Degrading agents, compositions, and applications of Bruton's tyrosine kinase and its mutants.

Abstract

This invention discloses a degrading agent for Bruton's tyrosine kinase and its mutants, or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, as well as the therapeutic application of drugs for treating diseases, disorders, or conditions caused by the degradation of Bruton's tyrosine kinase and its mutants. [Solution] The compounds of the present invention can degrade BTK protein and BTKC481S protein, have antiproliferative inhibitory activity against Mino and OCI-LY10 tumor cell lines, show good antitumor activity in the OCI-LY10 subcutaneous graft model, have inhibitory activity against B cell activation, and can be applied to the treatment of B cell or plasma cell proliferative disorders and autoimmune diseases. The compounds of the present invention have relatively good oral absorption and can be applied to the oral treatment of B cell or plasma cell proliferative disorders and autoimmune diseases in humans or animals.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceutical synthesis, and more specifically, relates to degrading agents, compositions, and applications of Bruton's tyrosine kinases and their mutants. [Background technology]

[0002] Bruton's tyrosine kinase (Btk), a member of the non-receptor tyrosine kinase Tec family, is an important signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays a crucial role in the B cell signaling pathway, linking stimulation of B cell receptors (BCRs) on the cell surface to downstream intracellular responses. Btk is a vital regulator of B cell development, activation, signaling, and survival. Btk also functions in numerous other hematopoietic cell signaling pathways, such as TNF-α production mediated by Toll-like receptors (TLRs) and cytokine receptors in macrophages, immunoglobulin E receptor (FcεR1) signaling in mast cells, Fas / APO-1 cell apoptosis inhibition signaling in B-repertory lymphoid cells, and collagen-stimulated platelet aggregation. For example, see CA Jeffries et al., J. Bio. Chem. (2003) 278: 26258-26264, and NJ Horwood et al., J. Exp. Med. (2003) 197: 1603-1611. Recent studies have shown that the Btk signaling pathway is a new hotspot in clinical treatment research for current non-Hodgkin lymphomas (NHL), particularly chronic lymphocytic leukemia (CLL), B-cell lymphomas, and autoimmune diseases. Small molecule Btk inhibitors act on the BCR signaling pathway, binding to Btk and inhibiting Btk autophosphorylation, thereby blocking cell signaling and inducing cell apoptosis by preventing Btk activation.

[0003] With the clinical use of BTK inhibitors, some CLL patients have already developed the problem of covalent BTK drug-acquired resistance due to BTK C481 mutations, and there is an urgent need for next-generation BTK drugs to address this acquired drug resistance.

[0004] In recent years, there has been remarkable progress in targeted protein degradation (PROTAC) technology, which achieves degradation of target proteins by inducing ubiquitination of those proteins. Drugs using this technology do not need to constantly occupy the target protein and can achieve target degradation at catalytic concentrations. Therefore, the development of targeted degradation molecules for BTK is expected to solve the problem of BTK-acquired drug resistance. [Overview of the project]

[0005] The object of the present invention is to provide a novel BTK degradation molecule, its optical isomer, or a pharmaceutically acceptable salt thereof, which has efficient BTK and 481-cysteine ​​mutant BTK degradation activity, exhibits antiproliferative inhibitory activity against Mino and OCI-LY10 tumor cell lines, shows good antitumor activity in the OCI-LY10 subcutaneous graft model, has inhibitory activity against B cell activation, and exhibits excellent oral PK properties.

[0006] The present invention further provides pharmaceutical compositions comprising the above-mentioned compounds and their optical isomers or pharmaceutically acceptable salts thereof. The present invention relates to proteolytic drugs or pharmaceutically acceptable salts capable of degrading BTK or 481-cysteine ​​mutant BTK, and to their use as drugs for the treatment of hyperproliferative diseases such as cancer and inflammation, and immune and autoimmune diseases.

[0007] A first aspect of the present invention is formula (I): [ka] (I) The present invention provides the compounds shown, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof. however, BTK CL This represents a chemical ligand that can bind to BTK kinase.

[0008] E3 CL This represents a chemical ligand that can bind to E3 ubiquitin ligase.

[0009] L is BTK CL and E3 CL It represents a chemical group or chemical bond that simultaneously connects two things.

[0010] In a preferred embodiment, E3 CL This is selected from chemical fragments that can bind to the E3 ubiquitin ligase CRBN.

[0011] L has the following structure: -X1-L1-X2-Cyc1-X3-L2-X4-Cyc2-X5-L3-X6-Cyc3-X7-L4-X8- has however, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from the following: absent (or chemically bonded), -O-, -S-, and -N(Ra)-.

[0012] L1, L2, L3, and L4 are each independently selected from absent, chemically bonded, a C1-C4 alkyl group, a C2-C4 alkenyl group, and a C2-C4 alkynyl group. The alkyl groups, alkenyl groups, and alkynyl groups may be substituted with oxo, alkyl groups, halogens, cyano groups, or halogenated alkyl groups.

[0013] Cyc1, Cyc2, and Cyc3 are each independently selected from absent, a 3-12 member heterocycle, a 5-12 member aromatic ring (e.g., a benzene ring), a 5-12 member heteroaromatic ring, a 3-12 member cycloalkane, a 4-12 member cycloalkyne, or a 3-12 member cycloalkene, where the heterocycle, aromatic ring, heteroaromatic ring, cycloalkane, cycloalkyne, and cycloalkene may be substituted with oxo, alkyl, halogen, cyano, or halogenated alkyl groups.

[0014] Ra is selected from H, C1-C4 alkyl groups. In a preferred embodiment, BTK CL The following structures are selected: [ka] Here, BTK CL If structure B, C, or D is selected, Rb is selected from H, halogen, cyano group, methyl group, -CF3, and C1-C3 alkoxy group. Rc may be one or more, each independently selected from H, CN, halogen, C1-C4 alkyl group, C1-C4 cycloalkyl group, C1-C4 halogenated alkyl group, C1-C4 alkoxy group, and C1-C4 alkylamino group. Rd is selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclic groups, and the C1-C6 alkyl groups, cycloalkyl groups, and heterocyclic groups may be further substituted with one or more substituents, the substituents being selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups. p is selected from integers between 0 and 4.

[0015] In a preferred embodiment, BTK CL The following structures are selected: [ka] Y1 is selected from N, CR2. Y2 and Y3 are independently selected from N and CH. Ring A is selected from 3- to 12-membered complex rings. Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-10 membered heterocycle. Here, the heteroaromatic ring or heterocycle may be further substituted with one or more substituents, the substituents selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups, where the two substituents of ring B can be linked to form a crosslinked ring, a spiro ring, or a fused ring. D is selected from chemical bonds, C1-C3 alkyl groups, -O-, -NH-, and -S-. R1 may be one or more, and each R1 is independently selected from halogen, C1-C6 alkyl group, C1-C6 halogenated alkyl group, -CN, -COOH, and -NH2. R2 is selected from hydrogen, cyano group, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, C1-C4 halogenated alkyl group, and C1-C4 alkoxy group. R3 may be one or more, and each R3 is independently selected from a 3-12 member heterocyclic group, a 5-12 member heteroaryl group, a 5-12 member aryl group (e.g., phenyl group), a 3-12 member cycloalkyl group, a halogen, a C1-C4 alkyl group, a C1-C4 halogenated alkyl group, a C1-C4 alkoxy group, a cyano group, an oxo group, a carboxyl group, an ester group, an amide group, or a hydroxyl group. Here, the heterocyclic group, heteroaryl group, and cycloalkyl group may be further substituted, and the substituents are selected from a halogen, a C1-C4 alkyl group, a C1-C4 halogenated alkyl group, a C1-C4 alkoxy group, a cyano group, an oxo group, a carboxyl group, an ester group, an amide group, or a hydroxyl group. Here, the two R3s of ring A can be linked to form a spiro ring, a crosslinked ring, or a condensed ring. m is selected from integers between 0 and 3. n is selected from integers between 0 and 2. JPEG2026074117000004.jpg8170 represents the atoms to which it is linked being linked to L. If Y1 is selected from CH, ring A is a monocyclic ring, and ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 4-6 membered alkyl heterocyclic ring, or an 8-10 membered spirocyclic ring, then R3 is not a C1-C4 alkyl group or a C1-C4 halogenated alkyl group.

[0016] Furthermore, preferred compounds of the present invention are compounds having the structure of general formula II(b), [ka] (IIb) The present invention has a stereoisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, and furthermore, preferred compounds of the present invention are compounds having the structures of general formula III(a) and III(b). [ka] or having its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, Ring B is not a bridging ring. R3 is selected from C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, 3-6 membered cycloalkyl groups, 3-6 membered heterocyclic groups, 5-6 membered aryl groups (e.g., phenyl groups), and 5-6 membered heteroaryl groups. Here, the cycloalkyl groups, heterocyclic groups, aryl groups (phenyl groups), and heteroaryl groups may be further substituted by one or more groups, and the substituents are selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amides, and hydroxyl groups, and two substituents in the cycloalkane, heterocyclic group, aryl group (phenyl group), and heteroaryl group can be linked to form a fused ring, a crosslinked ring, or a spiroring. If Y1 is selected from CH, then R3 is not a C1-C4 alkyl group or a C1-C4 halogenated alkyl group.

[0017] Furthermore, preferred compounds of the present invention are compounds having the structures of general formulas IV(a), IV(b), IV(c), and IV(d). [ka] or having its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, Here, the fused ring or spiro ring structure consisting of rings G and F is selected from the following: [ka] The above condensed ring and spiro ring structures may be further substituted with one or more substituents, the substituents of which are selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups.

[0018] Furthermore, preferred compounds of the present invention are compounds having the structure of general formula V(a) or V(b), [ka] or having its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, Z is selected from -CH2-, -CH2CH2-, and -O-.

[0019] In a more preferred embodiment, in general formulas III(a) and III(b), R3 is preferably selected from C1-C4 alkyl groups and ring D. Ring D is, [ka] Ring D may be further substituted with one or more substituents, the substituents may be on the C atom or the N atom, and the substituents may be selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups. The two substituents in ring A can be linked to form a spiro ring, a crosslinked ring, or a fused ring. When Y1 is CH, R3 is selected from ring D.

[0020] Furthermore, the preferred compounds of the present invention are compounds having the general formula VI,

Chemical formula

[0021] In a more preferred embodiment, in general formula VI, In some embodiments, ring B is preferably, [ka] Selected from, Furthermore, in a preferred embodiment, L is [ka] Selected from JPEG2026074117000014.jpg242170 and JPEG2026074117000015.jpg24170, E3 CL teeth, [ka] Selected from, Re is selected from H, F, Cl, -CH3, -OMe, -CN, -CF3, -CHF2, -CH(CH3)2, -cyclopropyl group, -C(O)NH2, -S(O)2Rf, -P(O)(Rf)2, Rd' is selected from H, Rf OCORg, RfOCOORg, ROCONRgRh, COORf, CONRfRg. Rf, Rg, and Rh are each independently selected from H, C1-C8 alkyl groups, 3-8 membered cycloalkyl groups, 3-8 membered heterocyclic groups, C1-C6 alkyl groups, 3-8 membered cycloalkyl groups, and C1-C6 alkyl groups, 3-8 membered heterocyclic groups. Alternatively, two adjacent Re atoms in the benzene ring may form a 7-10 membered benzo ring together with the benzene ring, and the C atom in the benzo ring may be further substituted with one or more heteroatoms, the heteroatoms selected from N, O, and S, and the benzo ring may optionally be substituted with H, F, Cl, -CH3, -OMe, -CN, -CF3, -CHF2, -CH(CH3)2, -cyclopropyl group, -C(O)NH2, W1 and W2 are selected from CH and N. q is selected from 0, 1, 2, and 3.

[0022] Furthermore, E3 (that is, E3 CL )teeth, [ka] JPEG2026074117000018.jpg244170 Selected from.

[0023] Preferably, the above-mentioned compound or its stereoisomer or mixture thereof or pharmaceutically acceptable salt thereof is the following compound: [Table 1] JPEG2026074117000020.jpg248170JPEG2026074117000021.jpg226170JPEG2026074117000022.jpg248170JPEG2026074117000023.jpg233170JPEG 2026074117000024.jpg237170JPEG2026074117000025.jpg234170JPEG2026074117000026.jpg237170JPEG2026074117000027.jpg224170JPEG2026 074117000028.jpg234170JPEG2026074117000029.jpg228170JPEG2026074117000030.jpg234170JPEG2026074117000031.jpg234170JPEG2026074117000032.jpg239170JPEG2026074117000033.jpg235170JPEG2026074117000034.jpg111170 or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are selected. Preferably, the compound is one of the following compounds: 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 001 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 002 5-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidinyl-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 003 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)pyrazine-2-formamide 004 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide 005 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxohexahydroimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide 006 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-6-ethyl-5-(3-(3-(3-methyl-2-oxyimidazoline-1-yl)piperidine-1-yl)pyrazine-2-formamide 007 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxohexahydrocyclopenta[d]imidazole-1(2H)-yl)piperidine-1-yl)pyrazine-2-formamide 008 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxooctahydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-formamide 009 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)pyrazine-2-formamide 010 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)pyrazine-2-formamide 011 3-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 012 3-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 013 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 014 3-((4-(4-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperazine-1-yl)phenyl)amino)-5-(3-(3-(oxetane-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 015 3-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 016 3-((4-(9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)-3,9-diazaspiro[5.5]undeka-3-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 017 3-((4-(6-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 018 3-((4-(2-(4-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-yl)-7-azaspiro[3.5]non-7-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 019 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-4-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 020 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(5-((2,6-dioxopiperidine-3-yl)amino)pyridine-2-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 021 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 022 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxo-1,2-dihydroisoquinoline-6-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 023 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 024 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-formamide 025 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxoimidazole[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide 026 5-(3-(3-cyclopentyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide 027 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-formyl)phenyl)amino)pyrazine-2-formamide 028 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)propa-1-in-1-yl)piperidine-1-yl)phenyl)amino)pyrazine-2-formamide 029 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide 030 3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 031 3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxyimidazoline-1-yl)piperidine-1-yl)pyrazine-2-carboxamide 032 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)azetidine-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide 033 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 034 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 035 4-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-formamide 036 2-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-5-fluoro-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)nicotinamide 037 2-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-5-methoxy-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)nicotinamide 038 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide 039 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-4-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 040 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)-2-fluorophenyl)amino)pyrazine-2-formamide 041 3-((3-cyano-4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide 042 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-3-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide 043 3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]cycloheptan-6-yl)piperidine-1-yl)pyrazine-2-formamide 044 3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(3-oxohexahydroimidazole[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide 045 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-formamide 046 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-isopropyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-formamide 047 2-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-6-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinamide 048 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 049 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)pyrazine-2-formamide 050 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 051 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide 052 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 053 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-ethyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 054 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-isopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 055 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(trifluoromethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 056 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 057 3-(3-(3-cyclopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 058 3-(3-(3-cyclobutyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 059 3-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 060 3-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 061 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 062 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 063 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 064 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(2-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 065 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(3-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 066 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(pyridine-3-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 067 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 068 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 069 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-oxytrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 070 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 071 3-(6-(3-cyclopentyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 072 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(2-oxo-3-phenylimidazoline-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 073 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 074 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)-1,2,4-triazine-6-formamide 075 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisooctyl-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 076 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 077 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 078 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 079 5-((2-(1-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 080 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 081 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 082 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 083 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 084 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 085 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 086 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 087 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 088 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 089 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 090 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 091 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 092 5-((2-(1-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 093 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 094 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 095 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 096 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoquinoline-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 097 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 098 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 099 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 100 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazole-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 101 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 102 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 103 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 104 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 105 5-((2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 106 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 107 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 108 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 109 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoquinoline-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoisoimidazole-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 110 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 111 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 112 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 113 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide 114 4-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-2-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-formamide 115 4-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-2-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-formamide 116 4-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-2-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-formamide 117 3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-formamide 118 5-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 119 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-methylpyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 120 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)-3-fluoropyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 121 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)-4-fluoropiperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 122 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 123 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 124 5-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 125 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 126 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-carbonyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 127 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 128 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 129 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 130 5-((4-(4-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 131 5-((4-(4-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 132 5-((3-chloro-4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 133 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 134 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(2,5-dioxopyrrolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 135 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(2,5-dioxopyrrolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 136 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(4-methyl-5,7-dioxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 137 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 138 (3-(5-(3-((4-(4-((6-Carbamoyl-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)phenyl)piperidine-1-yl)methyl)pyrrolidine-1-yl)-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiperidine-1-yl)methyl butyrate 139 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 140 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 141 5-((4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)phenyl)amino)-3-((R)-3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 142 3-(6-(1,3-dioxoisoindoline-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 143 3-(6-(1,3-dioxoisoindoline-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide 144 5-((4-(4-((1-(6-(((S)-2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 145 5-((4-(4-((1-(6-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 146 5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 147 5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorobenzoyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 148 5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 149 5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 150 5-((4-(4-(((R)-1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 151 5-((4-(4-(((S)-1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 152 5-((4-(4-(((R)-1-(6-(((S)-2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 153 5-((4-(4-(((S)-1-(6-(((S)-2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 154 5-((4-(1-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 155 5-((4-(1-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 156 5-((4-(1-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 157 5-((4-(1-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 158 5-((3-chloro-4-(4-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 159 5-((3-chloro-4-(4-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 160 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-(trifluoromethyl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 161 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-2,3-difluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 162 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-2,5-difluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 163 5-((3-chloro-4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 164 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-2,3-difluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 165 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 166 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 167 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 168 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 169 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 170 5-((4-(4-((1-(6-(((S)-2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 171 5-((4-(4-((1-(4-(((S)-2,6-dioxopiperidine-3-yl)carbamoyl)-3-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 172 5-((4-(4-((1-(6-(2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-3-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 173 5-((4-(4-((1-(5-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-2-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 174 5-((4-(4-((1-(5-((2,6-dioxopiperidine-3-yl)carbamoyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 175 5-((4-(4-((1-(7-((2,6-dioxopiperidine-3-yl)carbamoyl)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 176 5-((4-(4-((1-(7-((2,6-dioxopiperidine-3-yl)carbamoyl)benzo[d][1,3]dioxolan-4-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 177 4-(3-((4-(4-((6-Carbamoyl-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzimidazole-7-formamide 178 4-(4-((4-(((6-Carbamoyl-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-yl)methyl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-1H-benzimidazole-7-formamide 179 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)aminoformyl)-3-methylphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 180 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)aminoformyl)-3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 181 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)aminoformyl)-2,3-difluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 182 5 - ((4 - (4 - ((1 - (8 - ((2,6 - dioxopiperidin - 3 - yl)aminoformyl)-2,3 - dihydrobenz[b][1,4]dioxan - 5 - yl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)-3 - ((R)-3-(3 - methyl - 2 - oxoimidazolidin - 1 - yl)piperidin - 1 - yl)-1,2,4 - triazine - 6 - formamide 183 (R)-5 - ((4 - (4 - ((1 - (4 - (2,4 - dioxotetrahydropyrimidin - 1(2H)-yl)-3 - fluorophenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)-3-(3-(3 - methyl - 2 - oxoimidazolidin - 1 - yl)piperidin - 1 - yl)-1,2,4 - triazine - 6 - formamide 184 (R)-5 - ((4 - (4 - ((1 - (4 - (2,4 - dioxotetrahydropyrimidin - 1(2H)-yl)-2,3 - difluorophenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)-3-(3-(3 - methyl - 2 - oxoimidazolidin - 1 - yl)piperidin - 1 - yl)-1,2,4 - triazine - 6 - formamide 185 (R)-5 - ((4 - (4 - ((1 - (4 - (2,4 - dioxotetrahydropyrimidin - 1(2H)-yl)-2 - fluorophenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)-3-(3-(3 - methyl - 2 - oxoimidazolidin - 1 - yl)piperidin - 1 - yl)-1,2,4 - triazine - 6 - formamide 186 (R)-5 - ((4 - (4 - ((1 - (4 - (2,4 - dioxotetrahydropyrimidin - 1(2H)-yl)-3-(trifluoromethyl)phenyl)piperidin - 4 - yl)methyl)piperazin - 1 - yl)-3 - fluorophenyl)amino)-3-(3-(3 - methyl - 2 - oxoimidazolidin - 1 - yl)piperidin - 1 - yl)-1,2,4 - triazine - 6 - formamide 187 (R)-5-((4-(4-((1-(3-(Difluoromethyl)-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 188 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-isopropylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 189 (R)-5-((4-(4-((1-(7-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzo[d][1,3]dioxolan-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 190 (R)-5-((4-(4-((1-(7-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoxazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 191 (R)-5-((4-(4-((1-(7-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 192 (R)-5-((4-(4-((1-(8-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 193 (R)-5-((4-(4-((1-(3-Cyclopropyl-4-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 194 (R)-5-((4-(4-((1-(6-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyridine-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 195 (R)-5-((4-(4-((1-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 196 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-2-(methylsulfonyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 197 (R)-5-((4-(4-((1-(2-(dimethylphosphoryl)-4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 198 (R)-5-((4-(4-((1-(5-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)quinoline-8-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 199 5-((4-(4-((1-(6-((2,6-dioxopiperidine-3-yl)amino)pyridine-3-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 200 5-((4-(4-((1-(5-((2,6-dioxopiperidine-3-yl)amino)pyridine-2-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 201 5-((4-(4-((1-(6-((2,6-dioxopiperidine-3-yl)amino)pyridine-3-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 202 5-((4-(4-((1-(5-((2,6-dioxopiperidine-3-yl)amino)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 203 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-3-fluorophenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 204 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-3-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 205 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-3-methylphenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 206 5-((4-(4-((1-(4-((2,6-dioxopiperidine-3-yl)amino)-3-methylphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 207 5-((4-(4-((1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 208 5-((4-(4-((1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d][1,3]dioxolan-4-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 209 5-((4-(4-((1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d]oxazole-4-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 210 5-((4-(4-((1-(8-((2,6-dioxopiperidine-3-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 211 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 212 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 213 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazole[3,4-b]pyrrolidine-6-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 214 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-pyrazole[3,4-b]pyridine-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 215 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-7-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 216 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-7-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 217 5-((4-(4-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 218 5-((4-(4-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 219 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxo-1,2,3,4-tetrahydropyrrole[3,4-b]indole-6-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 220 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxo-2,3-dihydro-1H-benzofuran[2,3-c]pyrrole-6-yl)pyrroridine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 221 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxo-1,2,3,4-tetrahydropyrrole[3,4-b]indole-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 222 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxo-2,3-dihydro-1H-benzofuran[2,3-c]pyrrole-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 223 5-((4-(4-(3-(6-((2,6-dioxopiperidine-3-yl)aminoformyl)pyridine-3-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 224 5-((4-(4-((4-((2,6-dioxopiperidine-3-yl)aminoformyl)-3-fluorophenyl)ethynyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 225 5-((4-(4-(3-(4-((2,6-dioxopiperidine-3-yl)aminoformyl)-3-methylphenyl)prop-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 226 5-((4-(4-(3-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 227 5-((4-(4-(3-(4-((2,6-dioxopiperidine-3-yl)amino)-3-fluorophenyl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 228 5-((4-(4-(3-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d]oxazole-4-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 229 5-((4-(4-(3-(5-((2,6-dioxopiperidine-3-yl)aminoformyl)thiophen-2-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 230 5-((3-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 231 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxo-1,2-dihydroisoquinoline-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 232 (R)-5-((4-(4-((1-(3-Carbamoyl-4-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-Methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 233 (R)-5-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 234 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)-3-oxopiperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 235 (R)-5-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 236 (R)-5-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperidine-4-yl)-3-(hydroxymethyl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 237 (R)-5-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperidine-4-yl)-2-(hydroxymethyl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 238 (R)-5-((4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)azetidine-3-yl)acetyl)piperidine-4-yl)-2-(hydroxymethyl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 239 (R)-5-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenyl)piperidine-4-yl)methyl)piperidine-4-yl)-3-(hydroxymethyl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 240 (R)-3-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-6-fluoro-5-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)pyrazine-2-formamide 241 (R)-2-((4-(1-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperidine-4-yl)-3-fluorophenyl)amino)-3,5,6-trifluoro-4-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)benzamide 242 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)benzo[d]isoxazole-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 243 5-((4-(4-((1-(3-(2,6-dioxopiperidine-3-yl)imidazo[1,2-a]pyridine-7-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 244 (R)-5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-7-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 245 (R)-5-((4-(4-(3-(3-(2,4-Dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-7-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 246 5-((4-(4-((1-(1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 247 5-((4-(4-(3-(1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)propa-2-in-1-yl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 248 5-((4-(4-((1-(5-((2,6-dioxopiperidine-3-yl)aminoformyl)naphthalene-1-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 249 4-(4-((4-(((6-Carbamoyl-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-yl)methyl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)quinoline-8-formamide 250 5-((4-(4-((1-(4-(2,6-dioxopiperidine-3-yl)amino)-2-fluorophenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 251 5-((4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)amino)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 252 5-((4-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 253 5-((4-(4-((1-(4-((2,6-dioxopiperidin-3-yl)aminocarbonyl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 254 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 255 5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorophenyl)pyrrolidin-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-1,2,4-triazine-6-formamide 256 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methylphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 257 5-((4-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxyphenyl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 258 (R)-5-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-methoxyphenyl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide 259

[0024] Explanation of terms Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as those generally understood by those skilled in the art. Unless otherwise specified, all patent documents, disclosed information, etc., referenced in this invention are incorporated as a whole into the references. If the same term in this invention has multiple definitions, the definition in this section shall prevail.

[0025] The general descriptions above and the detailed descriptions below are illustrative and descriptive, and should be understood as not limiting to any of the claims. Note that in the specification and the attached claims, unless otherwise specified in the context, singular forms such as "one," "one," and "this" include plural forms. Furthermore, unless otherwise specified, "or" means "and / or." Note that similar terms such as "include" and "contain" are not restrictive terms.

[0026] "Substitution" refers to the substitution of a hydrogen atom with a substituent. It should be noted that substituents on a particular atom are limited to their valence. In the definition section, "C i -C j " refers to the range that includes the start and end points, where i and j are both integers and represent the number of carbon atoms. For example, C 1- C4, C 1- C8, C 3- Examples include C8.

[0027] The C, H, O, S, N, F, Cl, Br, I, etc., related to the groups and compounds described in the present invention all contain their isotopes. In addition, the C, H, O, S, N, F, Cl, Br, I related to the groups and compounds described in the present invention may optionally be substituted with one or more corresponding isotopes, which are carbon isotopes. 12 C, 13 C, 14 C, and the isotopes of hydrogen, protium (H), deuterium (D), and tritium (T), and the isotope of oxygen. 16 O, 17 O, 18 O and sulfur isotopes 32 S, 33 S, 34 S, 36 S and nitrogen isotope 14 N, 15 N and fluorine isotopes 17 F, 19 F and chlorine isotope 35 Cl, 37 Cl and bromine isotopes 79 Br, 81 This includes, but is not limited to, Br.

[0028] As used in this invention, the term "alkyl group" refers to a linear or branched saturated hydrocarbon group containing 1 to 8 carbon atoms, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, and isooctyl groups. The alkyl group may be substituted with one or more substituents, and in the case of polysubstituted substituents, the substituents may be the same or different, and the substituents may independently be D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0029] As used in this invention, the term "alkenyl group" refers to a linear or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C=C double bond, including vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, and 3-hexenyl group. This includes, but is not limited to, the following groups: 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 1-methyl-2-hexenyl group, 2-methyl-2-hexenyl group, 2-methyl-3-hexenyl group, 3,5-dimethyl-2-hexenyl group, 3,3-dimethyl-1-pentenyl group, 3-methyl-2-ethyl-1-butenyl group, 1-octenyl group, 2-octenyl group, etc. The alkenyl group may be substituted with one or more substituents, and in the case of polysubstituted substituents, the substituents may be the same or different, and the substituents are independently D, alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, hydroxyalkyl group, halogenated hydroxyalkyl group, alkylamino group, halogenated alkylamino group, cycloalkyl group, halogenated cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, hydroxyl group, halogen, cyano group, nitro group, amino group, aminoalkyl group, carboxyl group, amide group, and sulfonamide group.

[0030] As used in this invention, the term "alkynyl group" refers to a linear or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C≡C triple bond, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 3-methyl-1-butynyl group, 4-methyl-1-butynyl group, 2-methyl-3-butynyl group, 1-methyl-4-butynyl group, 1-hexynyl group, 2-hexynyl group This includes, but is not limited to, the following groups: synyl group, 3-hexynyl group, 4-hexynyl group, 1-methyl-2-pentynyl group, 1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 2-methyl-3-pentynyl group, 2,2-dimethyl-4-pentynyl group, 1-heptynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 5-heptynyl group, 2-methyl-3-hexynyl group, 3-methyl-1-hexynyl group, 3,3-dimethyl-1-hexynyl group, 4-methyl-1-hexynyl group, etc. The alkynyl group may be substituted with one or more substituents, and in the case of polysubstituted substituents, the substituents may be the same or different, and the substituents are independently D, alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, hydroxyalkyl group, halogenated hydroxyalkyl group, alkylamino group, halogenated alkylamino group, cycloalkyl group, halogenated cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, hydroxyl group, halogen, cyano group, nitro group, amino group, aminoalkyl group, carboxyl group, amide group, and sulfonamide group.

[0031] The term "alkylene group" as used in this invention refers to a straight-chain or branched-chain divalent saturated hydrocarbon group containing 1 to 8 carbon atoms, and includes, but is not limited to, methylene, ethylene, propylene, butylene, and pentene groups. The alkylene group may be substituted with one or more substituents, and in the case of polysubstituted substituents, the substituents may be the same or different. The substituents can be independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amide, methanesulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, and C3-C 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0032] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine, and iodine, and preferably fluorine, chlorine, and bromine.

[0033] As used in this invention, the term "cycloalkyl group" refers to a monocyclic or polycyclic (two monocyclic rings are linked by a chemical bond, or form a bridging ring, spiro ring, or fused ring) non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms, and one or more chemical bonds may be double or triple bonds. "Cycloalkyl group" includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, decalin, cyclopropyl condensed cyclopropyl, cyclopropyl condensed cyclobutyl, cyclopropyl condensed cyclopentyl, cyclopropyl condensed cyclohexyl, cyclopropyl condensed cycloheptyl, cyclobutyl condensed cyclobutyl, cyclobutyl condensed cyclopentyl, cyclobutyl condensed cyclohexyl, cyclopentyl condensed cyclopentyl, cyclopentyl condensed cyclohexyl, cyclopentyl condensed cycloheptyl, cyclohexyl condensed cyclohexyl, cyclopropyl-spiro-cyclopropyl, cyclopropyl-spiro-cyclobutyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, cyclopropyl Lu-spiro-cycloheptyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclobutyl-spiro-cycloheptyl, cyclopentyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclobutyl-spiro-cycloheptyl, cyclohexy-spiro-cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1 This includes, but is not limited to, hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.1]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.1]octyl, bicyclo[5.1.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]nonyl, bicyclo[3.2.2]nonyl, bicyclo[5.2.1]decyl, bicyclo[4.2.2]decyl, etc.The cycloalkyl group may be substituted with one or more substituents, and in the case of polysubstituted groups, the substituents may be the same or different, and the substituents may be independently D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, amino group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C. 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0034] As used in this invention, the term "cycloalkenyl group" refers to a monocyclic or polycyclic (where two monocyclic rings are chemically bonded, bridging, spiro-ringed, or fused) non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms and containing at least one C=C double bond, including cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptylalkenyl group, cycloalkenyl group, spiro[2.2]penta-1-alkenyl, spiro[2.2]penta-1,4-dienyl, spiro[2.3]hexa-1-alkenyl, spiro[2.3]hexa-1,4-dienyl, and spiro[3.3]hept This includes, but is not limited to, tan-1-alkenyl, spiro[3.3]heptane-1,5-dienyl, spiro[3.4]octa-1-alkenyl, spiro[3.4]octa-1,6-dienyl, spiro[3.4]octa-5-alkenyl, spiro[3.4]octa-6-alkenyl, spiro[3.4]octa-1-alkenyl, bicyclo[2.1.1]hexa-1-alkenyl, bicyclo[2.1.1]hexa-2-alkenyl, bicyclo[3.1.1]heptane-1-alkenyl, bicyclo[3.1.1]heptane-2-alkenyl, bicyclo[2.2.1]heptane-1-alkenyl, and bicyclo[2.2.1]heptane-2-alkenyl. The cycloalkene and cycloalkenyl groups may be substituted with one or more substituents, and in the case of polysubstituted substituents, the substituents may be the same or different, and the substituents may be independently D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halogenated C3-C 12Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 12 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0035] The term "heterocyclic group" as used in this invention refers to a monocyclic or polycyclic (two monocyclic rings linked by chemical bonds, or forming a bridging ring, spirocycle, or fused ring) non-aromatic ring group having 3 to 12 ring atoms, having one or more heteroatoms selected from N, O, and S, and one or more chemical bonds may be double or triple bonds. Examples of heterocyclic groups include pyranyl, piperidyl, piperazinyl, morpholinyl, dioxanyl, oxyranyl, oxetanyl, oxacyclohexyl, oxacycloheptyl, oxacyclooctyl, azacyclopropyl, azetidinyl, azacyclopentyl, azacycloheptyl, azacyclooctyl, thietanyl, thyranyl, azacyclooctanyl, oxethazeinzepinyl, diazazepinyl, thiazepinyl, dihydrofuryl, dihydrothienyl, dihydropyranyl, and thietanyl. Trahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroimidazolyl, hexahydropyridazinyl, hexahydropyrimidinyl, 1-azaspiro[2.2]pentyl, 1-azaspiro[2.3]hexyl, 4-azaspiro[2.3]hexyl, 5-azaspiro[2.3]hexyl, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azas Pyro[3.3]heptane, 1-azaspiro[2.5]octanil, 2-azaspiro[3.4]octanil, 6-azaspiro[3.4]octanil, 2,6-diazaspiro[3.4]octanil, 2-azaspiro[3.5]nonyl, 6-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-azaspiro[4.4]nonyl, 2-azaspiro[4.4]nonyl, 8 -Azaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decyl, 1-oxaspiro[2.2]pentyl, 1-oxaspiro[2.3]hexyl, 4-oxaspiro[2.3]hexyl, 5-oxaspiro[2.3]hexyl, 2-oxaspiro[3.3]heptyl, 1-oxaspiro[2.5]octanyl, 2-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 2-oxaspiro[3.5]nonyl, 6-oxaspiro[3.This includes, but is not limited to, [5] nonyl, 7-oxaspiro[3.5] nonyl, 1-oxaspiro[4.4] nonyl, 2-oxaspiro[4.4] nonyl, 8-oxaspiro[4.5] decyl, decahydroquinolinyl, decahydroisoquinolinyl, 2-azabicyclo[1.1.1]pentyl, 2-oxabicyclo[1.1.1]pentyl, azabicyclo[2.1.1]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[3.1.1]heptyl, oxabicyclo[3.1.1]heptyl, azabicyclo[2.2.1]heptyl, azabicyclo[4.1.1]octyl, azabicyclo[3.2.1]octyl, azabicyclo[3.2.1]octyl, etc. The heterocyclic group may be substituted with one or more substituents, and in the case of polysubstituted groups, the substituents may be the same or different. The substituents may independently be D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, amino group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C. 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0036] As used in this invention, the term "aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms, either a monocyclic or polycyclic fused ring (in the case of a polycyclic fused ring, one of the fused rings may be partially saturated), and includes, but is not limited to, benzene rings, naphthalene rings, anthracene rings, indene rings, dihydroindenyl groups (indanyl groups), dihydronaphthalene rings, and tetrahydronaphthalene rings. The aryl group may be unsubstituted or substituted, monosubstituted (e.g., ortho, meta, para substituted), disubstituted or trisubstituted, and in the case of polysubstituted, the substituents may be the same or different. The substituents can be independently D (deuterium), halogen, cyano group, nitro group, hydroxyl group, amino group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, acyl group, amide group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0037] As used in this invention, the term "heteroaryl group" refers to a monocyclic or polycyclic aromatic ring group having 5 to 14 ring atoms (in the case of polycyclic rings, one of the fused rings may be partially saturated), which corresponds to one or more carbon atoms in the above-mentioned "aryl group" being substituted with heteroatoms, such as N, O, S, etc. The heteroaromatic ring may be monocyclic or dicyclic, i.e., formed by the fusion of two rings. Heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furyl, triazolyl, oxazolyl, imidazolyl, indazolyl, indolyl, dihydroindolyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pteridinyl, purinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, benzoxadiazolyl, This includes, but is not limited to, benzoxazolyl, benzisoxazolyl, imidazopyridyl, imidazothiazolyl, pyrrolopyrridyl, thienopyrrolyl, thienotienyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrrolyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridinyl, imidazopyrimidinyl, imidazopyrimidinyl, imidazopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolopyrimidinyl, pyramidopyridyl, pyramidopyrimidinyl, pyramidopyrimidinyl, pyramidopyrimidinyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrimidinyl, pyridadinopyrimidinyl, pyridadinopyrimidinyl, pyridadinopyrimidinyl, pyridadinopyrimidinyl, pyridadinopyrimidinyl, pyridadinopyrimidinyl.The heteroaryl group may be unsubstituted, monosubstituted, or polysubstituted, and in the case of polysubstituted, the substituents may be the same or different, and the substituents may be independently D (deuterium), halogen, cyano group, nitro group, amino group, alkylamino group, hydroxyl group, carboxyl group, carboxylate group, acyl group, amide group, alkylamide group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group, hydroxyalkylamide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C. 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C 14 It is a heteroaryl group.

[0038] As used in this invention, the terms "spiro ring" and "spiro ring group" refer to a polycyclic structure in which at least two rings share one atom (generally a carbon atom), and in such a polycyclic structure, one or more chemical bonds may be double or triple bonds, and one or more heteroatoms may be present. The spiro ring group may be unsubstituted, monosubstituted, or polysubstituted, and in the case of polysubstituted, the substituents may be the same or different, and the substituents may be independently D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, amino group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halogenated C3-C12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0039] As used in this invention, the term "crosslinked ring group" refers to a polycyclic structure in which at least two rings share two or more atoms, and in such a polycyclic structure, one or more chemical bonds may be double or triple bonds, and one or more heteroatoms may be present. The crosslinked ring group may be unsubstituted, monosubstituted, or polysubstituted, and in the case of polysubstituted, the substituents may be the same or different, and the substituents may be independently D (deuterium), oxo, halogen, cyano group, nitro group, hydroxyl group, amino group, alkylamino group, alkenyl group, alkynyl group, carboxyl group, carboxylate group, acyl group, amide group, methanesulfone group, alkylamide group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halogenated C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, C6-C 12 Aryl group, C5-C 14 Heteroaryl group, C3-C 12 It is a heterocyclic group.

[0040] In this invention, the term "alkoxy group" refers to an alkyl group -O-, where an alkyl group is defined as described above. Examples of "alkoxy groups" used in this invention, but not limited to these, include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, etc. "Alkoxy group" also includes substituted alkoxy groups, the substituents of which include D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C 14 It may also be a heteroaryl group.

[0041] The term "hydroxyalkyl group" as used in this invention refers to an alkyl group-OH, where an alkyl group is defined as described above. Examples of "hydroxyalkyl groups" used in this invention, but not limited to these, include hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, and hydroxyisopropyl group. A "hydroxyalkyl group" further includes substituted hydroxyalkyl groups, the substituents of which include D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, and C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C14 It may be a heteroaryl group.

[0042] The term "aminoalkyl group" used in the present invention refers to -alkyl group-NH2, where the alkyl group is defined as above. Examples of the "aminoalkyl group" used in the present invention include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, etc. The "aminoalkyl group" further includes a substituted aminoalkyl group, and the substituents thereof are D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 cycloalkyl group, C3-C 12 heterocyclic group, C6-C 12 aryl group, C5-C 14 It may be a heteroaryl group, and the substituents thereof may be substituted on the alkyl group or on the N.

[0043] The term "alkylamino group" used in the present invention refers to -NH-alkyl group, where the alkyl group is defined as above. Examples of the "alkylamino group" used in the present invention include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, etc. The "alkylamino group" further includes a substituted alkylamino group, and the substituents thereof are D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C^{8} alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 cycloalkyl group, C3-C 12A complex ring group, C6-C 12 An aryl group, C5-C 14 It may be a heteroaryl group, and its substituent may be substituted on the alkyl group or on the N.

[0044] The "alkylcarbonyl group" used in the present invention refers to an alkyl group -C(O)-, where the alkyl group is defined as above. The "alkylcarbonyl group" further includes a substituted alkylcarbonyl group, and its substituent is D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 A cycloalkyl group, C3-C 12 A complex ring group, C6-C 12 An aryl group, C5-C 14 It may be a heteroaryl group. Here, "C(O)" represents C=O.

[0045] The term "alkoxycarbonyl group" used in the present invention refers to an alkyl group -O-C(O)-, where the alkyl group is defined as above. The "alkoxycarbonyl group" further includes a substituted alkoxycarbonyl group, and its substituent is D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 A cycloalkyl group, C3-C 12 A complex ring group, C6-C 12 An aryl group, C5-C 14 ​

[0046] The "heterocycloalkoxy group" used in this invention refers to a heterocycloalkyl group-O-, where a heterocycloalkyl group is defined as described above. The "heterocycloalkoxy group" further includes substituted heterocycloalkoxy groups, the substituents of which are D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C 14 It may also be a heteroaryl group.

[0047] As used in this invention, the term "cycloalkoxy group" refers to a cycloalkyl group-O-, where a cycloalkyl group is defined as described above. A "cycloalkoxy group" includes further substituted cycloalkoxy groups, the substituents of which are D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C 14 It may also be a heteroaryl group.

[0048] The term "cycloalkylamino group" as used in this invention refers to a cycloalkyl group -NH-, where a cycloalkyl group is defined as described above. A "cycloalkylamino group" further includes substituted cycloalkylamino groups, the substituents of which are D, halogen, oxo, amino group, hydroxyl group, cyano group, nitro group, carboxyl group, amide group, sulfonamide group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, halogenated C1-C8 alkyl group, halogenated C1-C8 hydroxyalkyl group, halogenated C1-C8 alkoxy group, halogenated C1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclic group, C6-C 12 Aryl group, C5-C 14 It may also be a heteroaryl group.

[0049] The term "alkylthio group" as used in this invention refers to an alkyl-S- group, where an alkyl group is defined as described above. Alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, propylthio groups, and butylthio groups.

[0050] The term "alkanoyl group" as used in this invention refers to an alkyl group -C(O)-, where an alkyl group is defined as described above.

[0051] The term "alkylsulfonyl group" as used in this invention refers to an alkyl group -S(O)2-, where an alkyl group is defined as described above.

[0052] The term "halogenated alkyl group" as used in this invention refers to a linear or branched alkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where "alkyl group" is defined as described above. Examples of "halogenated alkyl groups" used in this invention, but not limited to these, include fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trifluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, tetrafluoroethyl group, pentafluoroethyl group, and 1,1,1-trifluoropropane-2-yl. The "halogenated alkyl group" may be substituted with a halogen once or multiple times.

[0053] As used in this invention, the term "halogenated hydroxyalkyl group" refers to a hydroxyalkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where a hydroxyalkyl group is defined as described above. The "halogenated hydroxyalkyl group" may be substituted with a halogen once or multiple times.

[0054] As used in this invention, the term "halogenated alkoxy group" refers to a hydroxyalkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where the alkoxy group is defined as described above. The "halogenated alkoxy group" may be substituted with a halogen once or multiple times.

[0055] As used in this invention, the term "halogenated alkylamino group" refers to an alkylamino group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where the alkylamino group is defined as described above. The "halogenated alkylamino group" may be substituted with a halogen once or multiple times.

[0056] To avoid multiple ambiguities, for example, when referring to alkyl, cycloalkyl, heterocyclic, aryl, and / or heteroaryl group substitutions, these refer to substitutions of each of these groups individually or substitutions of these groups in combination.

[0057] "Pharmacologically acceptable salts" refer to salts formed between the compounds of the present invention and an acid or base that are suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts is those formed between the compounds of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, ascorbic acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, sulfanilic acid, hydroxyethanesulfonic acid, pamoic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts is a salt formed between the compound of the present invention and a base. Suitable bases for salt formation include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, and organic bases such as aqueous ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0058] A second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any of the above technical proposals. The pharmaceutical composition described in the present invention may consist of one or more of the compounds described in any of the above technical proposals and other compounds, or it may consist of one or more of the compounds described in any of the above technical proposals.

[0059] The present invention provides a drug formulation comprising at least one active ingredient, the active ingredient being one or more of the compounds described in any of the above technical proposals. The drug formulation comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, the active ingredient being any one or any more of the BTK inhibitor compounds of the present invention, optical isomers of the compound, pharmaceutically acceptable salts of the compound or its optical isomer, or solvates of the compound or its optical isomer.

[0060] The carrier includes common diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbent carriers, lubricants, etc., in the field of pharmaceuticals, and may also include flavoring agents, sweeteners, etc., if necessary.

[0061] The drug of the present invention can be formulated into multiple forms, such as tablets, powders, granules, capsules, oral solutions, and injections, and each of these dosage forms may be prepared by methods common in the field of pharmacy.

[0062] In another aspect, the present invention provides treatment for diseases, disorders, or conditions by inhibition of Bruton's tyrosine kinase (Btk) activity, IKZF1 activity, or by inhibition of Bruton's tyrosine kinase (Btk) activity, IKZF1 activity, using the compound described herein as General Formula VI and its optical isomers or pharmaceutically acceptable salts or solvates.

[0063] In a more preferred embodiment, the present invention provides a method for inhibiting Bruton's tyrosine kinase activity in a patient in need of treatment by administering a composition containing a therapeutically effective amount of at least one compound, wherein the structural formula of the compound is general formula VI. In some embodiments, the patients in need of treatment are those with autoimmune diseases such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjoegren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, and Goodpasture's syndrome. The patient suffers from the following conditions: syndrome, immune thrombocytopenic purpura (ITP), optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia generalis, Behcet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular totonia, scleroderma or vulvodynia, and chronic graft-versus-host disease (cGvHD).

[0064] In a further embodiment, the patient in need of treatment is suffering from cancer. In one embodiment, the cancer is a B-cell or plasma cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasmacytoplasma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, multiple myeloma, or lymphomatoid granulomatosis.

[0065] The present invention further provides applications of the compounds described in the present invention or pharmaceutically acceptable salts thereof in the preparation of BTK inhibitors, particularly in the preparation of drugs for treating proliferative disorders, including cancer. In other words, the present invention further provides applications of the compounds described in general formula VI, used alone or in combination with other drugs, and their optical isomers or pharmaceutically acceptable salts or solvates, in the treatment of proliferative disorders (e.g., cancer). Antitumor agents that can be used in combination with the compounds or pharmaceutically acceptable salts thereof according to the present invention include, but are not limited to, at least one of the following classes: mitotic inhibitors (e.g., vinblastine, vindesine, and vinorelbine), microtubule phosphate degradation inhibitors (e.g., paclitaxel), alkylating agents (e.g., cisplatin, carboplatin, and cyclophosphamide), antimetabolites (e.g., 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea), insertable antibiotics (e.g., adriamycin, mitomycin, and bleomycin), enzymes (e.g., asparaginase), topoisomerase inhibitors (e.g., etoposide and camptothecin), bioresponse modifiers (e.g., interferon), immune checkpoint inhibitors (e.g., PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors), CD20 mab, and BCL2 inhibitors.

[0066] The inventors of this invention have experimentally confirmed that the compound of the present invention can decompose BTK.

[0067] The inventors of the present invention experimentally confirmed that the compound of the present invention can decompose BTKC481S.

[0068] The inventors of the present invention experimentally confirmed that the compound of the present invention has antiproliferative inhibitory activity against Mino and OCI-LY10 tumor cell lines.

[0069] The inventors of the present invention have experimentally confirmed that the compound of the present invention has good oral absorption in mice.

[0070] The inventors of the present invention have experimentally confirmed that the compound of the present invention has good oral absorption in dogs.

[0071] The inventors of the present invention have experimentally confirmed that the compound of the present invention has a potent tumor growth inhibitory effect in vivo. [Modes for carrying out the invention]

[0072] Intermediate 1. Cyclopentyl-3-(piperidine-3-yl)imidazoline-2-one [ka] Synthesis Step 1. 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate tert-butyl(1-1) N-Boc-3-aminopiperidine (25.0 g, 125 mmol) and triethylamine (25.3 g, 250 mmol) were dissolved in dichloromethane (250 mL), and chloroethyl isocyanate (15.8 g, 150 mmol) was slowly added dropwise. After reacting for 4 hours, water was added, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate solution, filtered, and the solvent was removed under reduced pressure. Purification by column chromatography yielded 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate tert-butyl(1-1) as a solid. ESI-MS: m / z = 306 [M+H] + .

[0073] Synthesis step 2. 3-(2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl(1-2) 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate tert-butyl (4.03 g, 13.2 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and 60% sodium hydride (1.06 g, 26.4 mmol) was added under ice bath. The mixture was stirred overnight at room temperature. Another 60% sodium hydride (0.57 g, 14.1 mmol) was added, and the mixture was reacted for 2 hours. After quenching the reaction with water, the mixture was extracted with dichloromethane, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 3-(2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl (1-2). ESI-MS: m / z = 270 [M+H] + .

[0074] Synthesis step 3. 3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl(1-3) 3-(2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl (3.38 g, 12.5 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and 60% sodium hydride (1.01 g, 25.1 mmol) was added under ice bath. After 5 minutes, the mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. The mixture was again placed in an ice bath, and iodocyclopentane (3.68 g, 18.8 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours to allow the reaction to proceed. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl (1-3). ESI-MS: m / z = 338 [M+H] + .

[0075] Synthesis step 4. 1-Cyclopentyl-3-(piperidine-3-yl)imidazoline-2-one (intermediate 1) 3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-carboxylate tert-butyl (3.38 g, 10 mmol) was dissolved in dioxane (35 mL), and 4N HCl (31 mL) was slowly added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction mixture was reduced under reduced pressure to remove the solvent and obtain 1-cyclopentyl-3-(piperidine-3-yl)imidazolin-2-one (intermediate 1). ESI-MS: m / z = 238 [M+H] + .

[0076] Intermediate 2. 1-(oxetane-3-yl)-3-(piperidine-3-yl)imidazoline-2-one [ka] The synthesis method yielded one intermediate; intermediate 2 was obtained by replacing iodocyclopentane with 3-iodooxetane in synthesis step 3. ESI-MS: m / z = 226 [M+H] + .

[0077] Intermediate 3. 1-Cyclohexyl-3-(piperidine-3-yl)imidazoline-2-one [ka] The synthesis method yielded one intermediate, and intermediate 3 was obtained by replacing iodocyclopentane with iodocyclohexane in synthesis step 3. ESI-MS: m / z = 252 [M+H] + .

[0078] Intermediate 4. 1-(piperidine-3-yl)-3-(tetrahydro-2H-pyran-4-yl)imidazoline-2-one [ka] The synthesis method yielded one intermediate, and intermediate 4 was obtained by replacing iodocyclopentane in synthesis step 3 with 4-iodotetrahydropyran. ESI-MS: m / z = 254 [M+H] + .

[0079] Intermediate 5. 1-Methyl-3-(piperidine-3-yl)imidazoline-2-one [ka] The synthesis method involves one intermediate, and intermediate 5 was obtained by replacing iodocyclopentane with iodomethane in synthesis step 3. ESI-MS: m / z = 184 [M+H] + .

[0080] Intermediate 6. 1-(-2-azabicyclo[2.2.1]heptan-6-yl)-3-methylimidazoline-2-one [ka] The synthesis method is as shown in intermediate 5, where N-Boc-3-aminopiperidine in synthesis step 1 is replaced with tert-butyl 6-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate to obtain intermediate 6:1-(-2-azabicyclo[2.2.1]heptane-6-yl)-3-methylimidazolin-2-one. ESI-MS: m / z = 196 [M+H] + .

[0081] Intermediate 7. 1-(-2-azabicyclo[2.2.1]heptan-6-yl)-3-isopropylimidazoline-2-one [ka] The synthesis method is as shown for intermediate 6. In synthesis step 3, iodomethane was replaced with 2-iodopropane to obtain intermediate 7. ESI-MS: m / z = 224 [M+H] + .

[0082] Intermediate 8. 1-(-2-azabicyclo[2.2.2]octan-6-yl)-3-methylimidazoline-2-one [ka] The synthesis method is as shown in intermediate 5, where N-Boc-3-aminopiperidine in synthesis step 1 is replaced with 6-amino-2-azabicyclo[2.2.2]octane-2-carboxylate tert-butyl to obtain intermediate 8. ESI-MS: m / z = 210 [M+H] + .

[0083] Intermediate 9. 3-Chloro-5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] Intermediate 1: Dissolve 1-cyclopentyl-3-(piperidine-3-yl)imidazolin-2-one (2.38 g, 10 mmol) and N,N-diisopropylethylamine (7 mL) in DMF (20 mL) solution, place in an ice bath, add 3,5-dichloropyrazine-2-carbonitrile (1.74 g, 10 mmol), react for 15 minutes, then react at room temperature for 16 hours. After the reaction is complete, add water, extract with ethyl acetate, combine the organic layers, wash the organic layers twice with water, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter by suction, remove solvent under reduced pressure, and purify by column chromatography to obtain compound 3-chloro-5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile. ESI-MS: m / z = 375 [M+H] + .

[0084] Intermediate 10. 3-Chloro-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9. By replacing intermediate 1 with intermediate 2, intermediate 10 is obtained, resulting in ESI-MS: m / z = 363 [M+H]. + .

[0085] Intermediate 11. 3-Chloro-5-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and by replacing intermediate 1 with intermediate 3, intermediate 11 is obtained, resulting in ESI-MS: m / z = 389 [M+H]. + .

[0086] Intermediate 12. 3-Chloro-5-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and by replacing intermediate 1 with intermediate 4, intermediate 12 is obtained, resulting in ESI-MS: m / z = 391 [M+H]. + .

[0087] Intermediate 13. 3-Chloro-5-(3-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 2-(piperidine-3-yl)hexahydro-3H-pyrrolo[1,2-c]imidazole-3-one to obtain intermediate 13. ESI-MS: m / z = 347 [M+H] + .

[0088] Intermediate 14. 3-Chloro-5-(3-(3-oxohexahydroimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 2-(piperidine-3-yl)hexahydroimidazo[1,5-a]pyridine-3(2H)-one to obtain intermediate 14. ESI-MS: m / z = 361 [M+H] + .

[0089] Intermediate 15. 3-Chloro-5-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 5, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-6-ethylpyrazine-2-carbonitrile to obtain intermediate 15. ESI-MS: m / z = 349 [M+H] + .

[0090] Intermediate 16. 3-Chloro-5-(3-(3-methyl-2-oxohexacyclopenta[d]imidazole-1(2H)-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 1-methyl-3-(piperidine-3-yl)hexahydrocyclopenta[d]imidazole-2(1H)-one to obtain intermediate 16. ESI-MS: m / z = 361 [M+H] + .

[0091] Intermediate 17. 3-Chloro-5-(3-(3-methyl-2-oxooctahydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 1-methyl-3-(piperidine-3-yl)octahydro-2H-benzo[d]imidazole-2-one to obtain intermediate 17. ESI-MS: m / z = 375 [M+H] + .

[0092] Intermediate 18. 3-Chloro-5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 4-methyl-6-(piperidine-3-yl)-4,6-diazaspiro[2.4]heptan-5-one hydrochloride to obtain intermediate 18. ESI-MS: m / z = 347 [M+H] + .

[0093] Intermediate 19. 3-Chloro-5-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 5-methyl-7-(piperidine-3-yl)-5,7-diazaspiro[3.4]octan-6-one hydrochloride to obtain intermediate 19. ESI-MS: m / z = 361 [M+H] + .

[0094] Intermediate 20. 3-Chloro-5-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-methyl-3-(piperidine-3-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one hydrochloride to obtain intermediate 20. ESI-MS: m / z = 369 [M+H] + .

[0095] Intermediate 21. 3-Chloro-5-(3-(3-oxoimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-carbonitrile [ka] The synthesis method is as shown for intermediate 9, and intermediate 1 was replaced with 2-(piperidine-3-yl)imidazo[1,5-a]pyridine-3(2H)-one to obtain intermediate 21. ESI-MS: m / z = 355 [M+H] + .

[0096] Intermediate 22. (5-Chloro-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 5, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 22. ESI-MS: m / z = 322 [M+H] + .

[0097] Intermediate 23. (4-Chloro-2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 5, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 2,4-dichloro-5-cyanopiperidine to obtain intermediate 23. ESI-MS: m / z = 321 [M+H] + .

[0098] Intermediate 24. 2-Chloro-5-fluoro-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-cyanopyridine [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 5, and 3,5-dichloropyrazine-2-carbonitride was replaced with 3-cyano-2,6-dichloro-5-fluoropyridine to obtain intermediate 24. ESI-MS: m / z = 338 [M+H] + .

[0099] Intermediate 25. 2-Chloro-5-methoxy-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-cyanopyridine [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 5, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 2,6-dichloro-5-methoxynicotinonitrile to obtain intermediate 25. ESI-MS: m / z = 350 [M+H] + .

[0100] Intermediate 26. 3-Chloro-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-carbonitrile [ka] The synthesis method was as shown for intermediate 9, with intermediate 1 replaced by intermediate 6 to obtain intermediate 26. ESI-MS: m / z = 333 [M+H] + .

[0101] Intermediate 27. 3-Chloro-5-(-6-(3-isopropyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-carbonitrile [ka] The synthesis method was as shown for intermediate 9, with intermediate 1 replaced by intermediate 7 to obtain intermediate 27. ESI-MS: m / z = 361 [M+H] +.

[0102] Intermediate 28. 2-Chloro-6-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 6, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 2,6-dichloronicotinonitrile to obtain intermediate 28. ESI-MS: m / z = 332 [M+H] + .

[0103] Intermediate 29. 3-Chloro-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)pyrazine-2-carbonitrile [ka] The synthesis method was as shown for intermediate 9, with intermediate 1 replaced by intermediate 8 to obtain intermediate 29. ESI-MS: m / z = 347 [M+H] + .

[0104] Intermediate 30. 5-Chloro-3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 6, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 30. ESI-MS: m / z = 334 [M+H] + .

[0105] Intermediate 31. 5-Chloro-3-(3-(3-ethyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-ethyl-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 31. ESI-MS: m / z = 336 [M+H] + .

[0106] Intermediate 32. 5-Chloro-3-(3-(3-isopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-isopropyl-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 32. ESI-MS: m / z = 350 [M+H] + .

[0107] Intermediate 33. 5-Chloro-3-(3-(2-oxo-3-(trifluoromethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-(piperidine-3-yl)-3-(trifluoromethyl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 33. ESI-MS: m / z = 376 [M+H] + .

[0108] Intermediate 34. 5-Chloro-3-(3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, where intermediate 1 is replaced with 1-(piperidine-3-yl)-3-(2,2,2-trifluoroethyl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile is replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 34. ESI-MS: m / z = 390 [M+H] + .

[0109] Intermediate 35. 5-Chloro-3-(3-(3-cyclopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, where intermediate 1 is replaced with 1-cyclopropyl-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile is replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 35. ESI-MS: m / z = 348 [M+H] + .

[0110] Intermediate 36. 5-Chloro-3-(3-(3-cyclobutyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-cyclobutyl-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 36. ESI-MS: m / z = 362 [M+H] + .

[0111] Intermediate 37. 5-Chloro-3-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, with 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 37. ESI-MS: m / z = 376 [M+H] + .

[0112] Intermediate 38. 5-Chloro-3-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 3, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 38. ESI-MS: m / z = 390 [M+H] + .

[0113] Intermediate 39. 5-Chloro-3-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 2, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 39. ESI-MS: m / z = 364 [M+H] + .

[0114] Intermediate 40. 5-Chloro-3-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 4, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 40. ESI-MS: m / z = 392 [M+H] + .

[0115] Intermediate 41. 5-Chloro-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, where intermediate 1 is replaced with 1-phenyl-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile is replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 41. ESI-MS: m / z = 384 [M+H]+ .

[0116] Intermediate 42. 5-Chloro-3-(3-(2-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 1-(2-fluorophenyl)-3-(piperidine-3-yl)imidazolin-2-one and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 42. ESI-MS: m / z = 402 [M+H] + .

[0117] Intermediate 43. 5-Chloro-3-(3-(3-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, where intermediate 1 is replaced with 1-(3-fluorophenyl)-3-(piperidine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile is replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 43. ESI-MS: m / z = 402 [M+H] + .

[0118] Intermediate 44. 5-Chloro-3-(3-(2-oxo-3-(pyridine-3-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9. Intermediate 1 was replaced with 1-(piperidine-3-yl)-3-(pyridine-3-yl)imidazolin-2-one, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 44. ESI-MS: m / z = 385 [M+H] + .

[0119] Intermediate 45. 5-Chloro-3-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, where intermediate 1 is replaced with 4-methyl-6-(piperidine-3-yl)-4,6-diazaspiro[2.4]heptan-5-one hydrochloride, and 3,5-dichloropyrazine-2-carbonitrile is replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 45. ESI-MS: m / z = 348 [M+H] + .

[0120] Intermediate 46. 5-Chloro-3-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 5-methyl-7-(piperidine-3-yl)-5,7-diazaspiro[3.4]octan-6-one hydrochloride and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 46. ESI-MS: m / z = 362 [M+H] + .

[0121] Intermediate 47. 5-Chloro-3-(3-(3-oxotrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 2-(piperidine-3-yl)hexahydro-3H-pyrrolo[1,2-c]imidazole-3-one and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 47. ESI-MS: m / z = 348 [M+H] + .

[0122] Intermediate 48. 5-Chloro-3-(6-(3-cyclopentyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 1-(2-azabicyclo[2.2.1]heptan-6-yl)-3-cyclopentylimidazoline-2-one and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 48. ESI-MS: m / z = 388 [M+H] + .

[0123] Intermediate 49. 5-Chloro-3-(6-(2-oxo-3-phenylimidazoline-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 1-(2-azabicyclo[2.2.1]heptan-6-yl)-3-phenylimidazolin-2-one and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 49. ESI-MS: m / z = 396 [M+H] + .

[0124] Intermediate 50. 5-Chloro-3-(6-(3-oxotrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method is as shown for intermediate 9, with intermediate 1 replaced by 2-(2-azabicyclo[2.2.1]heptan-6-yl)hexahydro-3H-pyrrolo[1,2-c]imidazole-3-one, and 3,5-dichloropyrazine-2-carbonitrile replaced by 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 50. ESI-MS: m / z = 360 [M+H] + .

[0125] Intermediate 51. 5-Chloro-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)-1,2,4-triazine-6-carbonitrile [ka] The synthesis method was as shown for intermediate 9, but intermediate 1 was replaced with intermediate 8, and 3,5-dichloropyrazine-2-carbonitrile was replaced with 3,5-dichloro-1,2,4-triazine-6-nitrile to obtain intermediate 51. ESI-MS: m / z = 348 [M+H] + .

[0126] Intermediate 52. 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate tert-butyl [ka] Synthesis Step 1. N-Ethoxycarbonyl-4-hydroxy-4-methylpiperidine (52-1) N-ethoxycarbonyl-4-piperidone (10.00 g, 58.41 mmol) was dissolved in ether solution and cooled to -30°C. 3M methylmagnesium chloride (5.24 g, 70.1 mmol) THF solution was added, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added, and the mixture was filtered to remove the white solid. The aqueous layer was extracted with dichloromethane, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. Purification by column chromatography yielded the target compound, N-ethoxycarbonyl-4-hydroxy-4-methylpiperidine (52-1). ESI-MS: m / z = 188 [M+H] + .

[0127] Synthesis Step 2. N-Ethoxycarbonyl-4-(4-bromophenyl)-4-methylpiperidine(52-2) N-ethoxycarbonyl-4-hydroxy-4-methylpiperidine (3.08 g, 16.45 mmol) and 4-bromobenzene (25.83 g, 164.50 mmol) were placed in an ice bath at 0°C, and trifluoromethanesulfonic acid (24.69 g, 164.50 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 3 hours. After the reaction was complete, the reactants were added to ice water, alkalized with 1N NaOH, extracted three times with dichloromethane, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain the compound N-ethoxycarbonyl-4-(4-bromophenyl)-4-methylpiperidine (52-2). ESI-MS: m / z = 326 [M+H] + .

[0128] Synthesis step 3. 4-(4-bromophenyl)-4-methylpiperidine(52-3) N-ethoxycarbonyl-4-(4-bromophenyl)-4-methylpiperidine (7.00 g, 21.46 mmol) was dissolved in ethanol (20 mL), potassium hydroxide (24.08 g, 429.14 mmol) was added, and the mixture was reacted overnight at 80°C. After the reaction was complete, the mixture was distilled under reduced pressure to obtain the residue. The obtained residue was dissolved in dichloromethane solution, washed with water, extracted with dichloromethane, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The mixture was then used directly in the next step of the reaction. ESI-MS: m / z = 254 [M+H] + .

[0129] Synthesis step 4. 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate tert-butyl(52-4) Compound 4-(4-bromophenyl)-4-methylpiperidine (5.40 g, 21.25 mmol) was dissolved in dichloromethane (50 mL), and Boc anhydride (7.42 g, 33.99 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, water was added, and dichloromethane was added for extraction. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate tert-butyl (52-4). ESI-MS: m / z = 354 [M+H] + .

[0130] Synthesis step 5. 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate tert-butyl (intermediate 52) Under the protection of nitrogen gas, the compounds N-Boc-4-(4-bromophenyl)-4-methylpiperidine (2.60 g, 7.34 mmol), 2-(dicyclohexylphosphino))biphenyl (65.00 mg, 0.19 mmol), tri(dibenzylideneacetone)dipalladium (68.00 mg, 0.07 mmol), and LiHMDS (14.70 mL) were dissolved in anhydrous THF (15 mL) and reacted overnight at 65°C. After the reaction was complete, dichloromethane was added for extraction, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. Purification by column chromatography yielded compound 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate tert-butyl (intermediate 52). ESI-MS: m / z = 291 [M+H] + .

[0131] Intermediate 53. 4-(4-aminophenyl)piperazine-1-carboxylate tert-butyl [ka] Synthesis Step 1. 4-(4-nitrophenyl)piperazine-1-carboxylate tert-butyl(53-1) p-fluoronitrobenzene (1.41 g, 10 mmol), N,N-diisopropylethylamine (6.46 g, 50 mmol), and 1-Boc-piperazine (1.86 g, 10 mmol) were dissolved in DMF (20 mL), heated to 90°C, and stirred overnight to allow the reaction to proceed. Water was added, the mixture was extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 4-(4-nitrophenyl)piperazine-1-carboxylate tert-butyl (53-1). ESI-MS: m / z = 308 [M+H] + .

[0132] Synthesis Step 2. 4-(4-aminophenyl)piperazine-1-carboxylate tert-butyl (intermediate 53) Compound 4-(4-nitrophenyl)piperazine-1-carboxylate tert-butyl (1.54 g, 5 mmol) was dissolved in ethanol (20 mL), Pd / C (154 mg) was added, and the reaction was carried out under H2 conditions at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethyl acetate and methanol, the organic layers were combined, and the solvent was removed under reduced pressure to directly obtain the product 4-(4-aminophenyl)piperazine-1-carboxylate tert-butyl (intermediate 53). ESI-MS: m / z = 278 [M+H] + .

[0133] Intermediate 54. 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undeca-3-carboxylate tert-butyl [ka] The synthesis method is as shown for intermediate 53, but intermediate 54 was obtained by replacing 1-Boc-piperazine in synthesis step 1 with 3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl. ESI-MS: m / z = 346 [M+H] + .

[0134] Intermediate 55. 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl [ka] The synthesis method is as shown for intermediate 53, but intermediate 55 was obtained by replacing 1-Boc-piperazine in synthesis step 1 with 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl. ESI-MS: m / z = 290 [M+H] + .

[0135] Intermediate 56. 7-(4-aminophenyl)-7-azaspiro[3.5]non-2-one [ka] The synthesis method is as shown for intermediate 53, but intermediate 56 was obtained by replacing 1-Boc-piperazine (1 mmol) in synthesis step 1 with 7-azaspiro[3.5]nonan-2-one. ESI-MS: m / z = 231 [M+H] + .

[0136] Intermediate 57. 4-(4-aminobenzoyl)piperidine-1-carboxylate tert-butyl [ka] Synthesis Step 1. 4-(4-bromobenzeneformyl)piperidine-1-carboxylate tert-butyl(57-1) The compound bromobenzene (1.57 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) solution, 4-(chlorocarbonyl)-piperidine-1-carboxylate tert-butyl (2.97 g, 12 mmol) was added, and aluminum trichloride (1.33 g, 10 mmol) was added. The mixture was heated to 70°C and reacted for 10 hours. After the reaction was complete, the reaction mixture was slowly added to a 3 M HCl solution, extracted with ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 4-(4-bromobenzeneformyl)piperidine-1-carboxylate tert-butyl (57-1). ESI-MS: m / z = 368 [M+H] + .

[0137] Synthesis Step 2. 4-(4-aminobenzoyl)piperidine-1-carboxylate tert-butyl (intermediate 57) The synthesis method was the same as in step 5 of the synthesis of intermediate 31, but 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate tert-butyl was replaced with 4-(4-bromobenzeneformyl)piperidine-1-carboxylate tert-butyl to obtain intermediate 57. ESI-MS: m / z = 305 [M+H] + .

[0138] Intermediate 58. 4-(4-aminophenyl)piperidine-1-carboxylate tert-butyl [ka] Synthesis Step 1. 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl(58-1) 1-Bromo-4-nitrobenzene (2.02 g, 10 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-pyrazoleboronic acid pinacol ester (3.71 g, 12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (731.7 mg, 1 mmol), and potassium carbonate (4.15 g, 30 mmol) were dissolved in dioxane and aqueous solution. The reaction was carried out under reflux for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound (58-1). ESI-MS: m / z = 305 [M+H] + .

[0139] Synthesis Step 2. 4-(4-aminophenyl)piperidine-1-carboxylate tert-butyl (intermediate 58) Compound 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (3.05 g, 10 mmol) was dissolved in an ethanol-DMF mixture (volume ratio 1:1, 20 ml) and stirred at room temperature for 24 hours under an atmosphere of 10% palladium carbon (305 mg) and hydrogen gas. After the reaction was complete, the mixture was filtered, the solvent was removed under reduced pressure, and the compound (intermediate 58) was purified by column chromatography. ESI-MS: m / z = 277 [M+H] + .

[0140] Intermediate 59. 4-(4-aminophenyl)-4-fluoropiperidine-1-carboxylate tert-butyl [ka] Synthesis Step 1. 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate tert-butyl(59-1) Under the protection of nitrogen gas, p-bromoiodobenzene (2.83 g, 10 mmol) was dissolved in anhydrous THF (20 mL), and the mixture was placed in an environment of -78°C. N-butyllithium THF solution (1.92 g, 30 mmol) was added dropwise, and the mixture was reacted at -78°C for 2 hours. Then, N-tert-butoxycarbonyl-4-piperidone THF solution (2.40 g, 12 mmol) was added dropwise, and the mixture was reacted at -78°C for 2 hours. After the reaction was complete, water was added to quench the reaction, ethyl acetate was added for extraction, and the organic layers were combined. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound (59-1). ESI-MS: m / z = 356 [M+H] + .

[0141] Synthesis step 2. 4-(4-bromophenyl)-4-fluoropiperidine-1-carboxylate tert-butyl(59-2) 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate tert-butyl (3.56 g, 10 mmol) was dissolved in anhydrous dichloromethane (30 mL), and the mixture was placed in an environment of -78°C. Bis(2-methoxyethyl)aminosulfur trifluoride (11.06 g, 50 mmol) was added, and the mixture was transferred to an environment of room temperature and reacted for 72 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, and dichloromethane was added for extraction. The organic phases were combined, the solvent was removed under reduced pressure, and the compound was purified by column chromatography to obtain compound (59-2). ESI-MS: m / z = 358 [M+H] + .

[0142] Synthesis step 3. 4-(4-aminophenyl)-4-fluoropiperidine-1-carboxylate tert-butyl (intermediate 59) The synthesis method was as shown for intermediate 52, and intermediate 59 was obtained by replacing N-Boc-4-(4-bromophenyl)-4-methylpiperidine with compound 59-2 in synthesis step 5. ESI-MS: m / z = 295 [M+H] + .

[0143] Intermediate 60. 4-(4-amino-3-fluorophenyl)piperidine-1-carboxylate tert-butyl [ka] The synthesis method is as shown for intermediate 58, but intermediate 60 was obtained by replacing 1-bromo-4-nitrobenzene with 2-fluoro-4-bromonitrobenzene in synthesis step 1. ESI-MS: m / z = 295 [M+H] + .

[0144] Intermediate 61. 4-(4-amino-2-cyanophenyl)piperidine-1-carboxylate tert-butyl [ka] The synthesis method is as shown in intermediate 58, where 1-bromo-4-nitrobenzene in synthesis step 1 is replaced with 2-bromo-5-nitrobenzenecarbonitride to obtain intermediate 61. ESI-MS: m / z = 302 [M+H] + .

[0145] Intermediate 62. 4-(4-aminophenyl)-3-fluoropiperidine-1-carboxylate tert-butyl [ka] Synthesis Step 1. 3-Hydroxy-4-(4-nitrophenyl)piperidine-1-carboxylate tert-butyl(62-1) Under a nitrogen atmosphere, compound 58-1 (2.44 g, 8 mmol) is dissolved in anhydrous ethylene glycol dimethyl ether (12 mL), and the mixture is left at 0°C. Sodium borohydride (484.2 mg, 12.8 mmol) is added, and the mixture is stirred and reacted for 5 minutes. Ethyl boron trifluoride (2.27 g, 16 mmol) is added dropwise, and the mixture is stirred overnight at room temperature. The reaction mixture is left at 0°C, water is added until boiling stops, 10 M sodium hydroxide aqueous solution (5 mL) is added, and hydrogen peroxide (5 mL) is added dropwise. The mixture is then heated to room temperature and stirred for 2 hours. After dilution with water, the mixture is extracted with ethyl acetate, the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The mixture is purified by column chromatography to obtain compound (62-1). ESI-MS: m / z = 323 [M+H] + .

[0146] Synthesis step 2. 3-Fluoro-4-(4-nitrophenyl)piperidine-1-carboxylate tert-butyl(62-2) Compound 62-1 (2.26 g, 7 mmol) was dissolved in 1,2-dichloroethane (15 mL), and the reaction mixture was placed at 0°C. Diethylamine sulfur trifluoride (5.64 g, 35 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic layers were combined. The organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain compound (62-2). ESI-MS: m / z = 325 [M+H] + .

[0147] Synthesis step 3. 4-(4-aminophenyl)-3-fluoropiperidine-1-carboxylate tert-butyl (intermediate 62) Compound 62-2 (1.95 g, 6 mmol) was dissolved in methanol (12 mL), 10% palladium carbon (195 mg) was added, hydrogen gas was introduced, and the mixture was reacted overnight under a pressure of 3 atm. After the reaction was complete, the mixture was filtered, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound (intermediate 62). ESI-MS: m / z = 295 [M+H] + .

[0148] Intermediate 63. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] Synthesis Step 1. 4-(4-((3-cyano-6-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-4-methylpiperidine-1-carboxylate tert-butyl(63-1) Intermediate 9 (3.75 g, 10 mmol), intermediate 52 (2.91 g, 10 mmol), cesium carbonate (9.78 g, 30 mmol), BINAP (622.69 mg, 1 mmol), and Pd2(bda)3 (1.02 g, 1 mmol) were dissolved in dioxane (25 mL), refluxed, and stirred for 3 hours to allow the reaction to proceed. After the reaction was complete, the mixture was filtered, the solid was washed with dichloromethane solution, the organic layers were combined, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain compound (63-1). ESI-MS: m / z = 629 [M+H] + .

[0149] Synthesis Step 2. 4-(4-((3-carbamoyl-6-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-4-methylpiperidine-1-carboxylate tert-butyl(63-2) 4-(4-((3-cyano-6-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-4-methylpiperidine-1-carboxylate tert-butyl (6.29 g, 10 mmol) was dissolved in a mixed solvent of methanol and DMSO (1:1, 50 mL), cesium carbonate (1.63 g, 5 mmol) was added, and 30% H2O2 (10 mL) was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, acetonitrile solution was added and the mixture was stirred for 5 min. The mixture was then distilled under reduced pressure, the residue was dissolved in ethyl acetate solution, washed three times with water, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain compound (63-2). ESI-MS: m / z = 647 [M+H] + .

[0150] Synthesis Step 3. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide (intermediate 63) 4-(4-((3-carbamoyl-6-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-yl)amino)phenyl)-4-methylpiperidine-1-carboxylate (3.24 g, 5 mmol) was dissolved in dioxane (15 mL), and 4N HCl (16 mL) was added dropwise under ice bath conditions. The mixture was then transferred to room temperature and allowed to react for 30 minutes. After the reaction was complete, the reaction mixture was distilled under reduced pressure to obtain intermediate 63. ESI-MS: m / z = 547 [M+H] + .

[0151] Intermediate 64. 3-((4-(4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 10 to obtain intermediate 64. ESI-MS: m / z = 535 [M+H] + .

[0152] Intermediate 65. 5-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 11 to obtain intermediate 65. ESI-MS: m / z = 561 [M+H] + .

[0153] Intermediate 66. 3-((4-(4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 12 to obtain intermediate 66. ESI-MS: m / z = 563 [M+H] + .

[0154] Intermediate 67. 3-((4-(4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 13 to obtain intermediate 67. ESI-MS: m / z = 519 [M+H] + .

[0155] Intermediate 68. 3-((4-(4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxohexahydroimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, and intermediate 9 in synthesis step 1 is replaced with intermediate 14 to obtain intermediate 68. ESI-MS: m / z = 533 [M+H] + .

[0156] Intermediate 69. 5-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 15 to obtain intermediate 69. ESI-MS: m / z = 521 [M+H] + .

[0157] Intermediate 70. 5-(3-(3-methyl-2-oxohexahydrocyclopenta[d]imidazole-1(2H)-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide) [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 16 to obtain intermediate 70. ESI-MS: m / z = 533 [M+H] + .

[0158] Intermediate 71. 5-(3-(3-methyl-2-oxooctahydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 17 to obtain intermediate 71. ESI-MS: m / z = 547 [M+H] + .

[0159] Intermediate 72. 5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2.4]heptan-6-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 18 to obtain intermediate 72. ESI-MS: m / z = 519 [M+H] + .

[0160] Intermediate 73. 5-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 19 to obtain intermediate 73. ESI-MS: m / z = 533 [M+H] + .

[0161] Intermediate 74. 5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(piperazine-1-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 64, and intermediate 52 in synthesis step 1 is replaced with intermediate 53 to obtain intermediate 74. ESI-MS: m / z = 522 [M+H] + .

[0162] Intermediate 75. 3-((4-(3,9-diazaspiro[5.5]undecane-3-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 64. Intermediate 52 in synthesis step 1 is replaced with intermediate 54 to obtain intermediate 75. ESI-MS: m / z = 590 [M+H] + .

[0163] Intermediate 76. 3-((4-(2,6-diazaspiro[3,3]heptan-2-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 64, and intermediate 52 in synthesis step 1 is replaced with intermediate 55 to obtain intermediate 76. ESI-MS: m / z = 534 [M+H] + .

[0164] Intermediate 77. 5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(2-oxo-7-azaspiro[3.5]non-7-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 64, but intermediate 52 in synthesis step 1 is replaced with intermediate 56, and step 3 is omitted to obtain intermediate 77. ESI-MS: m / z = 575 [M+H] + .

[0165] Intermediate 78. 5-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)-3-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 20 to obtain intermediate 78. ESI-MS: m / z = 541 [M+H] + .

[0166] Intermediate 79. 3-((4-(4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxoimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 21 to obtain intermediate 79. ESI-MS: m / z = 527 [M+H] + .

[0167] Intermediate 80. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, and intermediate 52 in synthesis step 1 is replaced with intermediate 58 to obtain intermediate 80. ESI-MS: m / z = 533 [M+H] + .

[0168] Intermediate 81. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(piperidine-4-carbonyl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, and intermediate 52 in synthesis step 1 is replaced with intermediate 57 to obtain intermediate 81. ESI-MS: m / z = 561 [M+H] + .

[0169] Preparation of intermediate 82. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-fluorophenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 52 in synthesis step 1 is replaced with 4-fluoroaniline, and step 3 is omitted to obtain intermediate 82. ESI-MS: m / z = 468 [M+H] +.

[0170] Intermediate 83. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 52 in synthesis step 1 is replaced with 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl to obtain intermediate 83. ESI-MS: m / z = 505 [M+H] + .

[0171] Intermediate 84. 5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 64, where intermediate 52 in synthesis step 1 is replaced with 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl to obtain intermediate 84. ESI-MS: m / z = 493 [M+H] + .

[0172] Intermediate 85. 3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(4-methylpiperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 22 to obtain intermediate 85. ESI-MS: m / z = 494 [M+H] + .

[0173] Intermediate 86. 2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-4-((4-(4-methylpiperidine-4-yl)phenyl)amino)pyrimidine-5-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 23 to obtain intermediate 86. ESI-MS: m / z = 493 [M+H] + .

[0174] Intermediate 87. 5-Fluoro-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-2-((4-(4-methylpiperidine-4-yl)phenyl)amino)nicotinamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 24 to obtain intermediate 87. ESI-MS: m / z = 510 [M+H] + .

[0175] Intermediate 88. 5-Methoxy-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-2-((4-(4-methylpiperidine-4-yl)phenyl)amino)nicotinamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 25 to obtain intermediate 88. ESI-MS: m / z = 522 [M+H] + .

[0176] Intermediate 89. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, and intermediate 52 in synthesis step 1 is replaced with intermediate 59 to obtain intermediate 89. ESI-MS: m / z = 551 [M+H] + .

[0177] Intermediate 90. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((2-fluoro-4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 52 in synthesis step 1 is replaced with intermediate 60 to obtain intermediate 90. ESI-MS: m / z = 551 [M+H] + .

[0178] Intermediate 91. 3-((3-cyano-4-(piperidine-4-yl)phenyl)amino)-5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, and intermediate 52 in synthesis step 1 is replaced with intermediate 61 to obtain intermediate 91. ESI-MS: m / z = 558 [M+H] + .

[0179] Intermediate 92. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(3-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63. Intermediate 52 in synthesis step 1 is replaced with intermediate 62 to obtain intermediate 92. ESI-MS: m / z = 551 [M+H] + .

[0180] Intermediate 93. 5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 18, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 93. ESI-MS: m / z = 505 [M+H] + .

[0181] Intermediate 94. 5-(3-(3-oxohexahydroimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 14, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 94. ESI-MS: m / z = 505 [M+H] + .

[0182] Intermediate 95. 5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63. In synthesis step 1, intermediate 9 is replaced with intermediate 26, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 95. ESI-MS: m / z = 491 [M+H] + .

[0183] Intermediate 96. 5-(-6-(3-isopropyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 27, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 96. ESI-MS: m / z = 519 [M+H] + .

[0184] Intermediate 97. 6-(-6-(3-methyl-2-oxyimidazoline-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-((4-(piperidine-4-yl)phenyl)amino)nicotinamide [ka] The synthesis method is as shown for intermediate 63. In synthesis step 1, intermediate 9 is replaced with intermediate 28, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 97. ESI-MS: m / z = 490 [M+H] + .

[0185] Intermediate 98. 3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 30, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 98. ESI-MS: m / z = 492 [M+H] + .

[0186] Intermediate 99. 5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)-3-((4-(piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method is as shown for intermediate 63, where intermediate 9 in synthesis step 1 is replaced with intermediate 29, and intermediate 52 is replaced with intermediate 58 to obtain intermediate 99. ESI-MS: m / z = 505 [M+H] + .

[0187] Intermediate 100. 3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 22, and intermediate 52 is replaced with intermediate 58. Intermediate 100 was obtained. ESI-MS: m / z = 480 [M+H] + .

[0188] Intermediate 101. 3-(3-(3-ethyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as shown for intermediate 63. Intermediate 9 in synthesis step 1 was replaced with intermediate 31, and intermediate 52 was replaced with 58 to obtain intermediate 101. ESI-MS: m / z = 494 [M+H] + .

[0189] Intermediate 102. 3-(3-(3-isopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 32, and intermediate 52 is replaced with intermediate 58. Intermediate 102 was obtained. ESI-MS: m / z = 508 [M+H] + .

[0190] Intermediate 103. 3-(3-(2-oxo-3-(trifluoromethyl)imidazoline-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 33, and intermediate 52 is replaced with intermediate 58. Intermediate 103 was obtained. ESI-MS: m / z = 534 [M+H] + .

[0191] Intermediate 104. 3-(3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 34, and intermediate 52 is replaced with intermediate 58. Intermediate 104 was obtained. ESI-MS: m / z = 548 [M+H] + .

[0192] Intermediate 105. 3-(3-(3-cyclopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 35, and intermediate 52 is replaced with intermediate 58. Intermediate 105 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0193] Intermediate 106. 3-(3-(3-cyclobutyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 36, and intermediate 52 is replaced with intermediate 58. Intermediate 106 was obtained. ESI-MS: m / z = 520 [M+H] + .

[0194] Intermediate 107. 3-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 37, and intermediate 52 is replaced with intermediate 58. Intermediate 107 was obtained. ESI-MS: m / z = 534 [M+H] + .

[0195] Intermediate 108. 3-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 38, and intermediate 52 is replaced with intermediate 58. Intermediate 108 is obtained. ESI-MS: m / z = 548 [M+H] + .

[0196] Intermediate 109. 3-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 39, and intermediate 52 is replaced with intermediate 58. Intermediate 109 was obtained. ESI-MS: m / z = 522 [M+H] + .

[0197] Intermediate 110. 3-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 40, and intermediate 52 is replaced with intermediate 58. Intermediate 110 was obtained. ESI-MS: m / z = 550 [M+H] + .

[0198] Intermediate 111. 3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 41, and intermediate 52 is replaced with intermediate 58. Intermediate 111 was obtained. ESI-MS: m / z = 542 [M+H] ++ .

[0199] Intermediate 112. 3-(3-(3-(2-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 42, and intermediate 52 is replaced with intermediate 58. Intermediate 112 was obtained. ESI-MS: m / z = 560 [M+H] + .

[0200] Intermediate 113. 3-(3-(3-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 43, and intermediate 52 is replaced with intermediate 58. Intermediate 113 was obtained. ESI-MS: m / z = 560 [M+H] + .

[0201] Intermediate 114. 3-(3-(2-oxo-3-(pyridine-3-yl)imidazoline-1-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 44, and intermediate 52 is replaced with intermediate 58. Intermediate 114 was obtained. ESI-MS: m / z = 543 [M+H] + .

[0202] Intermediate 115. 3-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 45, and intermediate 52 is replaced with intermediate 58. Intermediate 115 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0203] Intermediate 116. 3-(3-(5-methyl-6-oxo-5,7-diazaspiro[3,4]octan-7-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 46, and intermediate 52 is replaced with intermediate 58. Intermediate 116 was obtained. ESI-MS: m / z = 520 [M+H] + .

[0204] Intermediate 117. 3-(3-(3-oxotrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 47, and intermediate 52 is replaced with intermediate 58. Intermediate 117 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0205] Intermediate 118. 3-(6-(3-cyclopentyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 48, and intermediate 52 is replaced with intermediate 58. Intermediate 118 was obtained. ESI-MS: m / z = 546 [M+H] + .

[0206] Intermediate 119. 3-(6-(2-oxo-3-phenylimidazoline-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 49, and intermediate 52 is replaced with intermediate 58. Intermediate 119 was obtained. ESI-MS: m / z = 554 [M+H] + .

[0207] Intermediate 120. 3-(6-(3-oxotrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 50, and intermediate 52 is replaced with 58. Intermediate 120 was obtained. ESI-MS: m / z = 518 [M+H] + .

[0208] Intermediate 121. 3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)-5-((4-(piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 51, and intermediate 52 is replaced with 58. Intermediate 121 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0209] Intermediate 122. 3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 22, and intermediate 52 is replaced with tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate. Intermediate 122 was obtained. ESI-MS: m / z = 452 [M+H] + .

[0210] Intermediate 123. 3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(piperazine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 22, and intermediate 52 is replaced with intermediate 53. Intermediate 123 was obtained. ESI-MS: m / z = 481 [M+H] + .

[0211] Intermediate 124. 3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-(4-oxopiperidine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 22, and intermediate 52 is replaced with 1-(4-aminophenyl)piperidine-4-one. Intermediate 124 was obtained. ESI-MS: m / z = 494 [M+H] + .

[0212] Intermediate 125. 5-((4-(4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 41. Intermediate 125 was obtained. ESI-MS: m / z = 556 [M+H] + .

[0213] Intermediate 126. 3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-5-((1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 41. Intermediate 52 is replaced with 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl. Intermediate 126 is obtained. ESI-MS: m / z = 514 [M+H] + .

[0214] Intermediate 127. 3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-5-((4-(piperazine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, replacing intermediate 9 in synthesis step 1 with intermediate 41. Intermediate 52 is replaced with intermediate 53. Intermediate 127 is obtained. ESI-MS: m / z = 543 [M+H] + .

[0215] Intermediate 128. 3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-5-((4-(4-oxopiperidine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 41. Intermediate 52 is replaced with 1-(4-aminophenyl)piperidine-4-one. Intermediate 128 was obtained. ESI-MS: m / z = 556 [M+H] + .

[0216] Intermediate 129. 3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(4-methylpiperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 30. Intermediate 129 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0217] Intermediate 130. 3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 30, and intermediate 52 is replaced with tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate. Intermediate 130 was obtained. ESI-MS: m / z = 464 [M+H] + .

[0218] Intermediate 131. 3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(piperazine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 30, and intermediate 52 is replaced with intermediate 53. Intermediate 131 was obtained. ESI-MS: m / z = 493 [M+H] + .

[0219] Intermediate 132. 3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-(4-oxopiperidine-1-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method is as shown for intermediate 63, but intermediate 9 in synthesis step 1 is replaced with intermediate 30, and intermediate 52 is replaced with 1-(4-aminophenyl)piperidine-4-one. Intermediate 132 was obtained. ESI-MS: m / z = 506 [M+H] + .

[0220] Intermediate 133. 2-(2,6-dioxopiperidine-3-yl)-5-(3-oxoazetidine-1-yl)isoindole-1,3-dione [ka] Synthesis Step 1. Synthesis of 2-(2,6-dioxo-piperidine-3-yl)-5-fluoroisoindole-1,3-dione (133-1) 4-Fluorophthalic anhydride (2.257 g, 13.59 mmol) was dissolved in 50 mL of glacial acetic acid. 3-Aminopiperidine-2,6-dione hydrochloride (2.46 g, 14.95 mmol) and potassium acetate (4.14 g, 42.18 mmol) were added, and the mixture was heated to 90°C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, 120 mL of water was added, and the mixture was treated with an ice bath for 40 minutes. A large amount of white solid precipitated, which was filtered by suction. The solid was washed with methanol, and the filter cake was dried to obtain the crude product. The crude product was purified by column chromatography to obtain 3.05 g of a white solid (133-1) with a yield of 81.25%. ESI-MS: m / z = 277 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.02 (dd, J = 8.3, 4.5 Hz, 1H), 7.86 (dd, J = 7.5, 2.3 Hz, 1H), 7.73 (ddd, J = 9.3, 8.2, 2.3 Hz, 1H), 5.18 (dd, J = 12.9, 5.4 Hz, 1H), 2.90 (ddd, J = 17.1, 13.9, 5.4 Hz, 1H), 2.70 - 2.52 (m, 2H), 2.08 (dtd, J = 13.0, 5.4, 2.3 Hz, 1H).

[0221] Synthesis step 2. 2-(2,6-dioxopiperidine-3-yl)-5-(3-oxoazetidine-1-yl)isoindole-1,3-dione (intermediate 133) 2-(2,6-dioxo-piperidine-3-yl)-5-fluoroisoindole-1,3-dione (663 mg, 2.40 mmol) was dissolved in 10 mL of DMSO, and azetidine-3-one hydrochloride (171 mg, 2.40 mmol) and 836 μl of DIPEA were added. The mixture was reacted overnight at 90°C. After the reaction was complete, 10 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. Purification by column chromatography yielded 79-668 mg of a yellow solid intermediate, with a yield of 85.0%, yielding intermediate 133. ESI-MS: m / z = 328 [M+H] + .

[0222] Intermediate 134: 2-(2,6-dioxopiperidine-3-yl)-5-(4-oxopiperidine-1-yl)isoindole-1,3-dione [ka] The synthesis method involves one intermediate and 33 combinations. In synthesis step 1, azetidine-3-one hydrochloride is replaced with piperidine-4-one to obtain intermediate 134. ESI-MS: m / z = 356[M+H] + .

[0223] Intermediate 135. 3-(1-oxo-5-(4-oxopiperidine-1-yl)isoindole-2-yl)piperidine-2,6-dione [ka] Synthesis Step 1. 5-(4-(dimethoxymethyl)piperidine-1-yl)isobenzofuran-1(3H)-one(135-1) 5-bromophthalide (1.0 g, 4.70 mmol), 4-(dimethoxymethyl)piperidine (1.20 g, 7.04 mol), potassium phosphate (2.99 g, 14.09 mmol), and ethylene glycol dimethyl ether (15 mL) were substituted three times with nitrogen gas. Tri(dibenzylideneacetone)dipalladium (860 mg, 0.94 mmol) and (±)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (535 mg, 0.94 mmol) were added sequentially to a 100 mL two-necked flask and reacted at 80°C for 16 hours. A saturated sodium chloride (60 mL) aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain product (135-1). ESI-MS: m / z = 292[M+H] + .

[0224] Synthesis step 2. 4-(4-(dimethoxymethyl)piperidine-1-yl)-2-(hydroxymethyl)benzoic acid (135-2) 5-(4-(dimethoxymethyl)piperidine-1-yl)isobenzofuran-1(3H)-one (943 mg, 3.23 mmol) was added to a mixed solvent (3 mL tetrahydrofuran, 3 mL methanol, 3 mL water), and sodium hydroxide (387 mg, 9.68 mmol) was added under an ice bath. The mixture was stirred for 1 hour at 25°C, and the completion of the reaction was monitored by TLC. The pH was adjusted to 4-5 with 1 M dilute hydrochloric acid, extracted with ethyl acetate, and the solvent was removed under reduced pressure. The product (135-2) was purified by column chromatography. ESI-MS: m / z = 310[M+H] + .

[0225] Synthesis step 3. 4-(4-(dimethoxymethyl)piperidine-1-yl)-2-(hydroxymethyl)methyl benzoate (135-3) 4-(4-(dimethoxymethyl)piperidine-1-yl)-2-(hydroxymethyl)benzoic acid (738 mg, 2.38 mmol) was dissolved in a mixed solvent of 5 mL methanol and 5 mL ethyl acetate. Under conditions of -10°C, trimethylsilyldiazomethane (2 M, 3.58 ml) was added, and the reaction was stirred for 30 minutes under conditions of -10°C. The reaction was monitored by TLC, and after completion, the reaction was quenched with ice water (30 mL), extracted with ethyl acetate (10 ml x 3), and purified by column chromatography to obtain product (135-3). ESI-MS: m / z = 324 [M + H] + .

[0226] Synthesis step 4. 2-(bromomethyl)-4-(4-(dimethoxymethyl)piperidine-1-yl)methyl benzoate (135-4) 693 mg, 2.14 mmol of 4-(4-(dimethoxymethyl)piperidine-1-yl)-2-(hydroxymethyl)methyl benzoate was dissolved in 10 mL of tetrahydrofuran. Triphenylphosphine (842 mg, 3.21 mmol) and carbon tetrabromide (1.06 g, 3.21 mmol) were added sequentially, and the mixture was stirred for 1 hour at 25°C. The reaction was monitored by TLC, and the reaction was quenched with 20 mL of ice water. The mixture was extracted with ethyl acetate, the organic phases were combined, the solvent was removed under reduced pressure, and the product (135-4) was purified by column chromatography. ESI-MS: m / z = 386 [M+H] + .

[0227] Synthesis step 5. 3-(5-(4-(dimethoxymethyl)piperidine-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione (135-5) 2-(bromomethyl)-4-(4-(dimethoxymethyl)piperidine-1-yl)methyl benzoate (432 mg, 1.12 mmol) was dissolved in 10 mL of acetonitrile solvent. Then, 3-aminopiperidine-2,6-dione hydrochloride (276 mg, 1.67 mmol) and N,N-diisopropylethylamine (585 μl, 3.36 mmol) were added in sequence. The reaction was carried out at 80°C for 16 hours, and the completion of the reaction was monitored by TLC. The product was filtered by suction in an ice bath, and the solid was washed with acetonitrile to obtain the crude product. ESI-MS: m / z = 402[M+H] + .

[0228] Synthesis step 6. 3-(1-oxo-5-(4-oxopiperidine-1-yl)isoindole-2-yl)piperidine-2,6-dione (intermediate 135) 3-(5-(4-(dimethoxymethyl)piperidine-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione (270 mg, 0.671 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL), and pyridine 4-methylbenzenesulfonate (337 mg, 1.342 mmol) was added. The mixture was stirred at 90°C, and after the reaction was complete, it was concentrated under reduced pressure and purified by column chromatography to obtain intermediate 135. ESI-MS: m / z = 342[M+H] + .

[0229] Intermediate 136. 3-(1-oxo-5-(3-oxoazetidine-1-yl)isoindole-2-yl)piperidine-2,6-dione [ka] The synthesis method is as shown for intermediate 135, but intermediate 136 is obtained by replacing 4-(dimethoxymethyl)piperidine with azetidine-3-ol in synthesis step 1. ESI-MS: m / z = 314 [M+H] + .

[0230] Intermediate 137. 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-acetal [ka] The synthesis method is as shown for intermediate 133, but intermediate 137 is obtained by replacing azetidine-3-one hydrochloride with azetidine-3-acetal in synthesis step 2. ESI-MS: m / z = 342 [M+H] + .

[0231] Intermediate 138. 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione [ka] The synthesis method was as shown for intermediate 133, but intermediate 138 was obtained by replacing azetidine-3-one hydrochloride with piperazine in synthesis step 2. ESI-MS: m / z = 343 [M+H] + .

[0232] Intermediate 139. 2-(2,6-dioxopiperidine-3-yl)-4-(3-oxoaza-1-yl)isoindole-1,3-dione [ka] The synthesis method is as shown for intermediate 133, but intermediate 139 was obtained by replacing 4-fluorophthalic anhydride with 3-fluorophthalic anhydride in synthesis step 1. ESI-MS: m / z = 328 [M+H] + .

[0233] Intermediate 140. 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)piperidine-4-acetal [ka] The synthesis method was as shown for intermediate 133, but intermediate 140 was obtained by replacing azetidine-3-one hydrochloride with 4-formylpiperidine in synthesis step 2. ESI-MS: m / z = 370 [M+H] + .

[0234] Intermediate 141. 2-(2,6-dioxopiperidine-3-yl)-5-(4-(3-(piperidine-4-yl)propa-2-in-1-yl)piperazine-1-yl)isoindole-1,3-dione [ka] Synthesis Step 1. 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione(141-1) The synthesis method was as shown for intermediate 133, but azetidine-3-one hydrochloride in synthesis step 2 was replaced with piperazine to obtain intermediate (141-1). ESI-MS: m / z = 343 [M+H] + .

[0235] Synthesis Step 2. 2-(2,6-dioxopiperidine-3-yl)-5-(4-(propa-2-in-1-yl)piperazine-1-yl)isoindole-1,3-dione(141-2) Compounds 2-(2,6-dioxopiperidine-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione (4.12 g, 12 mmol), 3-bromopropine (2.86 g, 24 mmol), and potassium carbonate (8.30 g, 60 mmol) were dissolved in acetonitrile (430 mL), stirred at room temperature for 12 hours, and the solvent was removed under reduced pressure. The residue was dissolved in water, extracted with ethyl acetate, and the organic layers were combined. The mixture was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain compound (141-2). ESI-MS: m / z = 381 [M+H] + .

[0236] Synthesis Step 3. 4-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-yl)propyne-1-yl)piperidine-1-carboxylate tert-butyl(141-3) Under the protection of nitrogen gas, compound 2-(2,6-dioxopiperidine-3-yl)-5-(4-(propa-2-in-1-yl)piperazine-1-yl)isoindole-1,3-dione (2.29 g, 6 mmol) was dissolved in anhydrous THF (30 mL), placed in an environment of -78°C, n-butyllithium (576 mg, 9 mmol) was added, and the reaction was allowed to proceed for 0.5 hours. Then, a THF solution containing 1-tert-butoxycarbonyl-4-iodopiperidine (2.8 g, 9 mmol) was added, the environment was changed to room temperature, the temperature was raised to 50°C, and the reaction was allowed to proceed for 24 hours. The solvent was removed by reducing the pressure, the residue was dissolved in water, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered by suction, the solvent was removed by reducing the pressure, and the mixture was purified by column chromatography to obtain compound (141-3). ESI-MS: m / z = 564 [M+H] + .

[0237] Synthesis step 4. 2-(2,6-dioxopiperidine-3-yl)-5-(4-(3-(piperidine-4-yl)propa-2-in-1-yl)piperazine-1-yl)isoindole-1,3-dione (intermediate 141) The synthesis steps were the same as those for intermediate 63 (synthesis step 3), with compound 63-2 replaced by compound 141-3 to obtain intermediate 141. ESI-MS: m / z = 464 [M+H] + .

[0238] Intermediate 142. 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindole-5-yl)pyrrolidine-3-acetal [ka] The synthesis method is as shown in intermediate 133, except that azetidine-3-one hydrochloride in synthesis step 2 is replaced with pyrrolidine-3-acetal. ESI-MS: m / z = 356[M+H] + .

[0239] Intermediate 143. 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-6-(3-oxoazetidine-1-yl)isoindorin-1,3-dione [ka] The synthesis method is as shown for intermediate 133, but intermediate 143 is obtained by replacing the 4-fluorophthalic anhydride in synthesis step 1 with 4,5-difluorophthalic anhydride. ESI-MS: m / z = 346[M+H] + .

[0240] Intermediate 144. 1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)pyrrolidine-3-acetal [ka] The synthesis method is as shown in intermediate 143, except that azetidine-3-one hydrochloride in synthesis step 2 is replaced with pyrrolidine-3-acetal. ESI-MS: m / z = 374[M+H] + .

[0241] Intermediate 145. 3-(1-oxo-5-(3-(piperazine-1-yl)propa-1-in-1-yl)isoindole-2-yl)piperidine-2,6-dione [ka] Synthesis Step 1. 4-Bromo-2-bromomethylbenzoate (145-1) 4-Bromo-2-methylbenzoate (2 g) was dissolved in carbon tetrachloride solution (25 mL), N-bromosuccinimide (1.86 g) and dibenzoyl peroxide (437 mg) were added, and the mixture was refluxed for 5 hours, monitored by TLC. After the reaction was complete, the carbon tetrachloride was removed by reducing the pressure, the mixture was redissolved in n-hexane, filtered by suction, and the filter cake was washed three times with n-hexane. Then the filter cake was washed again with a 1:4 (ethyl acetate:n-hexane) mixture, the organic phases were combined, the solvent was removed by reducing the pressure, and the compound was purified by column chromatography to obtain compound (145-1). ESI-MS: m / z = 307[M+H] + .

[0242] Synthesis step 2. 3-(5-bromo-1-oxoisoindole-2-yl)piperidine-2,6-dione(145-2) 3-aminopiperidine-2,6-dione hydrochloride (2.41 g) was dissolved in acetonitrile (50 mL), triethylamine (3.24 mL) was added, and the mixture was stirred for 10 minutes. Methyl 4-bromo-2-bromomethylbenzoate (2 g) was added dropwise, and the mixture was refluxed for 5 hours, monitored by TLC. After the reaction was complete, the solvent was removed under reduced pressure, 30 mL of methanol was added, and the mixture was refluxed for 30 minutes. The reaction was then filtered by suction to obtain compound (145-2). ESI-MS: m / z = 323 [M+H] + .

[0243] Synthesis step 3. 4-(propa-2-in-1-yl)piperazine-1-carboxylate tert-butyl ester (145-3) 1-tert-butoxycarbonylpiperazine (5 g, 26.84 mmol) was dissolved in tetrahydrofuran (100 mL), and potassium carbonate (5.57 g, 40.26 mmol) and 3-bromopropine (3.19 g, 26.84 mmol) were added under ice bath. The mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was performed to obtain compound (145-3). ESI-MS: m / z = 225[M+H] +.

[0244] Synthesis step 4. 4-(3-(2-(2-2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)propa-2-in-1-yl)piperazine-1-carboxylate tert-butyl ester (145-4) 3-(5-bromo-1-oxoisoindole-2-yl)piperidine-2,6-dione (500 mg), cuprous iodide (59 mg), and triethylamine (430 ul) were placed in a 25 mL two-necked flask. DMF (12 mL) was added, and the mixture was purged with nitrogen gas. 4-(propa-2-in-1-yl)piperazine-1-carboxylic acid tert-butyl ester (347 mg) and Pd2(pph3)2Cl2 (109 mg) were added, and the mixture was again purged with nitrogen gas. The reaction was allowed to proceed overnight at 90°C, monitored by TLC, and the reaction was completed. A large amount of water was added, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound (145-4). ESI-MS: m / z = 467[M+H] + .

[0245] Synthesis step 5. 3-(1-oxo-5-(3-(piperazine-1-yl)prop-1-in-1-yl)isoindole-2-yl)piperidine-2,6-dione(145) The synthesis method is the same as in step 3 of the synthesis of intermediate 63. Intermediate 145 was obtained. ESI-MS: m / z = 367[M+H] + .

[0246] Intermediate 146. 1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-acetal [ka] The synthesis method is as shown for intermediate 135, except that 4-(dimethoxymethyl)piperidine in synthesis step 1 is replaced with ethyl 4-piperidinecarboxylate, and 5-bromophthalide is replaced with 6-bromophthalide. The reaction conditions in synthesis step 6 are changed to dissolving the compound (3 mmol) in dichloromethane (10 mL), adding diisobutylaluminum hydride (7.5 mmol), stirring overnight at room temperature, and after the reaction is complete, extraction with ethyl acetate, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, and purification by column chromatography to obtain intermediate 146. ESI-MS: m / z = 356[M+H] + .

[0247] Intermediate 147. 1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisooctanol-5-yl)piperidine-4-carboxylic acid [ka] The synthesis method is as shown in intermediate 143, except that azetidine-3-one hydrochloride in synthesis step 2 is replaced with piperidine-4-aminoacetal. ESI-MS: m / z = 388[M+H] + .

[0248] Intermediate 148. 1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-acetal [ka] The synthesis method is as shown for intermediate 146, with 6-bromophthalide replaced by 5-bromophthalide. ESI-MS: m / z = 356 [M+H] +

[0249] Intermediate 149. 1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-acetal [ka] The synthesis method is as shown in intermediate 148, with 4-(dimethoxymethyl)piperidine replaced by 3-(dimethoxymethyl)pyrrolidine. ESI-MS: m / z = 342 [M+H] + .

[0250] [Table 2]

[0251] Intermediate 156: 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester [ka]

[0252] Synthesis Step 1: 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester 3,4-Difluoronitrobenzene (796 mg, 5.0 mmol) 20 mL The mixture was dissolved in DMF, and triethylamine (1.01 g, 10.0 mmol) and piperazine-1-carboxylate tert-butyl ester (1.03 g, 5.5 mmol) were added sequentially. The mixture was stirred and heated to 60°C for 3 hours. After confirming the completion of the reaction by TLC, water was added, the system was cooled to room temperature, filtered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.5 g of 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester. The yield was 92%. ESI-MS: m / z = 326.1 [M+H] + .

[0253] Synthesis Step 2: 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (1.5 g, 4.6 mmol) was dissolved in 10 mL of ethanol. 10 mL of water, ammonium chloride (394 mg, 7.36 mmol), and iron powder (219 mg, 3.9 mmol) were added sequentially to the system, and the reaction was carried out at 50°C for 1 hour. After the reaction was complete, the iron powder was removed by filtration through diatomaceous earth, and the mixture was extracted three times using DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 1.23 g of 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester was obtained by column chromatography with a yield of 91%. ESI-MS: m / z = 296.2 [M+H] + .

[0254] [Table 3]

[0255] [Table 4]

[0256] Intermediate 165: (R)-4-(4-((6-carbamoyl-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0257] [ka]

[0258] Synthesis Step 1: (R)-3-(2-oxoimidazolidine-1-yl)piperidine-1-carboxylate tert-butyl ester (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) was dissolved in 20 mL of tetrahydrofuran, the system was cooled to 0°C, 2-chloroethyl isocyanate (1.17 g, 11 mmol) was slowly added, and the mixture was stirred at 20°C for 1 hour. The system was then cooled to 0°C, potassium tert-butoxide (1.68 g, 15 mmol) was slowly added, and the mixture was heated to room temperature for 2 hours. The completion of the reaction was confirmed by TLC, water was added to quench the system, and the system was adjusted to weak acidity. The mixture was extracted three times with water and DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography 1.13 g of (R)-3-(2-oxoimidazolidine-1-yl)piperidine-1-carboxylic acid tert-butyl ester in a yield of 42%. ESI-MS: m / z = 270.2 [M+H] + .

[0259] Synthesis Step 2: (R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-carboxylate tert-butyl ester (R)-3-(2-oxoimidazolidine-1-yl)piperidine-1-carboxylate tert-butyl ester (1.13 g, 4.2 mmol) was dissolved in 10 mL of tetrahydrofuran, the system was cooled to 10°C, and potassium tert-butoxide (941 mg, 8.4 mmol) and dimethyl sulfate (635 mg, 5.04 mmol) were added in sequence. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 1.13 g of (R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-carboxylate tert-butyl ester in 95% yield. ESI-MS: m / z = 284.2 [M+H] + .

[0260] Synthesis Step 3: (R)-1-methyl-3-(piperidine-3-yl)imidazoline-2-one (R)-3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-carboxylate tert-butyl ester (1.13 g, 4.0 mmol) is dissolved in 8 mL of DCM, 2 mL of TFA is added, and the mixture is reacted at room temperature for 1 hour. After the reaction is complete, the mixture is extracted three times with DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (R)-1-methyl-3-(piperidine-3-yl)imidazolin-2-one, which is used directly in the next step. ESI-MS: m / z = 184.1 [M+H] + .

[0261] Synthesis Step 4: 4-(4-((6-carbamoyl-3-(methylthio)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester 700 mg, 3.00 mmol of 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate ethyl ester was dissolved in 10 mL of acetonitrile. DIPEA (1.7 g, 12.84 mmol) and 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester (885 mg, 3.00 mmol) were added sequentially to the system, and the reaction was allowed to proceed at room temperature for 30 minutes. Then, 30 mL of ammonia-methanol solution (7 mol / L) was added, and the system became turbid within 10 minutes. The reaction was continued at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, beaten with petroleum ether, filtered, and 1.3 g of 4-(4-((6-carbamoyl-3-(methylthio)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester was obtained as a yellow solid, with a yield of 93%. ESI-MS: m / z = 464 [M+H] + .

[0262] Synthesis Step 5: (R)-4-(4-((6-carbamoyl-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester (R)-1-methyl-3-(piperidine-3-yl)imidazolin-2-one (1.3 g, 2.78 mmol) is dissolved in 20 mL NMP, and mCPBA (85%, 2.4 g, 13.99 mmol) is added to the system and stirred at room temperature for 2 hours. After the reaction is complete, DIPEA (2 mL, 11.00 mmol) and (R)-1-methyl-3-(piperidine-3-yl)imidazolin-2-one (661 mg, 3.61 mmol) are added sequentially to the system and reacted at 80°C for 2 hours. After the reaction was complete, water was added to precipitate a solid, which was then filtered to obtain a yellow solid. DCM was added to dissolve the solid, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 300 mg of the yellow solid (R)-4-(4-((6-carbamoyl-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-5-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester by column chromatography (DCM / MeOH elution), with a yield of 16%. ESI-MS: m / z = 599.3 [M+H] + .

[0263] [Table 5] JPEG2026074117000190.jpg251161JPEG2026074117000191.jpg130170

[0264] Intermediate 185: 1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorophenyl)pyrrolidine-3-acetal [ka]

[0265] Synthesis Step 1: 3-((5-bromo-2-fluorophenyl)amino)propionic acid 5-Bromo-2-fluoroaniline (2 g, 10.58 mmol) was dissolved in 20 mL of toluene, and acrylic acid (787 mg, 12.69 mmol) was added to the system. The reaction was carried out at 100°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.5 g of 3-((5-bromo-2-fluorophenyl)amino)propionic acid in a yield of 90%. ESI-MS(M+H) + =262.0

[0266] Synthesis Step 2: 1-(5-bromo-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione 3-((5-bromo-2-fluorophenyl)amino)propionic acid (2.5 g, 9.54 mmol) was dissolved in 30 mL of acetic acid, urea (1.2 g, 19.08 mmol) was added to the system, and the reaction was carried out at 120°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 2 g of 1-(5-bromo-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione as a yellowish-brown solid by column chromatography (DCM / MeOH elution) with a yield of 73%. ESI-MS(M+H) + =287.0

[0267] Synthesis Step 3: 1-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione Dissolve 1-(5-bromo-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.74 mmol) in 10 mL of DMSO, and add 3-(1,3-dioxolan-2-yl)pyrrolidine (325 mg, 2.27 mmol), t-BuONa (511 mg, 5.22 mmol), Pd2(dba)3 (155 mg, 0.17 mmol), and X-Phos (201 mg, 0.34 mmol) in order to the system, and react at 80°C for 3 hours. After the reaction was complete, water was added and the mixture was quenched. Extraction was performed three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 100 mg of 1-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione as a yellowish-brown solid by column chromatography (DCM / MeOH elution). The yield was 16%. ESI-MS(M+H) + =350.1

[0268] Synthesis Step 4: 1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorophenyl)pyrrolidine-3-acetal 1-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (100 mg, 0.28 mmol) was dissolved in 2 mL of TFA and reacted at 80°C for 1 hour. Then, 0.1 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state, and the mixture was extracted five times by DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 80 mg of 1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-fluorophenyl)pyrrolidine-3-acetal by column chromatography, with a yield of 93%. ESI-MS(M+H) + =306.1

[0269] Intermediate 186: 1-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxyphenyl)pyrrolidine-3-acetal [ka] Refer to the synthetic route and method of intermediate 185, replace 5-bromo-2-fluoroaniline with 5-bromo-2-methoxyaniline in synthetic step 1, and perform ESI-MS(M+H) + =318.1

[0270] Intermediate 187: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoic acid [ka]

[0271] Synthesis Step 1: 3-((2-carboxyethyl)amino)-4-methylbenzoic acid 3-amino-4-methylbenzoic acid (10.0 g, 66.2 mmol) was dissolved in 30 mL of toluene, and acrylic acid (18 mL, 264.6 mmol) was added to the system. The reaction was carried out at 110°C for 4 hours. After the reaction was complete, DCM was added, and a solid precipitated. The mixture was filtered under reduced pressure to obtain 14.5 g of 3-((2-carboxyethyl)amino)-4-methylbenzoic acid as a white solid, with a yield of 98%. ESI-MS: m / z = 224 [M+H] + .

[0272] Synthesis Step 2: 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoic acid 3-((2-carboxyethyl)amino)-4-methylbenzoic acid (14.5 g, 65.0 mmol) was dissolved in 30 mL of acetic acid, and urea (9.8 g, 162.5 mmol) was added to the system. The reaction was carried out at 120°C for 12 hours. After the reaction was complete, water was added, and a solid precipitated from the system. The mixture was filtered, first beaten with water, then beaten with acetonitrile, and filtered again to obtain 11.5 g of 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methylbenzoic acid as a white solid, with a yield of 71%. ESI-MS: m / z = 249 [M+H] + .

[0273] [Table 6]

[0274] Intermediate 190: 1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-fluorophenyl)piperidine-4-acetal [ka]

[0275] Synthesis Step 1: 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-nitroaniline 5-Fluoro-2-nitroaniline (1 g, 6.41 mmol) was dissolved in 10 mL of DMF. 4-(1,3-dioxolan-2-yl)piperidine (1.2 g, 7.69 mmol) and cesium carbonate (6.2 g, 19.23 mmol) were added sequentially to the system, and the reaction was carried out at 80°C for 3 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 1.5 g of 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-nitroaniline was obtained by column chromatography with a yield of 79%. ESI-MS(M+H) + =294.1

[0276] Synthesis Step 2: 4-(1,3-dioxolan-2-yl)-1-(3-fluoro-4-nitrophenyl)piperidine 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-nitroaniline (1.5 g, 5.11 mmol) was dissolved in 15 mL of concentrated hydrochloric acid. HF (70%, 30 mL) was added to the system at 0°C, and the reaction was allowed to proceed at room temperature until complete dissolution. NaNO2 (423 mg, 6.13 mmol) was added to the system at -78°C, and the reaction was allowed to proceed at 0°C for 30 minutes, followed by raising the temperature to 60°C and continuing for 15-30 minutes. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 4-(1,3-dioxolan-2-yl)-1-(3-fluoro-4-nitrophenyl)piperidine 1 g was obtained by column chromatography with a yield of 66%. ESI-MS(M+H) + =297.1

[0277] Synthesis Step 3: 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluoroaniline 4-(1,3-dioxolan-2-yl)-1-(3-fluoro-4-nitrophenyl)piperidine (1 g, 3.37 mmol) was dissolved in 10 mL of tetrahydrofuran. Ammonium chloride (2 g, 33.78 mmol), water (10 mL), and iron powder (1.9 g, 33.78 mmol) were added sequentially to the system, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, the iron powder was removed by filtration through diatomaceous earth, the filtrate was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (EA / PE elution) to obtain 750 mg of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluoroaniline, with a yield of 83%. ESI-MS (M+H) + =267.1

[0278] Synthesis Step 4: 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)amino)propionic acid 750 mg, 2.81 mmol of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluoroaniline was dissolved in 10 mL of toluene. Acrylic acid (243 mg, 3.38 mmol) was added to the system, and the reaction was carried out at 100°C for 12 hours until complete. The reaction was completed by five extractions using DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography a yellow liquid of 860 mg of 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)amino)propionic acid in a yield of 90%. ESI-MS(M+H) + =339.2

[0279] Synthesis Step 5: 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione 3-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)amino)propionic acid (860 mg, 2.54 mmol) was dissolved in 10 mL of acetic acid, urea (315 mg, 5.08 mmol) was added to the system, and the reaction was carried out at 120°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 540 mg of 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione as a yellowish-brown solid by column chromatography (DCM / MeOH elution), with a yield of 58%. ESI-MS(M+H) + =364.2

[0280] Synthesis Step 6: 1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-fluorophenyl)piperidine-4-acetal 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (540 mg, 1.68 mmol) was dissolved in 6 mL of TFA and reacted at 80°C for 1 hour. Then, 0.5 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state. Extraction was performed five times with MeOH / DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained as a yellow solid by column chromatography: 1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-fluorophenyl)piperidine-4-acetal (490 mg) with a yield of 91%. ESI-MS(M+H) + =320.1

[0281] [Table 7] JPEG2026074117000198.jpg155170

[0282] Intermediate 209: (S)-N-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(4-formylpiperidine-1-yl)benzamide [ka]

[0283] Synthesis Step 1: 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-methyl fluorobenzoate Methyl 4-bromo-2-fluorobenzoate (2.5 g, 10.73 mmol) was dissolved in 20 mL of DMF. 4-(1,3-dioxolan-2-yl)piperidine (2.0 g, 12.87 mmol), cesium carbonate (8.7 g, 26.82 mmol), Sphos (880 mg, 2.15 mmol), and palladium acetate (240 mg, 1.07 mmol) were added to the system. The mixture was protected with nitrogen gas and reacted at 50°C for 2 hours. After the reaction, water was added to quench the mixture, and it was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid: 800 mg of methyl 4-(4-(1,3-dioxacyclo-2-yl)piperidine-1-yl)-2-fluorobenzoate in a yield of 24%. ESI-MS(M+H) + =310.1

[0284] Synthesis Step 2: 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorobenzoic acid 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorobenzoic acid methyl (240 mg, 0.78 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium hydroxide (90 mg, 3.88 mmol), water (2 mL), and methanol (4 mL) were added sequentially to the system, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted by DCM, beaten, filtered, and concentrated under reduced pressure to obtain 190 mg of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorobenzoic acid as a white solid, with a yield of 82%. ESI-MS(MH) + =296.1

[0285] Synthesis Step 3: (S)-4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide (S)-(2,6-dioxopiperidine-3-yl)aminocarboxylic acid tert-butyl (93 mg, 0.73 mmol) is dissolved in 5 mL of DCM, TFA (1 mL) is added to the system, and the mixture is reacted at room temperature for 1 hour. After the reaction is complete, the mixture is concentrated under reduced pressure. 5 mL of DMF, 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-2-fluorobenzoic acid (180 mg, 0.61 mmol), HATU (30 mg, 0.79 mmol), and TEA (0.5 mL, 1.22 mol) are added sequentially to the above product, and the mixture is reacted at room temperature for 1 hour until the reaction is complete. The mixture was extracted three times using DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 200 mg of (S)-4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide as a white solid by column chromatography (DCM / MeOH elution), with a yield of 80%. ESI-MS(M+H) + =406.2

[0286] Synthesis Step 4: (S)-N-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(4-formylpiperidine-1-yl)benzamide (S)-4-(4-(1,3-dioxopiperidine-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide (200 mg, 0.49 mmol) was dissolved in 2 mL of TFA and reacted at 80°C for 1 hour. Then, 1 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state, and the mixture was extracted five times by DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 146 mg of (S)-N-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(4-formylpiperidine-1-yl)benzamide as a white solid by column chromatography, with a yield of 83%. ESI-MS(M+H) + =362.1

[0287] Intermediate 210: N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)pyridineformamide [ka]

[0288] Synthesis Step 1: 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylate methyl Methyl 5-fluoropyridinecarboxylate (2.2 g, 14.18 mmol) was dissolved in 20 mL of DMF. 4-(1,3-dioxolan-2-yl)piperidine (2.7 g, 17.02 mmol) and potassium carbonate (5.8 g, 42.54 mmol) were added to the system, and the reaction was carried out at 90°C for 2 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid: 3.2 g of methyl 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylate with a yield of 78%. ESI-MS(M+H) + =293.1

[0289] Synthesis Step 2: 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylic acid 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylate methyl (1.5 g, 5.13 mmol) was dissolved in 20 mL of tetrahydrofuran. Lithium hydroxide (615 mg, 25.67 mmol) and water (7.5 mL) were added to the system, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated until the solvent was gone, beaten with DCM, filtered, and the filtrate was concentrated to obtain 1.3 g of 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylate as a white solid, with a yield of 93%. ESI-MS(M+H) + =279.1

[0290] Synthesis Step 3: 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)pyridineformamide 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)pyridinecarboxylic acid (500 mg, 1.08 mmol) was dissolved in 10 mL of DMF. 3-aminopiperidine-2,6-dione (255 mg, 1.97 mmol), HATU (752 mg, 1.97 mmol), and triethylamine (0.75 mL, 5.39 mmol) were sequentially added to the system, and the mixture was reacted at room temperature for 1 hour. After the reaction, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 350 g of 5-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)pyridineformamide as a gray solid by column chromatography (DCM / MeOH elution) with a yield of 51%. ESI-MS (M+H) + =389.2

[0291] Synthesis Step 4: N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)pyridineformamide 5-(4-(1,3-dioxopiperidine-2-yl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)pyridineformamide (100 mg, 0.26 mmol) was dissolved in 2 mL of TFA and reacted at 80°C for 1 hour. Then, 1 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state, and the mixture was extracted five times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 75 mg of N-(2,6-dioxopiperidine-3-yl)-5-(4-formylpiperidine-1-yl)pyridineformamide as a yellow solid, with a yield of 84%. ESI-MS(M+H) + =345.2

[0292] [Table 8] JPEG2026074117000202.jpg62170

[0293] Intermediate 222: 1-(6-((2,6-dioxopiperidine-3-yl)amino)pyridine-3-yl)pyrrolidine-3-acetal [ka]

[0294] Synthesis Step 1: Synthesis of 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-nitropyridine 5-Fluoro-2-nitropyridine (1.5 g, 10.56 mmol) was dissolved in 20 mL of DMF. 3-(1,3-dioxolan-2-yl)pyrrolidine (1.8 g, 12.67 mmol) and cesium carbonate (10 g, 31.68 mmol) were added to the system, and the reaction was carried out at 80°C for 2 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography a yellow liquid of 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-nitropyridine 2.2 g in yield 75%. ESI-MS(M+H) + =266.1

[0295] Synthesis Step 2: 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)pyridine-2-amine 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-2-nitropyridine (2.1 g, 7.92 mmol) was dissolved in 25 mL of tetrahydrofuran. Ammonium chloride (4.6 g, 79.24 mmol), water (5 mL), and iron powder (4.6 g, 79.24 mmol) were added sequentially to the system, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, the mixture was filtered while still hot to remove a large amount of iron powder. It was extracted three times by DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 1.7 g of 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)pyridine-2-amino as a yellow solid by column chromatography, with a yield of 93%. ESI-MS(M+H) + =236.1

[0296] Synthesis Step 3: 3-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)pyridine-2-yl)amino)piperidine-2,6-dione 5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)pyridine-2-amino (1.7 g, 7.23 mmol) was dissolved in 20 mL of DMF. 3-bromopiperidine-2,6-dione (2 g, 10.84 mmol), Pd(dppf)Cl2 (526 mg, 0.72 mmol), and Na2CO3 (2.6 g, 21.69 mmol) were added sequentially to the system, and the reaction was carried out at 100°C for 3 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography 2 g of 3-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)pyridine-2-yl)amino)piperidine-2,6-dione in 80% yield. ESI-MS(M+H) + =347.2

[0297] Synthesis Step 4: 1-(6-((2,6-Dioxopiperidine-3-yl)amino)pyridine-3-yl)pyrrolidine-3-acetal 3-(5-(3-(1,3-dioxopiperidine-2-yl)pyrrolidine-1-yl)pyridine-2-yl)amino)piperidine-2,6-dione (2 g, 5.78 mmol) was dissolved in 10 mL of TFA and reacted at 80°C for 1 hour. Then, 2 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state, and the mixture was extracted five times using DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.5 g of 1-(6-((2,6-dioxopiperidine-3-yl)amino)pyrrolidine-3-yl)pyrrolidine-3-acetal as a yellow solid, with a yield of 85%. ESI-MS(M+H) + =303.1

[0298] [Table 9] JPEG2026074117000205.jpg26170

[0299] Intermediate 233: (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)benzo[d][1,3]dioxolan-4-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl [ka]

[0300] Synthesis Step 1: 7-aminobenzo[d][1,3]dioxolane-4-carboxylic acid 7-Nitrobenzo[d][1,3]dioxolane-4-carboxylic acid (1 g, 5.52 mmol) was dissolved in 10 mL of THF. Ammonium chloride (2.9 g, 55.20 mmol), water (3 mL), and iron powder (3 g, 55.20 mmol) were added sequentially to the system, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 729 mg of 7-aminobenzo[d][1,3]dioxolane-4-carboxylic acid by column chromatography (EA / PE elution), with a yield of 85%. ESI-MS (M+H) + =182.0

[0301] Synthesis Step 2: Synthesis of 7-fluorobenzo[d][1,3]dioxolane-4-carboxylic acid 7-aminobenzo[d][1,3]dioxolane-4-carboxylic acid (729 mg, 4.02 mmol) was dissolved in 10 mL of concentrated hydrochloric acid, cooled to 0°C, and HF (70%, 20 mL) was added to the system at 0°C. The reaction was carried out at room temperature until the reactants were completely dissolved. NaNO2 (305 mg, 4.42 mmol) was added to the system at -78°C, and the reaction was carried out at 0°C for 30 minutes, after which the temperature was raised to 60°C and the reaction was continued for 15-30 minutes. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 628 mg of 7-fluorobenzo[d][1,3]dioxolane-4-carboxylic acid was obtained by column chromatography. The yield was 85%. ESI-MS(M+H) + =185.0

[0302] Synthesis Step 3: 7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolane-4-carboxylic acid 7-Fluorobenzo[d][1,3]dioxolane-4-carboxylic acid (628 mg, 3.41 mmol) was dissolved in 10 mL of DMF. Piperidine-4-ylmethanol (588 mg, 5.11 mmol) and cesium carbonate (3.3 g, 10.23 mmol) were added sequentially to the system, and the reaction was carried out at 80°C for 12 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 761 mg of 7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolane-4-carboxylic acid was obtained by column chromatography. The yield was 80%. ESI-MS(M+H) + =280.1

[0303] Synthesis Step 4: N-(2,6-dioxopiperidine-3-yl)-7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolan-4-formamide 7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolane-4-carboxylic acid (761 mg, 2.72 mmol) was dissolved in 10 mL of DMF. 3-aminopiperidine-2,6-dione (452 ​​mg, 3.53 mmol), DIPEA (1.0 g, 8.16 mmol), and HATU (1.3 g, 3.53 mmol) were added sequentially to the system, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 793 mg of N-(2,6-dioxopiperidine-3-yl)-7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolane-4-formamide by column chromatography (MeOH / DCM elution), with a yield of 75%. ESI-MS (M+H) + =390.2

[0304] Synthesis Step 5: (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)benzo[d][1,3]dioxolan-4-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl N-(2,6-dioxopiperidine-3-yl)-7-(4-(hydroxymethyl)piperidine-1-yl)benzo[d][1,3]dioxolan-4-formamide (793 mg, 2.03 mmol) was dissolved in 10 mL of DCM, and TsCl (580 mg, 3.05 mmol) and TEA (615 mg, 6.09 mmol) were sequentially added to the system. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 992 mg of (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)benzo[d][1,3]dioxolan-4-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl. The yield was 90%. ESI-MS(M+H) + =544.2

[0305] Intermediate 234: (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl [ka] Referring to the synthetic route and method of intermediate 233, piperidine-4-ylmethanol in synthetic step 3 was replaced with pyrrolidine-3-ylmethanol to obtain (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl. ESI-MS(M+H) + = 530.2

[0306] Intermediate 235: (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)-1H-benzo[d]imidazole-4-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl [ka] Referring to the synthetic route and method of steps 3, 4, and 5 of the synthesis of intermediate 233, 7-fluorobenzo[d][1,3]dioxolane-4-carboxylic acid in synthesis step 3 was replaced with 4-fluoro-1H-benzo[d]imidazole-7-carboxylic acid to obtain (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)-1H-benzo[d]imidazole-4-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl. ESI-MS(M+H) + =540.2

[0307] Intermediate 236: (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)-1H-benzo[d]imidazole-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl [ka] Referring to the synthetic route and method of intermediate 235, pyrrolidine-3-ylmethanol was replaced with piperidine-4-ylmethanol to obtain (1-(7-((2,6-dioxopiperidine-3-yl)aminoformyl)-1H-benzo[d]imidazole-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl. ESI-MS(M+H) + = 526.5

[0308] Intermediate 237: (1-(8-((2,6-dioxopiperidine-3-yl)aminoformyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl [ka] Referring to the synthetic route and method of intermediate 233, 7-nitrobenzo[d][1,3]dioxolane-4-carboxylic acid in synthetic step 1 was replaced with 8-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylic acid to obtain (1-(8-((2,6-dioxopiperidine-3-yl)aminoformyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-4-yl)4-methylbenzenesulfonate methyl. ESI-MS(M+H) + = 558.2

[0309] Intermediate 238: 1-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-4-yl)piperidine-4-acetal [ka]

[0310] Synthesis Step 1: 4-Fluoro-7-nitrobenzoxazole 5-Fluoro-2-nitrobenzamide (1 g, 5.43 mmol) was dissolved in 15 mL of water, cesium carbonate (5.3 g, 16.29 mmol) was added to the system, and the reaction was carried out at 120 W microwave for 10 minutes. After the reaction was complete, the mixture was extracted three times using DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 750 mg of 4-fluoro-7-nitrobenzoxazole, with a yield of 75%. ESI-MS(M+H) + =183.1

[0311] Synthesis Step 2: 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-7-nitrobenzoxazole 4-fluoro-7-nitrobenzoxazole (750 mg, 4.12 mmol) was dissolved in 10 mL of DMF, and 4-(1,3-dioxolan-2-yl)piperidine (776 mg, 4.94 mmol) and cesium carbonate (4 g, 12.36 mmol) were sequentially added to the system and reacted at 80°C for 3 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 900 mg of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-7-nitrobenzoxazole was obtained by column chromatography with a yield of 68%. ESI-MS (M+H) + =320.1

[0312] Synthesis Step 3: 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-amino 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)-7-nitrobenzoxazole (900 mg, 2.82 mmol) was dissolved in 10 mL of tetrahydrofuran. Ammonium chloride (1.6 g, 28.21 mmol), water (10 mL), and iron powder (1.6 g, 28.21 mmol) were added sequentially to the system, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 500 mg of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-amino was obtained by column chromatography with a yield of 61%. ESI-MS(M+H) + =290.1

[0313] Synthesis Step 4: 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)amino)propionic acid 500 mg, 1.73 mmol of 4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-amino (500 mg) was dissolved in 10 mL of toluene, and acrylic acid (128 mg, 2.07 mmol) was added to the system. The reaction was carried out at 100°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 580 mg of the yellow liquid 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)amino)propionic acid, with a yield of 94%. ESI-MS(M+H) + =362.2

[0314] Synthesis Step 5: 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-((4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)amino)propionic acid (580 mg, 1.60 mmol) was dissolved in 10 mL of acetic acid, urea (200 mg, 3.20 mmol) was added to the system, and the reaction was carried out at 120°C for 12 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 380 mg of 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione as a yellowish-brown solid by column chromatography (DCM / MeOH elution), with a yield of 58%. ESI-MS(M+H) + =387.2

[0315] Synthesis Step 6: 1-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-4-yl)piperidine-4-acetal 1-(4-(4-(1,3-dioxolan-2-yl)piperidine-1-yl)benzo[d]oxazole-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (380 mg, 0.98 mmol) was dissolved in 3 mL of TFA and reacted at 80°C for 1 hour. Then, 0.2 mL of concentrated hydrochloric acid was added to the system and reacted at 80°C for 3 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added to adjust the system to a basic state. Extraction was performed five times with MeOH / DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 310 mg of 1-(7-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)benzo[d]oxazole-4-yl)piperidine-4-acetal as a yellow solid, with a yield of 92%. ESI-MS(M+H) + =343.1

[0316] [Table 10]

[0317] Intermediate 241: (1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl [ka]

[0318] Synthesis Step 1: (1-(7-nitrobenzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methanol 4-Fluoro-7-nitrobenzo[d][1,3]dioxolane (3 g, 16.22 mmol) was dissolved in 20 mL of DMF. Pyrrolidine-3-ylmethanol (2 g, 19.46 mmol) and cesium carbonate (15.81 g, 48.64 mmol) were added sequentially to the system, and the reaction was carried out at 90°C for 2 hours. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid of 3.6 g of (1-(7-nitrobenzo[d][1,3]dioxolane-4-yl)pyrrolidine-3-yl)methanol with a yield of 85%. ESI-MS(M+H) + =267.1

[0319] Synthesis Step 2: (1-(7-aminobenzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methanol (1-(7-nitrobenzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methanol (2 g, 8.47 mmol) was dissolved in 30 mL of tetrahydrofuran. Ammonium chloride (7.5 g, 147.26 mmol), water (7.5 mL), and iron powder (8 g, 147.26 mmol) were added sequentially to the system, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, the mixture was filtered while still hot to remove a large amount of iron powder. The mixture was extracted three times using DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid of 1.2 g of (1-(7-aminobenzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methanol with a yield of 60%. ESI-MS(M+H) + =237.1

[0320] Synthesis Step 3: 3-((7-(3-(hydroxymethyl)pyrrolidine-1-yl)benzo[d][1,3]dioxolan-4-yl)amino)piperidine-2,6-dione (1-(7-aminobenzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)methanol (1.2 g, 5.08 mmol) was dissolved in 10 mL of DMF. 3-bromopiperidine-2,6-dione (1.3 g, 6.61 mmol) and sodium bicarbonate (1.28 g, 15.27 mmol) were added to the system, and the reaction was carried out at 70°C for 1 hour until complete. The mixture was extracted three times using DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid, yielding 1.3 g of 3-((7-(3-(hydroxymethyl)pyrrolidine-1-yl)benzo[d][1,3]dioxolan-4-yl)amino)piperidine-2,6-dione in 75% yield. ESI-MS(M+H) + =348.2

[0321] Synthesis Step 4: (1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate methyl 3-((7-(3-(hydroxymethyl)pyrrolidine-1-yl)benzo[d][1,3]dioxolan-4-yl)amino)piperidine-2,6-dione (1 g, 2.88 mmol) was dissolved in 10 mL of DCM, and p-toluenesulfonyl chloride (820 mg, 4.32 mmol) and 3.5 mL of DIPEA were sequentially added to the system. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained 1.2 g of methyl (1-(7-((2,6-dioxopiperidine-3-yl)amino)benzo[d][1,3]dioxolan-4-yl)pyrrolidine-3-yl)4-methylbenzenesulfonate as a yellow solid by column chromatography, with a yield of 85%. ESI-MS(M+H) + =502.2

[0322] [Table 11]

[0323] Intermediate 245: 1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)pyrrolidine-3-acetal [ka]

[0324] Synthesis Step 1: 3-(2,6-bis(benzyloxy)pyridine-3-yl)-6-bromo-1-methyl-1H-indazole 6-bromo-3-iodo-1-methyl-1H-indazole (2 g, 5.97 mmol) was dissolved in 20 mL of THF. 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)pyridine (3.7 g, 8.96 mmol), DPPF palladium dichloride (432 mg, 0.60 mmol), and cesium carbonate (5.8 g, 17.91 mmol) were added sequentially to the system. The mixture was protected with nitrogen gas and allowed to react at room temperature for 12 hours. After the reaction was complete, water was added to quench the mixture, and it was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid yielding 1.4 g of 3-(2,6-bis(benzyloxy)pyridine-3-yl)-6-bromo-1-methyl-1H-indazole in a yield of 49%. ESI-MS(M+H) + = 500.1

[0325] Synthesis Step 2: 6-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-3-(2,6-bis(benzyloxy)pyridine-3-yl)-1-methyl-1H-indazole Dissolve 3-(2,6-bis(benzyloxy)pyridine-3-yl)-6-bromo-1-methyl-1H-indazole (1.4 g, 2.81 mmol) in 20 mL of 1,4-dioxane. Add 3-(1,3-dioxolan-2-yl)pyrrolidine (485 mg, 3.37 mmol), Pd2(dba)3 (257 mg, 0.28 mmol), XPhos (267 mg, 0.56 mmol), and cesium carbonate (1.8 g, 5.62 mmol) in sequence to the system. Protect with nitrogen gas and react at 160°C for 12 hours. After the reaction is complete, water is added to quench the mixture, and it is extracted three times with DCM. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid: 860 mg of 6-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-3-(2,6-bis(benzyloxy)pyridine-3-yl)-1-methyl-1H-indazole in a yield of 50%. ESI-MS(M+H) + = 563.3

[0326] Synthesis Step 3: 3-(6-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione. Dissolve 6-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-3-(2,6-bis(benzyloxy)pyridine-3-yl)-1-methyl-1H-indazole (860 mg, 1.53 mmol) in 10 mL of 1,4-dioxane, add palladium hydroxide (21 mg, 0.15 mmol) to the system, introduce hydrogen gas, and react at room temperature for 12 hours. After the reaction is complete, the mixture is filtered and concentrated under reduced pressure to obtain 500 mg of 3-(6-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione as a white solid, with a yield of 85%. ESI-MS(M+H) + =385.2

[0327] Synthesis Step 4: 1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)pyrrolidine-3-acetal 3-(6-(3-(1,3-dioxopiperidine-2-yl)pyrrolidine-1-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (500 mg, 1.30 mmol) was dissolved in 5 mL of TFA and reacted at 80°C for 1 hour. 1 mL of concentrated hydrochloric acid was added dropwise, and the reaction was continued at 80°C for 2 hours. The mixture was quenched with aqueous sodium bicarbonate solution, extracted 5 times by DCM, and concentrated under reduced pressure to obtain 400 mg of 1-(3-(2,6-dioxopiperidine-3-yl)-1-methyl-1H-indazole-6-yl)pyrrolidine-3-acetal as a white solid, with a yield of 90%. ESI-MS(M+H) + = 341.2.

[0328] [Table 12]

[0329] Intermediate 255: 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)pyrrolidine-3-acetal [ka]

[0330] Synthesis Step 1: 3-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione Dissolve 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (1 g, 2.97 mmol) in 20 mL of DMF. Add 3-(1,3-dioxolan-2-yl)pyrrolidine (3.6 g, 3.56 mmol), Pd2(dba)3 (280 mg, 0.30 mmol), XPhos (285 mg, 0.59 mmol), and cesium carbonate (1.8 g, 5.62 mmol) in sequence to the system, protect with nitrogen gas, and react at 160°C for 12 hours. After the reaction was complete, water was added to quench the mixture, and it was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a yellow solid: 530 mg of 3-(5-(3-(1,3-dioxolan-2-yl)pyrrolidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione in 45% yield. ESI-MS(M+H) + = 401.2.

[0331] Synthesis Step 2: 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)pyrrolidine-3-acetal 3-(5-(3-(1,3-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (530 mg, 1.33 mmol) was dissolved in 5 mL of TFA and reacted at 80°C for 1 hour. 1 mL of concentrated hydrochloric acid was added dropwise, and the reaction was continued at 80°C for 2 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to adjust the system to a basic state. The mixture was extracted 5 times by DCM, concentrated under reduced pressure, and obtained 450 mg of 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)pyrrolidine-3-acetal as a white solid by column chromatography, with a yield of 95%. ESI-MS(M+H) + = 357.2.

[0332] [Table 13]

[0333] Intermediate 263: 3-(6-((2,6-dioxopiperidine-3-yl)aminoformyl)pyridine-3-yl)propa-2-in-1-ylmethanesulfonate [ka]

[0334] Synthesis Step 1: 5-(3-hydroxypropa-1-in-1-yl)pyridinecarboxylic acid 5-bromopyridinecarboxylic acid (2 g, 10.00 mmol) was dissolved in 20 mL of ethylene glycol dimethyl ether. Propargyl alcohol (675 mg, 12.00 mmol), tetrakistriphenylphosphine paradiu (570 mg, 0.50 mmol), cuprous iodide (380 mg, 2.00 mmol), and DIPEA (4 mL, 30.00 mmol) were added sequentially to the system, and the reaction was carried out at 120°C for 20 min. After the reaction was complete, the mixture was filtered, concentrated under reduced pressure, dissolved in DCM, and obtained by column chromatography to yield 750 mg of a yellow liquid 5-(3-hydroxypropa-1-in-1-yl)pyridinecarboxylic acid in a yield of 40%. ESI-MS(M+H) + = 178.0.

[0335] Synthesis Step 2: 5-(3-((methylsulfonyl)oxy)propa-1-in-1-yl)pyridinecarboxylic acid 750 mg, 4.23 mmol of 5-(3-hydroxypropa-1-in-1-yl)pyridinecarboxylic acid was dissolved in 15 mL of DCM. Methylsulfonyl chloride (724 mg, 6.35 mmol) and TEA (855 mg, 8.47 mmol) were sequentially added to the system, and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was complete, water was added to precipitate a solid, and DCM was added for extraction. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and obtained by column chromatography as a white solid of 700 mg of 5-(3-((methylsulfonyl)oxy)propa-1-in-1-yl)pyridinecarboxylic acid with a yield of 70%. ESI-MS(M+H) + = 256.0.

[0336] Synthesis Step 3: 3-(6-((2,6-dioxopiperidine-3-yl)aminoformyl)pyridine-3-yl)prop-2-in-1-ylmethanesulfonate 700 mg, 2.73 mmol of 5-(3-((methylsulfonyl)oxy)propa-1-in-1-yl)pyridinecarboxylic acid was dissolved in 15 mL of DMF. 3-aminopiperidine-2,6-dione (418 mg, 3.27 mmol), HATU (1.2 g, 3.27 mmol), and DIPEA (827 mg, 8.19 mmol) were added sequentially to the system, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, water was added to precipitate a solid. DCM was added for extraction, the mixture was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. Column chromatography yielded 740 mg of 3-(6-((2,6-dioxopiperidine-3-yl)aminoformyl)pyridine-3-yl)propa-2-in-1-ylmethanesulfonate as a white solid, with a yield of 75%. ESI-MS(M+H) + =366.1.

[0337] [Table 14]

[0338] Example 1. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] Intermediate 63 (5.47 g, 10 mmol) and intermediate 133 (3.28 g, 10 mmol) were dissolved in 40 mL of dichloroethane solution of triethylamine (101 mg, 1 mmol), and the mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (10.60 g, 50 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, ethyl acetate and aqueous solution were added for extraction, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure. The compound was purified by column chromatography to obtain compound 001. ESI-MS: m / z = 858 [M+H] + .

[0339] Example 2. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 64 to obtain compound 002. ESI-MS: m / z = 846 [M+H] + .

[0340] Example 3. 5-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidinyl-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 65 to obtain compound 003. ESI-MS: m / z = 872 [M+H] + .

[0341] Example 4. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 66 to obtain compound 004. ESI-MS: m / z = 874 [M+H] + .

[0342] Example 5. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 67 to obtain compound 005. ESI-MS: m / z = 830 [M+H] + .

[0343] Example 6. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxohexahydroimidazo[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 68 to obtain compound 006. ESI-MS: m / z = 844 [M+H] + .

[0344] Example 7. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-6-ethyl-5-(3-(3-(3-methyl-2-oxyimidazoline-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 69 to obtain compound 007. ESI-MS: m / z = 832 [M+H] + .

[0345] Example 8. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxohexahydrocyclopenta[d]imidazole-1(2H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 70 to obtain compound 008. ESI-MS: m / z = 844 [M+H] + .

[0346] Example 9. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxooctahydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 71 to obtain compound 009. ESI-MS: m / z = 858 [M+H] + .

[0347] Example 10. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 72 to obtain compound 010. ESI-MS: m / z = 830 [M+H] + .

[0348] Example 11. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(5-methyl-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 73 to obtain compound 011. ESI-MS: m / z = 844 [M+H] + .

[0349] Example 12. 3-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 2, with intermediate 133 replaced by intermediate 134 to obtain compound 012. ESI-MS: m / z = 874 [M+H] + .

[0350] Example 13. 3-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 2, with intermediate 133 replaced by intermediate 135 to obtain compound 013. ESI-MS: m / z = 860 [M+H] + .

[0351] Example 14. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 2, with intermediate 133 replaced by intermediate 136 to obtain compound 014. ESI-MS: m / z = 832 [M+H] + .

[0352] Example 15. 3-((4-(4-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperazine-1-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 74 to obtain compound 015. ESI-MS: m / z = 833 [M+H] + .

[0353] Example 16. 3-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)methyl)piperazine-1-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 15, with intermediate 133 replaced by intermediate 137 to obtain compound 016. ESI-MS: m / z = 847 [M+H] + .

[0354] Example 17. 3-((4-(9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-3,9-diazaspiro[5.5]undeka-3-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 75, and intermediate 1339 was replaced with compound 133-1 to obtain compound 017. ESI-MS: m / z = 846 [M+H] + .

[0355] Example 18. 3-((4-(6-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 17, with intermediate 75 replaced by intermediate 76 to obtain compound 018. ESI-MS: m / z = 790 [M+H] + .

[0356] Example 19. 3-((4-(2-(4-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-yl)-7-azaspiro[3.5]non-7-yl)phenyl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 77, and intermediate 133 was replaced with intermediate 138 to obtain compound 019. ESI-MS: m / z = 901 [M+H] + .

[0357] Example 20. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 133 replaced by intermediate 139 to obtain compound 020. ESI-MS: m / z = 858 [M+H] + .

[0358] Example 21. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(5-((2,6-dioxopiperidine-3-yl)amino)pyridine-2-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 133 replaced by 3-((6-(3-oxoazetidine-1-yl)pyridine-3-yl)amino)piperidine-2,6-dione to obtain compound 021. ESI-MS: m / z = 805 [M+H] + .

[0359] Example 22. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, and intermediate 133 was replaced with 3-(3-methyl-2-oxo-4-(3-oxoazetidine-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione to obtain compound 022. ESI-MS: m / z = 859 [M+H] + .

[0360] Example 23. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxo-1,2-dihydroisoquinoline-6-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 133 replaced by 3-(1-oxo-6-(3-oxoazetidine-1-yl)isoquinoline-2(1H)-yl)piperidine-2,6-dione to obtain compound 023. ESI-MS: m / z = 856 [M+H] + .

[0361] Example 24. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, and intermediate 133 was replaced with 3-(1-oxo-6-(3-oxoazetidine-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)piperidine-2,6-dione to obtain compound 023. ESI-MS: m / z = 858 [M+H] + .

[0362] Example 25. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 78 to obtain compound 025. ESI-MS: m / z = 852 [M+H] + .

[0363] Example 26. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-5-(3-(3-oxoimidazon[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 79 to obtain compound 026. ESI-MS: m / z = 838 [M+H] + .

[0364] Example 27. 5-(3-(3-cyclopentyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 80 to obtain compound 027. ESI-MS: m / z = 844 [M+H] + .

[0365] Example 28. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-formyl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 81, and intermediate 133 was replaced with intermediate 140 to obtain compound 028. ESI-MS: m / z = 914 [M+H] + .

[0366] Example 29. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(4-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)propa-1-in-1-yl)piperidine-1-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis steps were the same as those for synthesis step 1 of intermediate 63, with compound intermediate 9 replaced by intermediate 82 and intermediate 52 replaced by intermediate 141 to obtain compound 029. ESI-MS: m / z = 911 [M+H] + .

[0367] Example 30. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 83, and intermediate 133 was replaced with intermediate 140 to obtain compound 030. ESI-MS: m / z = 858 [M+H] + .

[0368] Example 31. 3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 84, and intermediate 133 was replaced with intermediate 140 to obtain compound 031. ESI-MS: m / z = 846 [M+H] + .

[0369] Example 32. 3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-5-(3-(3-(oxetan-3-yl)-2-oxyimidazoline-1-yl)piperidine-1-yl)pyrazine-2-carboxamide [ka] The synthesis method was as described in Example 31, with intermediate 140 replaced by intermediate 137 to obtain compound 032. ESI-MS: m / z = 818 [M+H] + .

[0370] Example 33. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 83, and intermediate 133 was replaced with intermediate 137 to obtain compound 033. ESI-MS: m / z = 830 [M+H] + .

[0371] Example 34. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, with intermediate 133 replaced by intermediate 142 to obtain compound 034. ESI-MS: m / z = 886 [M+H] + .

[0372] Example 35. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 85 to obtain compound 035. ESI-MS: m / z = 833 [M+H] + .

[0373] Example 36. 4-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-2-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrimidine-5-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 86 to obtain the compound. ESI-MS: m / z = 832 [M+H] + .

[0374] Example 37. 2-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-5-fluoro-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)nicotinamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 87 to obtain compound 037. ESI-MS: m / z = 849 [M+H] + .

[0375] Example 38. 2-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-methylpiperidine-4-yl)phenyl)amino)-5-methoxy-6-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)nicotinamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 88 to obtain compound 038. ESI-MS: m / z = 861 [M+H] + .

[0376] Example 39. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 80 to obtain compound 039. ESI-MS: m / z = 872 [M+H] + .

[0377] Example 40. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)-4-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 89 to obtain compound 040. ESI-MS: m / z = 890 [M+H] + .

[0378] Example 41. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)-2-fluorophenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 90 to obtain compound 041. ESI-MS: m / z = 890 [M+H] + .

[0379] Example 42. 3-((3-cyano-4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 91 to obtain compound 042. ESI-MS: m / z = 897 [M+H] + .

[0380] Example 43. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-3-fluoropiperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 92 to obtain compound 043. ESI-MS: m / z = 890 [M+H] + .

[0381] Example 44. 3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(4-methyl-5-oxo-4,6-diazaspiro[2.4]cycloheptan-6-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 93 to obtain compound 044. ESI-MS: m / z = 844 [M+H] + .

[0382] Example 45. 3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-5-(3-(3-oxohexahydroimidazole[1,5-a]pyridine-2(3H)-yl)piperidine-1-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 34, with intermediate 63 replaced by intermediate 94 to obtain compound 045. ESI-MS: m / z = 858 [M+H] + .

[0383] Example 46. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 95 to obtain compound 046. ESI-MS: m / z = 802 [M+H] + .

[0384] Example 47. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-isopropyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyrazine-2-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 96 to obtain compound 047. ESI-MS: m / z = 830 [M+H] + .

[0385] Example 48. 2-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-6-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 97 to obtain compound 048. ESI-MS: m / z = 801 [M+H] + .

[0386] Example 49. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98 to obtain compound 049. ESI-MS: m / z = 803 [M+H] + .

[0387] Example 50. 3-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-5-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octan-2-yl)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 99 to obtain compound 050. ESI-MS: m / z = 816 [M+H] + .

[0388] Example 51. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(-6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as described in Example 49, with intermediate 133 replaced by intermediate 143 to obtain compound 051. ESI-MS: m / z = 821 [M+H] + .

[0389] Example 52. 5-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-3-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)pyrazine-2-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 80, and intermediate 133 was replaced with intermediate 144 to obtain compound 052. ESI-MS: m / z = 890 [M+H] + .

[0390] Example 53. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 140 to obtain compound 053. ESI-MS: m / z = 833 [M+H] + .

[0391] Example 54. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisooctyl-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-ethyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 101, and intermediate 133 was replaced with intermediate 140 to obtain compound 054. ESI-MS: m / z = 847 [M+H] + .

[0392] Example 55. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-isopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 102, and intermediate 133 was replaced with intermediate 140 to obtain compound 055. ESI-MS: m / z = 861 [M+H] + .

[0393] Example 56. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(trifluoromethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 103, and intermediate 133 was replaced with intermediate 140 to obtain compound 056. ESI-MS: m / z = 887 [M+H] + .

[0394] Example 57. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(2,2,2-trifluoroethyl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 104, and intermediate 133 was replaced with intermediate 140 to obtain compound 057. ESI-MS: m / z = 901 [M+H] + .

[0395] Example 58. 3-(3-(3-cyclopropyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 105, and intermediate 133 was replaced with intermediate 140 to obtain compound 058. ESI-MS: m / z = 859 [M+H] + .

[0396] Example 59. 3-(3-(3-cyclobutyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 106, and intermediate 133 was replaced with intermediate 140 to obtain compound 059. ESI-MS: m / z = 873 [M+H] + .

[0397] Example 60. 3-(3-(3-cyclopentyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 107, and intermediate 133 was replaced with intermediate 140 to obtain compound 060. ESI-MS: m / z = 887 [M+H] + .

[0398] Example 61. 3-(3-(3-cyclohexyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 108, and intermediate 133 was replaced with intermediate 140 to obtain compound 061. ESI-MS: m / z = 901 [M+H] + .

[0399] Example 62. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(oxetan-3-yl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 109, and intermediate 133 was replaced with intermediate 140 to obtain compound 062. ESI-MS: m / z = 875 [M+H] + .

[0400] Example 63. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 110, and intermediate 133 was replaced with intermediate 140 to obtain compound 063. ESI-MS: m / z = 903 [M+H] + .

[0401] Example 64. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 140 to obtain compound 064. ESI-MS: m / z = 895 [M+H] + .

[0402] Example 65. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(2-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 112, and intermediate 133 was replaced with intermediate 140 to obtain compound 065. ESI-MS: m / z = 913 [M+H] + .

[0403] Example 66. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-(3-fluorophenyl)-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 113, and intermediate 133 was replaced with intermediate 140 to obtain compound 066. ESI-MS: m / z = 913 [M+H] + .

[0404] Example 67. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-(pyridine-3-yl)imidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 114, and intermediate 133 was replaced with intermediate 140 to obtain compound 067. ESI-MS: m / z = 896 [M+H] + .

[0405] Example 68. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(4-methyl-5-oxo-4,6-diazaspiro[2,4]heptan-6-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 115, and intermediate 133 was replaced with intermediate 140 to obtain compound 068. ESI-MS: m / z = 859 [M+H] + .

[0406] Example 69. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(5-methyl-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 116, and intermediate 133 was replaced with intermediate 140 to obtain compound 069. ESI-MS: m / z = 873 [M+H] + .

[0407] Example 70. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-oxytrihydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 117, and intermediate 133 was replaced with intermediate 140 to obtain compound 070. ESI-MS: m / z = 859 [M+H] + .

[0408] Example 71. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 140 to obtain compound 071. ESI-MS: m / z = 845 [M+H] + .

[0409] Example 72. 3-(6-(3-cyclopentyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-5-((4-((1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 118, and intermediate 133 was replaced with intermediate 140 to obtain compound 072. ESI-MS: m / z = 899 [M+H] + .

[0410] Example 73. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(2-oxo-3-phenylimidazoline-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 119, and intermediate 133 was replaced with intermediate 140 to obtain compound 073. ESI-MS: m / z = 907 [M+H] + .

[0411] Example 74. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-oxotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 120, and intermediate 133 was replaced with intermediate 140 to obtain compound 074. ESI-MS: m / z = 871 [M+H] + .

[0412] Example 75. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.2]octane-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 121, and intermediate 133 was replaced with intermediate 140 to obtain compound 075. ESI-MS: m / z = 859 [M+H] + .

[0413] Example 76. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisooctyl-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-carboxamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 142 to obtain compound 076. ESI-MS: m / z = 819 [M+H] + .

[0414] Example 77. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 100 to obtain compound 077. ESI-MS: m / z = 791 [M+H] + .

[0415] Example 78. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 85, and intermediate 133 was replaced with intermediate 134 to obtain compound 078. ESI-MS: m / z = 833 [M+H] + .

[0416] Example 79. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 85 to obtain compound 079. ESI-MS: m / z = 805 [M+H] + .

[0417] Example 80. 5-((2-(1-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 122 to obtain compound 080. ESI-MS: m / z = 763 [M+H] + .

[0418] Example 81. 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 122, and intermediate 133 was replaced with intermediate 140 to obtain compound 081. ESI-MS: m / z = 805 [M+H] + .

[0419] Example 82. 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 123, and intermediate 133 was replaced with intermediate 140 to obtain compound 082. ESI-MS: m / z = 834 [M+H] + .

[0420] Example 83. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 134 to obtain compound 083. ESI-MS: m / z = 819 [M+H] + .

[0421] Example 84. 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 124, and intermediate 133 was replaced with intermediate 145 to obtain compound 084. ESI-MS: m / z = 844 [M+H] + .

[0422] Example 85. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 147 to obtain compound 085. ESI-MS: m / z = 851 [M+H] + .

[0423] Example 86. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 146 to obtain compound 086. ESI-MS: m / z = 819 [M+H] + .

[0424] Example 87. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisooctyl-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxyimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with intermediate 148 to obtain compound 087. ESI-MS: m / z = 819 [M+H] + .

[0425] Example 88. 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 100, and intermediate 133 was replaced with 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-aminoacetal to obtain compound 088. ESI-MS: m / z = 834 [M+H] + .

[0426] Example 89. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 142 to obtain compound 089. ESI-MS: m / z = 881 [M+H] + .

[0427] Example 90. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 111 to obtain compound 090. ESI-MS: m / z = 853 [M+H] + .

[0428] Example 91. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 125, and intermediate 133 was replaced with intermediate 134 to obtain compound 091. ESI-MS: m / z = 895 [M+H] + .

[0429] Example 92. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, yielding intermediate 63 as intermediate 125 and compound 092. ESI-MS: m / z = 867 [M+H] + .

[0430] Example 93. 5-((2-(1-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, with intermediate 63 replaced by intermediate 126 to obtain compound 093. ESI-MS: m / z = 825 [M+H] + .

[0431] Example 94. 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 126, and intermediate 133 was replaced with intermediate 140 to obtain compound 094. ESI-MS: m / z = 867 [M+H] + .

[0432] Example 95. 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 127, and intermediate 133 was replaced with intermediate 140 to obtain compound 095. ESI-MS: m / z = 896 [M+H] + .

[0433] Example 96. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 134 to obtain compound 096. ESI-MS: m / z = 881 [M+H] + .

[0434] Example 97. 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoquinoline-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 128, and intermediate 133 was replaced with intermediate 145 to obtain compound 097. ESI-MS: m / z = 906 [M+H] + .

[0435] Example 98. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 147 to obtain compound 098. ESI-MS: m / z = 913 [M+H] + .

[0436] Example 99. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 146 to obtain compound 099. ESI-MS: m / z = 881 [M+H] + .

[0437] Example 100. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazoline-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with intermediate 145 to obtain compound 100. ESI-MS: m / z = 881 [M+H] + .

[0438] Example 101. 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(3-(2-oxo-3-phenylimidazole-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 111, and intermediate 133 was replaced with 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-aminoacetal to obtain compound 101. ESI-MS: m / z = 896 [M+H] + .

[0439] Example 102. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 142 to obtain compound 102. ESI-MS: m / z = 831 [M+H] + .

[0440] Example 103. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 98 to obtain compound 103. ESI-MS: m / z = 831 [M+H] + .

[0441] Example 104. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 129, and intermediate 133 was replaced with intermediate 134 to obtain compound 104. ESI-MS: m / z = 845 [M+H] + .

[0442] Example 105. 5-((4-(1-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-4-methylpiperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 129 to obtain compound 105. ESI-MS: m / z = 817 [M+H] + .

[0443] Example 106. 5-((2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)azetidine-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as described in Example 1, with intermediate 63 replaced by intermediate 130 to obtain compound 106. ESI-MS: m / z = 775 [M+H] + .

[0444] Example 107. 5-((2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 130, and intermediate 133 was replaced with intermediate 140 to obtain compound 107. ESI-MS: m / z = 817 [M+H] + .

[0445] Example 108. 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 131, and intermediate 133 was replaced with intermediate 140 to obtain compound 108. ESI-MS: m / z = 846 [M+H] + .

[0446] Example 109. 5-((4-(1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl)-[1,4'-bipiperidinyl]-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 134 to obtain compound 109. ESI-MS: m / z = 831 [M+H] + .

[0447] Example 110. 5-((4-(4-(3-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoquinoline-5-yl)propa-2-in-1-yl)piperazine-1-yl)piperidine-1-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoisoimidazole-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 132, and intermediate 133 was replaced with intermediate 145 to obtain compound 110. ESI-MS: m / z = 856 [M+H] + .

[0448] Example 111. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 147 to obtain compound 111. ESI-MS: m / z = 863 [M+H] + .

[0449] Example 112. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 146 to obtain compound 112. ESI-MS: m / z = 831 [M+H] + .

[0450] Example 113. 5-((4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with intermediate 148 to obtain compound 113. ESI-MS: m / z = 831 [M+H] + .

[0451] Example 114. 5-((4-(1-((1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)phenyl)amino)-3-(6-(3-methyl-2-oxoimidazolin-1-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1,2,4-triazine-6-formamide [ka] The synthesis method was as in Example 1, but intermediate 63 was replaced with intermediate 98, and intermediate 133 was replaced with 1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)piperidine-4-aminoacetal to obtain compound 114. ESI-MS: m / z = 846 [M+H] + .

[0452] Example 115: 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide(130) [ka] Intermediate 165 (150 mg, 0.25 mmol) was dissolved in 2 mL of DCM, and TFA (1.00 mL) was added to the system. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain 122 mg of the yellow liquid (R)-5-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide. The above product was dissolved in 3 mL of DMF, and DIPEA (97 mg, 0.75 mmol) and intermediate 142 (107 mg, 0.30 mmol) were added sequentially to the system. The mixture was stirred at room temperature for 10 minutes, and then acetic acid (0.1 mL) and sodium borohydride cyanohydride (47 mg, 0.75 mmol) were added to the system. The mixture was reacted at room temperature for 1 hour. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to adjust the pH to basic, and a solid precipitated. The solution was filtered to obtain a yellow solid, dissolved with DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (DCM / MeOH elution) yielded 84 mg of 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide in 40% yield. ESI-MS: m / z = 838.4 [M+H] + . 1H-NMR (400 MHz, CDCl3) δ 10.87 (brs, 1H), 8.23 ​​(brs, 1H), 7.62 - 7.71 (m, 2H), 7.50 - 7.52 (m, 1H), 7.20 - 7.30 (m, 1H), 6.92 - 6.97 (m, 2H), 6.65 - 6.69 (m, 1H), 5.54 (brs, 1H), 4.91 - 4.94 (m, 1H), 3.73 - 3.79 (m, 1H), 2.98 - 3.61 (m, 13H), 2.43 - 2.89 (m, 13H), 2.09 - 2.25 (m, 2H), 1.85 - 2.01 (m, 8H).

[0453] Example 116: 5-((4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)-3-fluorophenyl)amino)-3-((R)-3-(3-methyl-2-oxoimidazolin-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide(134) [ka] Intermediate 165 (150 mg, 0.25 mmol) was dissolved in 3 mL of DCM, and TFA (1.00 mL) was added to the system. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain 124 mg of the yellow liquid (R)-5-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)-3-(3-(3-methyl-2-oxoimidazolidine-1-yl)piperidine-1-yl)-1,2,4-triazine-6-formamide. The above product was added to 3 mL of DMF, and DIPEA (97 mg, 0.75 mmol) and intermediate 140 (111 mg, 0.30...

Claims

1. General formula (I): 【Chemistry 1】 (I) A compound having the structure shown, or its stereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof however, BTK ＣＬ This represents a chemical ligand that can bind to BTK kinase. E3 ＣＬ This represents a chemical ligand that can bind to E3 ubiquitin ligase. L is BTK ＣＬ and E3 ＣＬ A compound characterized by representing a chemical group or chemical bond that connects two or more.

2. E3 ＣＬ The compound according to claim 1, characterized in that it is selected from chemical fragments that can bind to CRBN E3 ubiquitin ligase.

3. L has the following structure: -X1-L1-X2-Cyc1-X3-L2-X4-Cyc2-X5-L3-X6-Cyc3-X7-L4-X8- however, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from nonexistent, -O-, -S-, and -N(Ra)-. L1, L2, L3, and L4 are each independently selected from absence, chemical bond, C1-C4 alkyl group, C2-C4 alkenyl group, and C2-C4 alkynyl group, where the alkyl group, alkenyl group, and alkynyl group may be substituted with oxo, alkyl, halogen, cyano group, or halogenated alkyl group. Cyc1, Cyc2, and Cyc3 are each independently selected from absent, a 3-12 member heterocycle, a 5-12 member aromatic ring, a 5-12 member heteroaromatic ring, a 3-12 member cycloalkane, a 4-12 member cycloalkyne, and a 3-12 member cycloalkene, where the heterocycle, aromatic ring, heteroaromatic ring, cycloalkane, cycloalkyne, and cycloalkene may be substituted with oxo, alkyl, halogen, cyano, or halogenated alkyl groups. The compound according to claim 2, characterized in that Ra is selected from H and C1-C4 alkyl groups.

4. BTK ＣＬ The following structures are selected: 【Chemistry 2】 Here, BTK ＣＬ If structure B, C, or D is selected, Rb is H, halogen, cyano group, methyl group, -CF ３ , selected from C1-C3 alkoxy groups, One or more Rc are independently selected from H, CN, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, C1-C4 halogenated alkyl group, C1-C4 alkoxy group, and C1-C4 alkylamino group. Rd is selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclic groups, where the alkyl group, cycloalkyl group, and heterocyclic group may be further substituted with one or more substituents, the substituents being selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups. The compound according to claim 3, characterized in that p is selected from an integer between 0 and 4.

5. BTK ＣＬ is selected from the following structures: 【Transformation 3】 Y １ N, CR ２ Selected from, Y ２ , Y ３ These are independently selected from N and CH. Ring A is selected from 3- to 12-membered complex rings. Ring B is selected from a 5-6 membered heteroaromatic ring or a 5-10 membered heterocycle, where the heteroaromatic ring or heterocycle may be further substituted with one or more substituents, the substituents being selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups, where two substituents simultaneously substituted in ring B can be linked to form a crosslinked ring, a spiro ring, or a fused ring. D is selected from a chemical bond, a C1-C3 alkyl group, -O-, -NH-, and -S-, and one or more R １ These are, independently, H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl, -CN, -COOH, and -NH. ２ Selected from, R ２ This is selected from hydrogen, cyano group, halogen, C1-C4 alkyl group, C3-C8 cycloalkyl group, C1-C4 halogenated alkyl group, and C1-C4 alkoxy group. One or more R ３ The substituents are selected from a 3-12 member heterocyclic group, a 5-12 member heteroaryl group, a 5-12 member aryl group, a 3-12 member cycloalkyl group, a halogen, a C1-C4 alkyl group, a C1-C4 halogenated alkyl group, a C1-C4 alkoxy group, a cyano group, an oxo group, a carboxyl group, an ester group, an amide group, and a hydroxyl group, where the heterocyclic group, heteroaryl group, aryl group, and cycloalkyl group may be further substituted, and the substituents are selected from a halogen, a C1-C4 alkyl group, a C1-C4 halogenated alkyl group, a C1-C4 alkoxy group, a cyano group, an oxo group, a carboxyl group, an ester group, an amide group, and a hydroxyl group, and the two R groups in ring A ３ These can be linked together to form spiro rings, crosslinking rings, and condensed rings. m is selected from integers between 0 and 3. n is selected from integers between 0 and 2. 【change】 This indicates that the atom to which it is linked is linked to L. Y １ If is selected from CH, and ring A is a monoring, and ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 4-6 membered alkyl heteroring, or an 8-10 membered spiroring, then R ３ The compound according to claim 3, characterized in that it is not a C1-C4 alkyl group or a C1-C4 halogenated alkyl group.

6. A compound having the structure shown in general formula IIb, 【Chemistry 4】 (IIb) The compound according to claim 4, characterized in that it is a stereoisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. Compounds having the structures shown in general formulas III(a) and III(b), 【Transformation 5】 or its stereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Ring B is not a bridging ring. R ３ The substituent is selected from C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, 3-6 membered cycloalkyl groups, 3-6 membered heterocyclic groups, 5-6 membered aryl groups, and 5-6 membered heteroaryl groups, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group may be further substituted with one or more substituents, the substituents being selected from halogens, C1-C4 alkyl groups, C1-C4 halogenated alkyl groups, C1-C4 alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups, and two substituents in the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group can be linked to form a fused ring, a crosslinked ring, or a spiro ring. Y １ If selected from CH, R ３ The compound according to claim 5, characterized in that it is not a C1-C4 alkyl group or a C1-C4 halogenated alkyl group.

8. Compounds having the structure shown in general formula IV(a), IV(b), IV(c), or IV(d), 【Transformation 6】 or its stereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof However, the fused ring structure or spiro ring structure consisting of rings G and F is selected from the following: 【Transformation 7】 The compound according to claim 5, characterized in that the above-mentioned fused ring structure and spiro ring structure may be further substituted with one or more substituents, the substituent being selected from halogen, C1-C4 alkyl group, C1-C4 halogenated alkyl group, C1-C4 alkoxy group, cyano group, oxo, carboxyl group, ester group, amide group, and hydroxyl group.

9. Compounds having the structure shown in general formula V(a) or V(b), 【Transformation 8】 or its stereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Z is -CH ２ -ien-CH ２ CH ２ A compound according to claim 5, selected from - and -O-.

10. R ３ Preferably, it is selected from C1-C4 alkyl groups and ring D. Ring D is, 【Chemistry 9】 The substituent is selected from the following, and ring D may be further substituted with one or more, and the substituent may be on the C atom or the N atom, and the substituent is selected from halogen, C1-C4 alkyl group, C1-C4 halogenated alkyl group, C1-C4 alkoxy group, cyano group, oxo, carboxyl group, ester group, amide group, hydroxyl group, Y １ If R is CH, ３ The compound according to claim 7, characterized in that is selected from ring D.

11. Compounds having the structure shown in general formula (VI), 【Chemistry 10】 (VI) or its stereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, prodrug, however, L is a benzene ring and E3 ＣＬ It represents a chemical group or chemical bond that connects them. E3 ＣＬ is, E ３ This represents a chemical ligand that can bind to ubiquitin ligase. Y １ N, CR ２ Selected from, Y ２ , Y ３ These are independently selected from N and CH. D is selected from chemical bonds, One or more R １ These are H, halogen, and C, respectively. １ -C ６ alkyl group, C １ -C ６ Halide alkyl groups, -CN, -COOH, -NH ２ Selected from, R ２ H, cyano group, halogen, C １ -C ４ alkyl group, C ３ -C ８ Cycloalkyl groups, C １ -C ４ Alkyl halogenated compounds, C １ -C ４ Selected from alkoxy groups, Ring B is selected from a 5-6 membered heteroaryl group and a 5-10 membered heterocyclic group, where the heteroaryl group and heterocyclic group may be further substituted with one or more substituents, the substituents being halogens, C １ -C ４ alkyl group, C １ -C ４ Alkyl halogenated compounds, C １ -C ４ The substituents are selected from alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups, and the two substituents simultaneously substituted in ring B can be linked to form a crosslinked ring, a spiro ring, or a fused ring. R ３ C １ -C ４ alkyl group, C １ -C ４ Selected from halogenated alkyl groups, 3-6 membered cycloalkyl groups, 3-6 membered heterocyclic groups, 5-6 membered aryl groups, and 5-6 membered heteroaryl groups, where the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group may be further substituted with one or more substituents, the substituents being halogens, C １ -C ４ alkyl group, C １ -C ４ Alkyl halogenated compounds, C １ -C ４ Selected from alkoxy groups, cyano groups, oxo groups, carboxyl groups, ester groups, amide groups, and hydroxyl groups, two substituents in a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group can be linked to form a fused ring, a crosslinked ring, or a spiro ring. n is selected from integers between 0 and 2. Y １ If is selected from CH, and ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 4-6 membered hetero ring, or an 8-10 membered spiro ring, then R ３ C １ -C ４ alkyl group, C １ -C ４ The compound according to claim 5, characterized in that it is not a halogenated alkyl group.

12. L is 【Chemistry 11】 【change】 【change】 Selected from, E3 ＣＬ teeth, 【Chemistry 12】 Selected from, Re is H, F, Cl, -CH ３ , -OMe, -CN, -CF ３ ,-CHF ２ , -CH(CH ３ ) ２ -Cyclopropyl group, -C(O)NH ２ , -S(O) ２ Rf, -P(O)(Rf) ２ Selected from, Rd' is selected from H, -RfOCORg, -RfOCORg, -RfOCONRgRh, -COORf, -CONRfRg, Rf, Rg, and Rh are each independent of H and C. １ -C ８ Selected from alkyl groups, 3-8 membered cycloalkyl groups, 3-8 membered heterocyclic groups, C1-C6 membered alkyl groups, 3-8 membered cycloalkyl groups, and C1-C6 alkyl groups, Alternatively, two adjacent Re in the benzene ring can form a 7- to 10-membered benzo ring together with the benzene ring, and the C atoms in the benzo ring may be further substituted with one or more heteroatoms, the heteroatom being selected from N, O, S, and the benzo ring is optionally H, F, Cl, -CH ３ , -OMe, -CN, -CF ３ , -CHF ２ , -CH(CH ３ ), ２ , -cyclopropyl group, -C(O)NH ２ and is substituted with W １ , W ２ It is selected from CH and N. The compound according to any one of claims 1 to 11, characterized in that q is selected from 0, 1, 2, and 3.

13. E3 ＣＬ teeth, 【Chemistry 13】 【change】 The compound according to claim 12, characterized by being selected from the above.

14. The compound according to claim 1, characterized by being selected from the following compounds, or stereoisomers thereof, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof. Table 1

15. A pharmaceutical composition characterized by comprising one or more compounds described in any one of claims 1 to 14.

16. Application of the compound according to any one of claims 1 to 14 in the preparation of a drug for treating, alone or in combination with other drugs, a disease, disorder, or condition caused by inhibition or degradation of Bruton's tyrosine kinase activity.

17. The application according to claim 16, characterized in that the aforementioned disease, disorder, or symptom is a disease, disorder, or symptom caused by inhibition or degradation of Bruton's tyrosine kinase mutations.

18. The application according to claim 16, characterized in that the disease is selected from one or more of B-cell or plasma cell proliferation disorders and autoimmune diseases.

19. The application according to claim 18, characterized in that the B-cell or plasma cell proliferative disease includes diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, plasmacytoplasm, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia or lymphomatoid granulomatosis, and multiple myeloma.

20. The aforementioned autoimmune diseases include inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuritis, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, and celiac disease. The application according to claim 18, characterized in that it includes K's disease, Goodpasture syndrome, immune thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia generalis, Behçet's disease, chronic fatigue, familial autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular totonia, scleroderma or vulvodysia and chronic graft-versus-host disease.

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