H),2.05-1.90(m,1H),1.23(d,J=4.0Hz,1H).

[0460] Example 15: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((5-(2,6-dioxoperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-2-yl)methyl)-2-oxoacetamide (C-18)

[0461] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(2-(aminomethyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione hydrochloride to obtain the title compound of this step (4.6 mg).

[0462] MS m / z(ESI): 592.1 [M+H] + .

[0463] 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.59(d,J=8.0Hz,1H),7.87(d,J=4.0Hz,1H),7.83(dd,J=8.0 ,4.0Hz,1H),7.18(s,1H),7.05(d,J=8.0Hz,2H),6.66(d,J=8.0Hz,1H),6.56(s,2H),5.00(dd,J=12. 0,4.0Hz,3H),4.70-4.57(m,4H),4.36(d,J=16.0Hz,1H),4.23(d,J=16.0Hz,1H),4.17-4.09(m,2H), 3.85-3.73(m,1H),2.94-2.83(m,1H),2.60(s,1H),2.38(dd,J=12.0,4.0Hz,1H),2.03-1.95(m,1H).

[0464] Example 16: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((5-(2,6-dioxoperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrolo-3-yl)methyl)-2-oxoacetamide (C-19)

[0465] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(3-(aminomethyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrole-5-yl)piperidine-2,6-dione hydrochloride to obtain the title compound of this step (3.58 mg).

[0466] MS m / z(ESI): 592.2 [M+H] + .

[0467] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.35(t,J=8.0Hz,1H),7.88(d,J=4.0Hz,1H),7.83(d,J=8.0H z,2H),7.11-7.01(m,2H),6.64(d,J=8.0Hz,1H),6.59-6.51(m,2H),5.08-4.94(m,3H),4.61(t,J=8. 0Hz,2H),4.45(d,J=8.0Hz,2H),4.39(d,J=16.0Hz,1H),4.27(d,J=16.0Hz,1H),4.16-4.08(m,2H), 3.83-3.75(m,1H),2.94-2.85(m,1H),2.59(d,J=16.0Hz,1H),2.31-2.23(m,1H),2.05-1.98(m,1H).

[0468] Example 17: Preparation of 2-(4-(4-(4-aminophenoxy)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-24)

[0469] Following the synthetic route of compound C-14, 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(4-(4-nitrophenoxy)piperidin-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (6.60 mg).

[0470] MS m / z (ESI): 648.2 [M+H] + .

[0471] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.55(t,J=8.0Hz,1H),7.98(d,J=2.0Hz,1H),7.93(dd,J=8.0,4.0Hz,1H), 7.61(d,J=8.0Hz,1H),7.59-7.53(m,1H),7.29(d,J=8.0Hz,1H),6.75-6.69(m,2H),6.53-6.48(m,2H),5.13(dd, J=12.0,4.0Hz,1H),4.74-4.55(m,5H),4.41(d,J=16.0Hz,1H),4.34-4.28(m,1H),3.42-3.37(m,2H),3.05(t,J= 8.0Hz,2H),2.96-2.87(m,1H),2.60(d,J=16.0Hz,1H),2.46-2.39(m,1H),2.02-1.98(m,3H),1.78-1.72(m,2H).

[0472] Example 18: Preparation of 2-(4-(3-(4-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((5-(2,6-dioxoperidin-3-yl)-4-oxo-5,6-dihydro-4H-furano[2,3-c]pyrrolo-2-yl)methyl)-2-oxoacetamide (C-20)

[0473] Following the synthetic route of compound C-14, 3-(5-(aminomethyl)-4-fluoro-1-oxoisoindoline-2-yl)piperidine-2,6-dione hydrochloride was replaced with 3-(2-(aminomethyl)-4-oxo-4,6-dihydro-5H-furano[2,3-c]pyrrole-5-yl)piperidine-2,6-dione hydrochloride to obtain the title compound of this step (1.80 mg).

[0474] MS m / z (ESI): 576.2 [M+H] + .

[0475] 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.39(t,J=4.0Hz,1H),7.84(d,J=4.0Hz,1H),7.81(dd,J=8.0,4.0H z,1H),7.13-7.01(m,2H),6.66(d,J=8.0Hz,1H),6.62(s,1H),6.58-6.52(m,2H),5.05-4.96(m,3H),4.61 (t,J=8.0Hz,2H),4.51(d,J=4.0Hz,2H),4.44(d,J=16.0Hz,1H),4.28(d,J=16.0Hz,1H),4.12(dd,J=8.0, 4.0Hz,2H),3.80(d,J=8.0Hz,1H),2.93-2.84(m,1H),2.59(s,1H),2.30-2.24(m,1H),1.97-1.94(m,1H).

[0476] Example 19: Preparation of 2-(4-(1-(4-aminophenyl)azacyclobutane-3-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-12)

[0477] Following the synthetic route of compound C-8, 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(1-(4-nitrophenyl)azacyclobutane-3-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (6.60 mg).

[0478] MS m / z (ESI): 586.2 [M+H] + .

[0479] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.62(t,J=4.0Hz,1H),8.04(d,J=4.0Hz,1H),8.00(d,J=12.0Hz,1H),7.79 (d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.57(s,1H),7.49(d,J=8.0Hz,1H),6.49(d,J=8.0Hz,2H),6.31(d,J=8.0 Hz,2H),5.12(dd,J=12.0,8.0Hz,1H),4.57(d,J=8.0Hz,2H),4.47(d,J=20.0Hz,1H),4.33(d,J=20.0Hz,1H),4.23 -4.11(m,3H),3.67(t,J=4.0Hz,2H),3.13-2.80(m,1H),2.72-2.55(m,2H),2.44-2.28(m,2H),2.09-1.93(m,1H).

[0480] Example 20: Preparation of 2-(4-(3-(3-aminophenyl)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-25)

[0481] Following the synthetic route of compound C-4, 2-(6-(3-(4-nitrophenyl)azacyclobutane-1-yl)pyridin-3-yl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(3-(3-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (7 mg).

[0482] MS m / z (ESI): 586.3 [M+H] + .

[0483] 1H NMR (400MHz, DMSO-d6): δ11.00(br,1H),9.47(t,J=8.0Hz,1H),7.89(d,J=4.0Hz,1H),7.86-7.83(m,1H),7.72(d,J=8.0Hz ,1H),7.54(s,1H),7.47(d,J=8.0Hz,1H),7.98(t,J=8.0Hz,1H),6.67(d,J=8.0Hz,1H),6.62(s,1H),6.50(d,J=8.0Hz,1H) ,6.45(d,J=8.0Hz,1H),5.12-5.09(m,3H),4.64(t,J=8.0Hz,2H),4.54(d,J=4.0Hz,2H),4.49-4.44(m,1H),4.35-4.30(m, 1H), 4.17 (t, J = 8.0Hz, 2H), 3.83-3.75 (m, 1H), 2.98-2.85 (m, 1H), 2.65-2.58 (m, 1H), 2.45-2.35 (m, 1H), 2.01-1.98 (m, 1H).

[0484] Example 21: Preparation of 2-(4-(3-(4-aminophenoxy)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-26)

[0485] Following the synthetic route of compound C-8, 2-(3-chloro-4-(1-(4-nitrophenyl)piperidin-4-yl)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (1.96 mg).

[0486] MS m / z (ESI): 602.2 [M+H] + .

[0487] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.47(t,J=8.0Hz,1H),7.88(d,J=4.0Hz,1H),7.83(dd,J=12.0,8.0Hz,1H),7.72(d,J=8.0 Hz,1H),7.54(s,1H),7.46(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),6.64-6.58(m,2H),6.57-6.51(m,2H),5.11(dd,J=12.0,8.0Hz ,1H),4.98-4.93(m,1H),4.86(s,2H),4.66(dd,J=8.0,4.0Hz,2H),4.53(d,J=8.0Hz,2H),4.46(d,J=16.0Hz,1H),4.32(d,J=16.0 Hz,1H),4.14(dd,J=8.0,4.0Hz,2H),3.04-2.83(m,1H),2.60(d,J=16.0Hz,1H),2.39(dd,J=12.0,8.0Hz,1H),2.06-1.93(m,1H).

[0488] Example 22: Preparation of 2-(4-(3-(4-aminophenoxy)azacyclobutane-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-29)

[0489] Following the synthetic route of compound C-14, 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(3-(4-nitrophenoxy)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (1.96 mg).

[0490] MS m / z (ESI): 620.2 [M+H] + .

[0491] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.47(t,J=4.0Hz,1H),7.86(d,J=4.0Hz,1H),7.81(d,J=8.0Hz,1H),7.6 1(d,J=8.0Hz,1H),7.57-7.50(m,1H),6.66(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,2H),6.52(d,J=8.0Hz,2H),5.7 6(s,2H),5.12(dd,J=16.0,12.0Hz,1H),4.95(s,1H),4.71-4.62(m,2H),4.62-4.53(m,3H),4.40(d,J=20.0Hz ,1H),4.21-4.07(m,2H),3.09-2.81(m,1H),2.60(d,J=16.0Hz,1H),2.42(d,J=12.0Hz,1H),2.12-1.91(m,1H).

[0492] Example 23: Preparation of 2-(4-(4-(4-aminophenyl)piperidin-1-yl)-3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindoline-5-yl)methyl)-2-oxoacetamide (C-30)

[0493] Following the synthetic route of compound C-14, 2-(3-chloro-4-(3-(4-nitrophenyl)azacyclobutane-1-yl)phenyl)-2-oxoacetic acid was replaced with 2-(3-chloro-4-(4-(4-nitrophenyl)piperidin-1-yl)phenyl)-2-oxoacetic acid to obtain the title compound of this step (1.96 mg).

[0494] MS m / z(ESI): 632.2 [M+H] + .

[0495] 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),9.55(t,J=4.0Hz,1H),7.98(d,J=4.0Hz,1H),7.93(dd,J=8.0,4.0Hz,1H),7.6 2(d,J=8.0Hz,1H),7.59-7.48(m,1H),7.29(d,J=8.0Hz,1H),6.93(d,J=8.0Hz,2H),6.51(d,J=8.0Hz,2H),5.13(dd, J=12.0,8.0Hz,1H),4.87(s,2H),4.59(dd,J=8.0,4.0Hz,3H),4.41(d,J=16.0Hz,1H),3.61(d,J=12.0Hz,2H),2.93- 2.84(m,3H),2.60(d,J=16.0Hz,2H),2.47-2.37(m,1H),2.06-1.96(m,1H),1.83(d,J=8.0Hz,2H),1.79-1.59(m,2H).

[0496] Biological tests

[0497] Experimental Example 1: Inhibition of the Proliferative Activity of Compounds on BT474 Breast Cancer Cells

[0498] 1. Experimental System:

[0499] Cell Name / Source: BT474 / ATCC

[0500] Reagent Kit Name / Manufacturer: CellCounting-Lite 2.0 Luminescent Cell Viability Assay, Nanjing Novizan Biotechnology Co., Ltd.

[0501] 2. Experimental parameters:

[0502] Cell count: 3000 cells / well; Culture medium: DMEM + 10% FBS; DMSO content: 0.25%; Compound incubation conditions: 37℃, 5% CO2; Incubation time: 120 hours; Detection temperature: room temperature; Detection instrument: TECAN SPARK microplate reader.

[0503] 3. Experimental steps:

[0504] BT474 cells were cultured in vitro as a monolayer in 10% FBS + DMEM medium at 37°C in an incubator containing 5% CO2. Cells were seeded into 96-well plates at 3000 cells / well and cultured overnight. After incubation, pre-diluted test compounds were added; DMSO was added to the negative control group, and culture medium was added to the blank control group. After 120 hours of incubation, the Cell assay reagent was added to each well. Read the chemiluminescence unit value (RLU) in the chemiluminescence detection mode of the microplate reader.

[0505] 4. Data Processing:

[0506] Calculate the percentage inhibition rate of different concentrations of compounds using the following formula:

[0507] Percentage inhibition rate = (1 - (chemiluminescence signal value of test compound - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) × 100%. The half-maximal inhibitory concentration (IC50) of the compound is calculated by fitting a curve using a four-parameter model. 50 ).

[0508] 5. Experimental Results:

[0509] The inhibitory activity of the compound on the proliferation of BT474 cells was determined according to the above method, and the results are shown in Table 1.

[0510] Table 1. Results of the inhibitory effect of the compounds on the proliferation activity of BT474 cells

[0511] in conclusion:

[0512] The compounds of the present invention have strong inhibitory activity against BT474 cell proliferation. For example, other compounds not listed also have inhibitory activity against BT474 cell proliferation with IC50 values ​​ranging from 1 to 150 nM.

[0513] Experiment Example 2: Inhibition of the proliferation activity of the compound on small cell lung cancer cells NCI-H146

[0514] 1. Experimental System:

[0515] Cell Name / Source: NCI-H146 / ATCC

[0516] Reagent Kit Name / Manufacturer: CellCounting-Lite 2.0 Luminescent Cell Viability Assay, Nanjing Novizan Biotechnology Co., Ltd.

[0517] 2. Experimental parameters:

[0518] Cell count: 10,000 cells / well; Culture medium: RPMI 1640 + 10% FBS; DMSO content: 0.25%; Compound incubation conditions: 37℃, 5% CO2; Incubation time: 72 hours; Detection temperature: room temperature; Detection instrument: TECAN SPARK microplate reader.

[0519] 3. Experimental steps:

[0520] NCI-H146 cells were cultured in suspension in vitro under the following conditions: RPMI 1640 + 10% FBS, 37°C, and an incubator containing 5% CO2. Cells were seeded into 96-well plates at 10,000 cells / well. Pre-diluted test compounds were then added. DMSO was added to the negative control group, and culture medium was added to the blank control group. After incubation for 72 hours, the test reagent was added to each well. 2.0, read the chemiluminescence unit value (RLU) in the chemiluminescence detection mode of the microplate reader.

[0521] 4. Data Processing:

[0522] Calculate the percentage inhibition rate of different concentrations of compounds using the following formula:

[0523] Percentage inhibition rate = (1 - (chemiluminescence signal value of test compound - chemiluminescence signal value of blank control) / (chemiluminescence signal value of negative control - chemiluminescence signal value of blank control)) × 100%. The half-maximal inhibitory concentration (IC50) of the compound is calculated by fitting a curve using a four-parameter model. 50 ).

[0524] 5. Experimental Results:

[0525] The inhibitory activity of the compound on the proliferation of NCI-H146 cells was determined according to the above method, and the results are shown in Table 2.

[0526] Table 2. Results of the inhibitory effect of the compounds on the proliferation activity of NCI-H146 cells.

[0527] in conclusion:

[0528] The compounds of the present invention have strong inhibitory activity against NCI-H146 cells. For example, other compounds not listed also have inhibitory activity against NCI-H146 cell proliferation with IC50 values ​​ranging from 1 to 50 nM.

[0529] Experimental Example 3: Protein Degradation Test of Compounds in BT474 Breast Cancer Cells

[0530] 1. Experimental System:

[0531] Cell Name / Source: BT474 / ATCC

[0532] 2. Experimental parameters

[0533] Cell count: 6*10 5 Cells / well, culture medium: DMEM + 10% FBS, DMSO content: 0.1%, compound incubation conditions: 37℃, 5% CO2, incubation time: 24 hours, detection temperature: room temperature, testing instrument: ultra-high sensitivity chemiluminescence imaging system - manufacturer Bio-rad.

[0534] 3. Experimental steps:

[0535] BT474 cells were cultured in vitro as a monolayer in 10% FBS + DMEM medium at 37°C in an incubator containing 5% CO2. Cells were seeded into 6-well plates one day in advance, at a density of 6 x 10⁶ cells / well. 5 Cells / well; the next day, add pre-diluted test compound, and add culture medium to the blank control group, incubate for 24 hours. Collect cells, add lysis buffer (Cell Signaling Technology 9803), lyse on ice for 25-30 minutes, centrifuge for 10 minutes, and collect the supernatant protein sample. Use Pierce... TM Protein quantification was performed using the BCA Protein Assay Kit (Thermo Scientific 23225). Protein concentration was normalized, and 1X loading buffer was added. The mixture was then denatured at 95°C for 10 minutes.

[0536] Take an appropriate amount of protein sample and perform SDS-PAGE gel electrophoresis. Electrophoresis for 30-50 minutes. After the protein sample is pressed into a line, continue electrophoresis until the loading buffer reaches the bottom of the separating gel, then stop electrophoresis.

[0537] After electrophoresis, proteins were transferred to a PVDF membrane using a wet transfer method, with transfer time of 45–90 minutes. The transferred PVDF membrane was then placed in blocking buffer and blocked for 1–2 hours. Bands were then cut from the PVDF membrane according to the molecular weight of the target proteins (GSPT-1, IKZF3, CK1α, and internal reference proteins), and incubated with the corresponding primary antibody overnight at 4°C with shaking. The membrane was washed three times with TBS containing 0.1% Tween 20. The membrane was then incubated with secondary antibody solution (horseradish peroxidase-labeled goat anti-rabbit or goat anti-mouse IgG, diluted 1:1000–5000 in 0.1% Tween 20 TBS) at room temperature for 1 hour. After washing the membrane three times as described above, it was developed with Western Chemiluminescent HRP Substrate (Millipore\WBKL S0500), and photographed using an ultra-high sensitivity chemiluminescence imaging system. Grayscale values ​​were then obtained for the GSPT1 band, IKZF3 band, CK1α band, and internal reference band.

[0538] 4. Data Processing:

[0539] Protein degradation rate (D) = (1-G) 目的蛋白 / G0)×100%; where G 目的蛋白 The gray density (target protein band) / gray density (internal control band) of the target protein degradation were observed for different concentrations of compound treatment groups. G0 = gray density (target protein band) / gray density (corresponding internal control band) of blank control group.

[0540] 5. The experimental results are shown in Tables 3-1, 3-2 and 3-3.

[0541] Table 3-1. Degradation activity of the compounds on GSPT1 protein in BT474 cells.

[0542] Table 3-2. IKZF3 protein degradation activity of the compounds in BT474 cells.

[0543] Table 3-3. Degradation activity of the compounds on CK1α protein in BT474 cells.

[0544] Among them, "++++" indicates a degradation effect between 100% and 80%; "++++" indicates a degradation effect between 80% and 60%; "+++" indicates a degradation effect between 60% and 30%; "++" indicates a degradation effect between 30% and 10%; and "+" indicates a degradation effect <10%.

[0545] The compounds of this application, such as compound 2, exhibit good degradation effects on GSPT1 protein and good selectivity.

[0546] Experimental Example 4: Protein Degradation Test of Compounds in Small Cell Lung Cancer Cells NCI-H146

[0547] 1. Experimental System:

[0548] Cell Name / Source: NCI-H146 / ATCC

[0549] 2. Experimental parameters

[0550] Cell count: 1.2*10 6 Cells / well, culture medium: 1640 + 10% FBS, DMSO content: 0.1%, compound incubation conditions: 37℃, 5% CO2, incubation time: 20 hours, detection temperature: room temperature, testing instrument: ultra-high sensitivity chemiluminescence imaging system - manufacturer Bio-rad.

[0551] 3. Experimental steps:

[0552] NCI-H146 cells were cultured in suspension in vitro under 10% FBS + 1640 medium at 37°C in an incubator containing 5% CO2. Cells were seeded into 6-well plates on the same day at a density of 1.2 x 10⁻⁶ cells / well. 6 Cells / well; then add pre-diluted test compound, blank control group with culture medium, incubate for 20 hours. Collect cells, add lysis buffer (Cell Signaling Technology 9803), lyse on ice for 25-30 minutes, centrifuge for 10 minutes, collect supernatant protein sample. Use Pierce... TM Protein quantification was performed using the BCA Protein Assay Kit (Thermo Scientific 23225). Protein concentration was normalized, and 1X loading buffer was added. The mixture was then denatured at 95°C for 10 minutes.

[0553] Take an appropriate amount of protein sample and perform SDS-PAGE gel electrophoresis. Electrophoresis for 30-50 minutes. After the protein sample is pressed into a line, continue electrophoresis until the loading buffer reaches the bottom of the separating gel, then stop electrophoresis.

[0554] After electrophoresis, proteins were transferred to a PVDF membrane using a wet transfer method, with transfer time of 45–90 minutes. The transferred PVDF membrane was then placed in blocking buffer and blocked for 1–2 hours. Bands were then cut from the PVDF membrane according to the molecular weight of the target proteins (GSPT-1 and internal control proteins), and incubated with the corresponding primary antibodies overnight at 4°C with shaking. The membrane was washed three times with TBS containing 0.1% Tween 20. The membrane was then incubated with secondary antibody solution (horseradish peroxidase-labeled goat anti-rabbit or goat anti-mouse IgG, diluted 1:1000–5000 in 0.1% Tween 20 TBS) at room temperature for 1 hour. After washing three times as described above, the membrane was developed using Western chemiluminescent HRP Substrate (Millipore / WBKL S0500), and photographed using an ultra-high sensitivity chemiluminescence imaging system. Grayscale values ​​of the GSPT1 and internal control bands were obtained after grayscale processing.

[0555] 4. Data Processing:

[0556] Protein degradation rate (D) = (1-G) 目的蛋白 / G0)×100%; where G 目的蛋白 The gray density (target protein band) / gray density (internal control band) of the target protein degradation were observed for different concentrations of compound treatment groups. G0 = gray density (target protein band) / gray density (corresponding internal control band) of blank control group.

[0557] 5. The experimental results are shown in Table 4-1.

[0558] Table 4-1. Degradation activity of the compounds on GSPT1 protein in NCI-H146 cells.

[0559] Among them, "++++" indicates a degradation effect between 100% and 80%; "++++" indicates a degradation effect between 80% and 60%; "+++" indicates a degradation effect between 60% and 30%; "++" indicates a degradation effect between 30% and 10%; and "+" indicates a degradation effect <10%.

[0560] The compounds in this application, such as compound 13, have a good degradation effect on GSPT1 protein.

[0561] The above embodiments do not limit the scope of the invention in any way. In addition to those described herein, various modifications of 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, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein said compound has a structure as shown in formula (I): in, X 1 Selected from CH2 and -C(=O)-; Ring A is selected from phenyl and 5-6-membered heteroaryl groups; Y is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 4 replace; Z is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 3 replace; R 1 Selected from H and C 1-6 alkyl; R 2 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OC 1-6 alkyl; R 3 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1- 6-alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -OC 1-6 Alkylene-N(R) a )R b -C(=O)-N(R) a )-C 1-6 Alkylene-OR a -C(=O)-N(R) a )-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 6 replace; R 4 Each is independently selected from H, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -N(R) a )-C 1-6 Alkylene-OR a -N(R) a )-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -OC 1- 6-alkylene-N(R) a )R b -C 1-6 Alkylene-OR a -C 1-6 Alkylene-N(R) a )R b C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 5 replace; R 5 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ; R 6 Each is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-6 Alkylene-OR a -N(R) a )-C(=O)-C 1-6 Alkylene-N(R) a )R b -OR a -OC 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-OR a -C(=O)-C 1-6 Alkylene-N(R) a )R b -C 1-6 Alkylene-OR a and -C 1-6 Alkylene-N(R) a )R b ; L is selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C 1-6 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-10 Cycloalkyl groups, 3-12 membered heterocyclic groups, and divalent structures composed of one or more of the above structural units; R a Each is independently selected from H and C. 1-6 alkyl; R b Each is independently selected from H and C. 1-6 alkyl; m is selected from 1, 2, and 3; p is independently selected from 0, 1, 2, 3, 4, 5, and 6; q is selected independently from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

2. The compound of claim 1, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or their metabolites, prodrugs, or pharmaceutically acceptable salts or esters, wherein the compound has a structure of formula (II-A), (II-B), (II-C), or (II-D): in, X 2 X 3 X 4 Each is independently selected from O, S, and Se; Y, Z, L, and R. 1 R 2 and m as defined in claim 1.

3. The compound of claim 1 or 2, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or their metabolites, prodrugs, or pharmaceutically acceptable salts or esters, wherein the compound has a structure of formula (III-A), (III-B), (III-C), (III-D), (III-E), or (III-F): in, X 2 X 3 X 4 Each is independently selected from O, S, and Se; Y, Z, L, and R. 1 R 2 And m as defined in claim 1 or 2.

4. The compound according to any one of claims 1-3, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or their metabolites, prodrugs, or pharmaceutically acceptable salts or esters, Y is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 4 replace; Z is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 3 replace; R 2 Selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and -OC 1-4 alkyl; R 3 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -N(R) a )-C 1- 4-alkylene-OR a -N(R) a )-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -OC 1-4 Alkylene-N(R) a )R b -C(=O)-N(R) a )-C 1-4 Alkylene-OR a -C(=O)-N(R) a )-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a -C 1-4 Alkylene-N(R) a )R b C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 6 replace; R 4 Each is independently selected from H, halogen, cyano, nitro, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -N(R) a )-C 1-4 Alkylene-OR a -N(R) a )-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -OC 1- 4-alkylene-N(R) a )R b -C 1-4 Alkylene-OR a -C 1-4 Alkylene-N(R) a )R b C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 5 replace; R 5 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a and -C 1-4 Alkylene-N(R) a )R b ; R 6 Each is independently selected from H, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, -N(R) a )R b -N(R) a )-C(=O)-C 1-4 Alkylene-OR a -N(R) a )-C(=O)-C 1-4 Alkylene-N(R) a )R b -OR a -OC 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-OR a -C(=O)-C 1-4 Alkylene-N(R) a )R b -C 1-4 Alkylene-OR a and -C 1-4 Alkylene-N(R) a )R b ; L is selected from C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C 1-4 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q -、C 3-8 Cycloalkyl groups, 3-10 membered heterocyclic groups, and divalent structures composed of one or more of the above structural units; R a Each is independently selected from H and C. 1-4 alkyl; R b Each is independently selected from H and C. 1-4 alkyl; m is selected from 1, 2, and 3; p is independently selected from 0, 1, 2, 3, 4, 5, and 6; q is selected independently from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

5. The compound of any one of claims 1-4, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound has a structure of formula (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (IV-I), (IV-J), or (IV-K): in, R 2 Y, Z and L are as defined in any one of claims 1-4.

6. The compound of any one of claims 1-5, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein: Y is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 4 replace; Preferably, Y is selected from phenyl and pyridyl, said phenyl and pyridyl groups optionally being converted by one or more R groups. 4 replace.

7. The compound of any one of claims 1-6, or its stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or their metabolites, prodrugs, or pharmaceutically acceptable salts or esters, wherein: R 4 Each is independently selected from H, halogen, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl, -OC 1-4 alkylene -OH, -C 1-4 alkylene-OH, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 5 replace; R 5 Each is independently selected from H, halogen, hydroxyl, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkylene -OH, -C(=O)-C 1-4 alkylene -OH, -C 1-6 Alkylene -OH and -OC 1-6 alkyl; Preferably, R 4 Each is independently selected from H and halogens (e.g., chlorine).

8. The compound of any one of claims 1-7, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein: Z is selected from C 6-10 Aryl and 5-10 heteroaryl groups, wherein the aryl and heteroaryl groups are optionally separated by one or more R groups. 3 replace; Preferably, Z is selected from phenyl and pyridinyl, said phenyl and pyridinyl groups optionally being converted by one or more R groups. 3 replace; Preferably, Z is selected from phenyl, which is optionally mixed with one or more R 3 replace.

9. The compound of any one of claims 1-8, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein: R 3 Each is independently selected from H, halogen, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, hydroxyl, -OC 1-4 alkylene -OH, -C 1-4 alkylene -OH, -C 1-4 Alkylene-NH-C 1-4 Alkyl, C 3-8 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are optionally surrounded by one or more R groups. 6 replace; R 6 Each is independently selected from H, halogen, hydroxyl, amino, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene -OH, -C(=O)-C 1-4 Alkylene-NH-C 1-4 Alkyl, -C 1-4 alkylene -OH, -C 1-4 Alkylene-NH-C 1-4 Alkyl and -OC 1-4 alkyl; Preferably, R 3 Selected from H, amino, and -CH2-OH.

10. The compound of any one of claims 1-9, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein: L is selected from C 1-4 Alkylene, -C 1-4 Haloalkylene -, -O-(CH2) p -、-N(R a )-(CH2) p -、-(CH2-CH2-O) q - 3-12 member heterocyclic groups (e.g., 3-10 member heterocyclic groups) and divalent structures composed of one or more of the above structural units; Preferably, L is selected from C 1-4 Alkylene, -O-(CH2) p - 3-12 member heterocyclic groups (e.g., 3-10 member heterocyclic groups) and divalent structures composed of one or more of the above structural units; More preferably, L is selected from -O-(CH2). p -、 Where n1, n2, n3, and n4 are each independently 1, 2, or 3. Indicates a single bond or a double bond; More preferably, L is selected from Position 1 is connected to Y, and position 2 is connected to Z.

11. The compound of any one of claims 1-10, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein: Selected from 12. The compound of any one of claims 1-11, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

14. The use of any one of the compounds of claims 1-12, or stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, or metabolites or prodrugs or pharmaceutically acceptable salts or esters thereof, or the pharmaceutical composition of claim 13, in the preparation of a medicament for the prevention and / or treatment of diseases, particularly those related to GSPT1 protein dysregulation; Preferably, the disease is a tumor or cancer; More preferably, the disease is non-Hodgkin's lymphoma, leukemia, and / or solid tumor; for example, the non-Hodgkin's lymphoma includes one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and T-cell lymphoma; the leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia; and the solid tumor includes one or more of lung cancer (e.g., small cell lung cancer), liver cancer, breast cancer, and glioma.

15. A method for preventing and / or treating diseases, particularly those related to GSPT1 protein dysregulation, comprising administering to a subject in need of the compound of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of claim 13. Preferably, the disease is a tumor or cancer; More preferably, the disease is non-Hodgkin's lymphoma, leukemia, and / or solid tumor; for example, the non-Hodgkin's lymphoma includes one or more of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and T-cell lymphoma; the leukemia includes one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia; and the solid tumor includes one or more of lung cancer (e.g., small cell lung cancer), liver cancer, breast cancer, and glioma.

16. A method for degrading GSPT1 protein in cells, comprising contacting the cells with a compound of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of claim 13.

17. A method for preparing a compound of formula (I), comprising one or more of the following steps: in, X 1 Y, Z, L, R 1 R 2 Ring A and m are as defined in any one of claims 1-12; Step A: Compound I-1 undergoes an oxidation reaction to give compound I-2; Step B: Compound I-2 and compound I-3 undergo a condensation reaction to obtain compound I.

18. The following compounds, or their salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, and isotope-labeled compounds, in, X 1 Y, Z, L, R 1 R 2 Ring A and m are as defined in any one of claims 1-12; Q is a halogen, such as fluorine; PG 1 The protecting group is a hydrogen or carboxyl group, and the carboxyl protecting group is, for example, C. 1-6 Alkyl, allyl, benzyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, methoxyethoxymethyl, pentafluorophenyl, 4-p-methylbenzyloxybenzyl; PG 2 The protecting group is a hydrogen or amino group, such as an alkoxycarbonyl amino group, for example, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl (or ethoxycarbonyl); or an acyl amino group, for example, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), oro(p) Nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; alkyl amino protecting groups, such as triphenylmethyl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn); PG 3 The protecting group is a hydrogen or hydroxyl group, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl or p-nitrobenzoyl.

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