Isoindoline derivatives, benzoindole derivatives and their uses

Abstract

This application relates to the field of biomedical technology, and more specifically to the compound represented by formula (I), its pharmaceutically acceptable salt, its deuterated compound, its stereoisomer, its tautomer, or mixtures thereof, and the use of said compound as an immunomodulator for dual targeting of IKZF1 and IKZF3. TIFF2026511128000306.tif30170

Description

[Technical Field]

[0001] This application belongs to the field of pharmaceutical chemistry and relates to immunomodulators for dual targeting of IKZF1 and IKZF3 and their use. [Background technology]

[0002] Multiple myeloma (MM) is a hematological malignancy caused by abnormal proliferation of plasma cells (Terpos E, Politou M, Rahemtulla. The role of markers of bone remodeling in multiple myeloma. Blood Reviews 2005;19:125-142). It is primarily characterized by the highly active proliferation of plasma cells in the bone marrow, accompanied by excessive secretion of monoclonal immunoglobulins. Only a small number of patients have non-secretory MM, which does not produce M protein. Significant breakthroughs have been made in the treatment of multiple myeloma (MM), with several drugs approved by the FDA for the treatment of MM, including proteasome inhibitors (bortezomib), immunomodulators (lenalidomide and pomalidomide), CD38 monoclonal antibodies (daratumumab and elotuzumab), and histone deacetylase (HDAC) inhibitors (panobinostat) (Taylor D. Multiple Myeloma Therapy in 2015: “An Extraordinary Moment in Oncology”. Am Health Drug Benefits 2016;9:1-12). Of these, molecularly adhesive immunomodulators are currently the focus of drug development.

[0003] Molecular glue degraders are a group of small molecules that can induce and stabilize the binding of E3 ubiquitin ligase to target proteins, resulting in ubiquitination and proteasomal degradation of target proteins. Compared to bifunctional molecular degraders (protac), molecular glues have a lower binding affinity to target proteins, but can bind to E3 ubiquitin ligases and mediate their linkage to the target protein through them. Therefore, molecular glues can degrade target proteins without a specific binding pocket. In addition, the target protein of the molecular glue itself needs to have a non-functional, weak affinity to the E3 ligase. Molecular glues can bind to the gap between interfaces, strengthening these two linkages and resulting in a strong functional interaction. Currently, molecular glues for MM, such as lenalidomide and pomalidomide, act by recruiting CRBN ubiquitin ligase, promoting the binding of CRBN to the zinc finger protein transcription factor IKZF1 / 3, thereby leading to the ubiquitination and degradation of IKZF1 / 3 (Gao SB. Novel immunomodulatory drugs and neo-substrates. Biomarker Res 2020;8:2). Since IKZF1 / 3 can promote MM cell proliferation by regulating the expression of the oncogenes IRF4 and c-myc, molecular glue-induced degradation of IKZF1 / 3 can significantly inhibit MM cell proliferation. While lenalidomide has good efficacy against MM, drug tolerance usually develops in most patients after two years of use. Pomalidomide is a preferred drug for MM patients who have developed drug resistance to lenalidomide. Several studies have shown that the combination of pomalidomide and dexamethasone can inhibit the proliferation of lenalidomide-resistant tumor cells and induce apoptosis.Pomalidomide showed improved efficacy in patients with drug resistance to lenalidomide, but approximately one-third of patients developed point mutations in the CRBN gene after continuous administration, potentially leading to drug resistance to pomalidomide (Gooding et al., Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood 2021;14:232-237). Furthermore, while lenalidomide and pomalidomide can inhibit the proliferation of multiple myeloma, the incidence of G3 / G4 neutropenia can reach up to 35% and approximately 50%, respectively (Ghobrial et al., J Support Oncol. 2003;1:194-205, Thakurta et al., Oncotarget 2021;12:1555-63). In a Phase I clinical trial, the molecular glue CC-92480, developed by Bristol-Myers Squibb Company, had an objective response rate (ORR) of 54.4% but a neutropenia incidence of up to 53% (Richardson PG. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed / refractory multiple myeloma (RRMM). J Clinical Oncol 2020;38:8500). Therefore, the development of a molecular glue that is effective in patients with drug resistance to lenalidomide and pomalidomide, while simultaneously having lower hematological toxicity, particularly lower neutrophil toxicity, is extremely important for the treatment of MM. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Terpos E, Politou M, Rahemtulla. The role of markers of bone remodeling in multiple myeloma. Blood Reviews 2005;19:125-142 [Non-Patent Document 2] Taylor D. Multiple Myeloma Therapy in 2015: “An Extraordinary Moment in Oncology”. Am Health Drug Benefits 2016;9:1-12 [Non-Patent Document 3] Gooding et al., Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood 2021;14:232-237 [Non-Patent Document 4] Ghobrial et al., J Support Oncol. 2003;1:194-205 [Non-Patent Document 5] Thakurta et al., Oncotarget 2021;12:1555-63 [Non-Patent Document 6] Richardson PG. First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed / refractory multiple myeloma (RRMM). J Clinical Oncol 2020;38:8500 [Overview of the Initiative] [Means for solving the problem]

[0005] One object of the present application is to provide a compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture of these, [Chemical Formula] wherein, ring A is selected from 3- to 10-membered monocyclic heterocyclyl, 6- to 13-membered bridged heterocyclyl, or 6- to 13-membered fused heterocyclyl, ring B is selected from 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl, ring C is selected from optionally substituted 5- to 10-membered heteroaryl or optionally substituted 5- to 10-membered heterocyclyl, The dashed line between R1 and R2 represents connection or non-connection, When R1 and R2 are not connected, R1 is selected from H or D, and R2 is selected from O, NH, or S, When R1 and R2 are connected, R1 and R2 together with the carbon atom to which they are attached form an optionally substituted 5- to 6-membered aromatic ring, R3 is selected from H, D, or halogen, R a is each independently selected from H, C1-C6 alkyl, cyano, C1-C6 haloalkyl, or C3-C 10 cycloalkyl, and this C1-C6 alkyl and C3-C 10 cycloalkyl may each be substituted with one or more of H, halogen, hydroxy, or cyano, or two Rs a bonded to the same carbon atom together with the carbon atom to which they are attached form a C3-C6 cycloalkyl or 4- to 6-membered heterocyclyl, R4 is a single bond, -C(O)-, -NR 11 C(O)-, -NR 11 -, -CR 11 R 12 -, -CR 11 R 12 -(4- to 6-membered heterocyclyl)-, 4- to 6-membered heterocyclyl, -(C3-C6 cycloalkyl)-NR11 C(O)-, or -O-(C5~C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocyclyl and cycloalkyl may each be substituted with one or more selected from H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, or R4 and any one of R a Together with the atoms to which they are bonded, they form C3-C8 cycloalkyl or 4-6 membered heterocyclines. R5 is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen. R6, R7, R8, R9, and R 10 Each is independently selected from H or D, R 11 and R 12 Each of these is independently selected from H or C1-C6 alkyl groups, or R 11 and R 12 Together with the carbon atoms to which they are bonded, they form C3-C8 cycloalkyl or 4-6 membered heterocyclines. R b is selected from H, halogen, C1-C6 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted amino, or cyano, or two adjacent R b These, together with the carbon atoms to which they are bonded, form C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or 5-6 membered aryl groups. m is selected from 0, 1, 2, or 3. p is selected from 0, 1, 2, 3, or 4. p' is selected from 0, 1, 2, or 3. q is selected from 0, 1, 2, 3, or 4.

[0006] In some embodiments, R1 and R2 are not connected, R1 is selected from H or D, and R2 is selected from O or S. In some embodiments, R1 and R2 are not connected, R1 is selected from H or D, and R2 is selected from O, preferably R1 is selected from H and R2 is selected from O.

[0007] In some embodiments, R1 and R2 are linked together, and together with the carbon atoms to which they are bonded, they form a benzene ring.

[0008] In some embodiments, ring A is selected from a 4-8 member monocyclic heterocyclyl or a 6-10 member bridged heterocyclyl containing 1-3 heteroatoms selected from N, O, or S (preferably N or O, more preferably N). In some embodiments, ring A is selected from a 4-8 member monocyclic heterocycloalkyl or a 6-10 member bridged heterocycloalkyl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S (preferably N or O, more preferably N).

[0009] In some embodiments, ring A is selected from a 4-6 member monocyclic heterocyclyl or a 6-8 member bridged heterocyclyl. In some embodiments, ring A is selected from a 4-6 member monocyclic heterocycloalkyl or a 6-8 member bridged heterocycloalkyl containing 1-2 heteroatoms selected from N, O, or S (preferably N or O, more preferably N).

[0010] In some preferred embodiments, ring A is [ka] Selected from, at least one of X1 and X2 is N, and the other is optionally C or N, and n1, n2, and k are each independently selected from 1 or 2, more preferably ring A is [ka] Selected from.

[0011] In some preferred embodiments, ring A is [ka] Selected from.

[0012] In some more preferred embodiments, ring A is [ka] Selected from, at least one of X1 and X2 is N, and the other is optionally C or N, and n1, n2, and k are each independently selected from 1 or 2. * This represents the connection point with R4, and more preferably, ring A is [ka] Selected from.

[0013] In some more preferred embodiments, ring A is [ka] Selected from, * This indicates the connection point with R4.

[0014] In some embodiments, R a Each of these is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, and this C1-C6 alkyl may be substituted with one or more of H, halogen, hydroxyl, or cyano, or two R atoms bonded to the same carbon atom. a These, along with the carbon atoms to which they are bonded, form C3-C6 cycloalkyl groups.

[0015] In some preferred embodiments, R aEach of these is independently selected from H, C1-C3 alkyl, or C1-C3 haloalkyl, and each of these C1-C3 alkyl or C1-C3 haloalkyl may be substituted with one or more of H, hydroxyl, or cyano, preferably R a The molecule is selected from H, -CH2OH, -CH2CH2OH, -CN, or -CH2CN.

[0016] In some embodiments, R a Each of these is independently selected from H or C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), and this C1-C6 alkyl may be substituted with one or more hydroxyl or cyano compounds, or two R compounds bonded to the same carbon atom. a These, together with the carbon atoms to which they are bonded, form a C3-C6 cycloalkyl group (preferably a C3-C5 cycloalkyl group or a C3-C4 cycloalkyl group).

[0017] In some embodiments, q is selected from 0, 1, or 2.

[0018] In some preferred embodiments, two R atoms bonded to the same carbon atom a These, together with the atoms to which they are bonded, form a C3-C6 cycloalkyl group, preferably two R atoms bonded to the same carbon atom. a These, along with the atoms to which they bond, form a cyclopropyl group.

[0019] In some preferred embodiments, structural units [ka] teeth, [ka] Selected from. In some preferred embodiments, structural units [ka] teeth, [ka] Selected from.

[0020] Preferably, [ka] teeth, [ka] Selected from, * This indicates the connection point with R4.

[0021] In some embodiments, ring B is selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S (preferably N or O, more preferably N). In some embodiments, ring B is selected from a 6 membered heteroaryl containing 1-3 (preferably 1-2) heteroatoms selected from N or O (preferably N). In some embodiments, ring B is selected from 6 membered heteroaryls, such as pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

[0022] In some preferred embodiments, ring B is [ka] The formula is selected from, where X3, X4, and X5 are each independently selected from C or N, and at least one of X3, X4, and X5 is N, preferably one to two of X3, X4, and X5 are N.

[0023] In some preferred embodiments, ring B is [ka] Selected from.

[0024] In some more preferred embodiments, ring B is [ka] Selected from, in the formula, * The symbol represents the connection point with R4, and X3, X4, and X5 are each independently selected from C or N, with at least one of X3, X4, and X5 being N, preferably one or two of X3, X4, and X5 being N, and more preferably ring B is [ka] Selected from, * This indicates the connection point with R4.

[0025] In some embodiments, R b Each is independently selected from H, halogen, C1-C6 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted amino, or cyano, and m is selected from 0, 1, 2, or 3. In some embodiments, R b Each is independently selected from H, halogen, C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C1-C3 haloalkyl, C3-C6 cycloalkyl, amino, or cyano, and m is selected from 0, 1, or 2 (preferably m is 0 or 1). In some embodiments, R b Each of these is independently selected from H, halogen, C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C3 haloalkyl, and m is selected from 0, 1, or 2 (preferably m is 0 or 1).

[0026] In some preferred embodiments, R bEach is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, or bromopropyl (e.g., trifluoromethyl, trichloromethyl, or tribromomethyl), and m is selected from 0 or 1. In some preferred embodiments, R b Each is independently selected from H, F, Cl, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl, and m is selected from 0 or 1. In some preferred embodiments, R b Each of the following is independently selected from H, F, Cl, methyl, ethyl, propyl, or trifluoromethyl, and m is selected from 0 or 1.

[0027] In some embodiments, ring C is selected from a substituted or substituted 5-6 membered heteroaryl or 5-6 membered heterocyclil. In some embodiments, ring C is selected from a 5-6 membered heteroaryl or 5-6 membered heterocyclil containing 1-3 heteroatoms selected from N, O, or S, wherein the 5-6 membered heteroaryl or 5-6 membered heterocyclil is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, -C(O)R 13 , or may be replaced with one or more selected from cyano, R 13 The element is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl.

[0028] In some embodiments, ring C is selected from a 5-6 membered heteroaryl or 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, or S, wherein the 5-6 membered heteroaryl or 5-6 membered heterocyclyl is a C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a C3-C6 cycloalkyl (preferably C3-C5 cycloalkyl or C3-C4 cycloalkyl), a C1-C3 haloalkyl (e.g., C1-C3 fluoroalkyl, C1-C3 chloroalkyl, or C1-C3 bromoalkyl), a halogen (preferably F, Cl, or Br), or -C(O)R 13 , or may be substituted with one or more cyano compounds (e.g., 1 to 3, 1 to 2, or 1), R 13 is selected from H, NH2, or C1-C3 alkyl (preferably R 13 (Selected from NH2).

[0029] In some preferred embodiments, ring C is [ka] Selected from, in the formula, R c These are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, and -C(O)R 13 , or selected from cyano, z is selected from 0, 1, 2, 3, or 4, Y1 is selected from S or N, Y2 is selected from C or N, R 13 This is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl. Preferably, R c The following are independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, F, Cl, Br, -C(O)NH2, or cyano, and more preferably R cz is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, F, Cl, -C(O)NH2, or cyano, and z is selected from 0, 1, or 2.

[0030] In some preferred embodiments, ring C is [ka] Selected from, in the formula, R c These are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, and -C(O)R 13 , or selected from cyano, z is selected from 0, 1, 2, 3, or 4, R 13 This is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl. Preferably, R c The following are independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, F, Cl, Br, -C(O)NH2, or cyano, and more preferably R c z is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, F, Cl, -C(O)NH2, or cyano, and z is selected from 0, 1, or 2.

[0031] In some preferred embodiments, ring C is [ka] Selected from, in the formula, R c These are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, and -C(O)R 13 , or selected from cyano, z is selected from 0, 1, 2, 3, or 4, R 13 This is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl. Preferably, R c The following are independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, F, Cl, Br, -C(O)NH2, or cyano, and more preferably R c z is independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, F, Cl, -C(O)NH2, or cyano, and z is selected from 0, 1, or 2.

[0032] In some embodiments, R4 is a single bond, -C(O)-, -NR 11 C(O)-, -NR 11 -, -CR 11 R 12 -, -CR 11 R 12 -(4-6 member heterocycloalkyl)-, 4-6 member heterocycloalkyl, -(C3-C6 cycloalkyl)-NR 11 C(O)-, or -O-(C5~C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocycloalkyl and cycloalkyl may be substituted with one or more selected from H or C1-C3 alkyl, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, or S, R 11 and R 12 Each of these is independently selected from H or C1-C3 alkyl groups.

[0033] In some embodiments, R4 is selected from a single bond, -C(O)-, -NHC(O)-, -NH-, -CH2-(5-6 member heterocyclyl)-, 5-6 member heterocyclyl, -(C5-C6 cycloalkyl)-NHC(O)-, or -O-(C5-C6 cycloalkyl)-NHC(O)-.

[0034] In some embodiments, R4 is a single bond, -C(O)-, -NHC(O)-, -NH-, -CH2-(5-6 member heterocycloalkyl)-, 5-6 member heterocycloalkyl, -(C5-C6 cycloalkyl)-NHC(O)-, or -O-(C5-C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, or S (preferably 1 to 2 heteroatoms selected from N or O (e.g., N)).

[0035] In some preferred embodiments, R4 is a single bond, -C(O)-, -NHC(O)-, -NH- [ka] Selected from.

[0036] In some preferred embodiments, R4 is selected from a single bond.

[0037] In some embodiments, R3 is selected from H or D, preferably R3 is H. In some embodiments, p is selected from 0, 1, or 2, preferably p is 0.

[0038] In some embodiments, R5 is H. In some embodiments, p' is selected from 0, 1, or 2, and preferably p' is 0.

[0039] Several operating mechanisms, R6, R7, R8, R9, and R 10 Each of these is independently H.

[0040] In some embodiments, in the compound of formula (I), ring A is selected from a 4-8 member monocyclic heterocycloalkyl or a 6-10 member bridged heterocycloalkyl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S (preferably N or O, more preferably N), and preferably ring A is selected from a 4-6 member monocyclic heterocycloalkyl or a 6-8 member bridged heterocycloalkyl containing 1-2 heteroatoms selected from N, O, or S (preferably N or O, more preferably N). Ring B is selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S (preferably N or O, more preferably N), and preferably ring B is selected from a 6 membered heteroaryl containing 1-3 (preferably 1-2) heteroatoms selected from N or O (preferably N). The C ring is selected from a 5-6 membered heteroaryl or 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, or S, and this 5-6 membered heteroaryl or 5-6 membered heterocyclyl is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, -C(O)R 13 , or may be replaced with one or more selected from cyano, R 13 The C ring is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl, preferably the C ring is selected from a 5-6 membered heteroaryl or 5-6 membered heterocyclil containing 1-3 heteroatoms selected from N, O, or S, and this 5-6 membered heteroaryl or 5-6 membered heterocyclil is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, -C(O)R 13 , or may be replaced with one or more selected from cyano, R 13 This is selected from H, NH2, or C1-C3 alkyl groups. The dashed line between R1 and R2 indicates connection or disconnection. If R1 and R2 are not connected, R1 is selected from H or D, and R2 is selected from O or S, preferably R1 is selected from H and R2 is selected from O. When R1 and R2 are linked, R1 and R2 together with the carbon atom to which they are attached form a benzene ring, R3 is selected from H or D, preferably, R3 is H, R a is each independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, and this C1-C6 alkyl may be substituted with one or more of H, halogen, hydroxy, or cyano, or two Rs attached to the same carbon atom a together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, preferably, R a is each independently selected from H, C1-C6 alkyl, or cyano, and this C1-C6 alkyl may be substituted with one or more of hydroxy or cyano, or two Rs attached to the same carbon atom a together with the carbon atom to which they are attached form a C3-C6 cycloalkyl (preferably C3-C5 cycloalkyl or C3-C4 cycloalkyl), R4 is a single bond, -C(O)-, -NR 11 C(O)-, -NR 11 -, -CR 11 R 12 -, -CR 11 R 12 -(4-6 member heterocycloalkyl)-, 4-6 member heterocycloalkyl, -(C3-C6 cycloalkyl)-NR 11 C(O)-, or -O-(C5-C6 cycloalkyl)-NR 11 C(O)-, and this heterocycloalkyl and cycloalkyl may each be substituted with one or more selected from H or C1-C3 alkyl, and the above heterocycloalkyl contains heteroatoms selected from 1-3 N, O, or S, R 11 and R 12 are each independently selected from H or C1-C3 alkyl, R5 is H, R6, R7, R8, R9, and R 10 are each independently H, R b Each of these is independently selected from H, halogen, C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C1-C3 haloalkyl, C3-C6 cycloalkyl, amino, or cyano, preferably R b Each of these is independently selected from H, halogen, C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C3 haloalkyl. m is selected from 0, 1, or 2, preferably m is 0 or 1. p is selected from 0, 1, or 2, preferably p is 0. p' is selected from 0, 1, or 2. q is selected from 0, 1, or 2.

[0041] In some embodiments, in the compound of formula (I), ring A is [ka] Selected from, where at least one of X1 and X2 is N, and the other is optionally C or N, n1, n2, and k are each independently selected from 1 or 2, preferably ring A is [ka] Selected from, in the formula, * This indicates the connection point with R4. Ring B is, [ka] Selected from, where X3, X4, and X5 are each independently selected from C or N, and at least one of X3, X4, and X5 is N, preferably, ring B is [ka] Selected from, in the formula, * This indicates the connection point with R4. Ring C is, [Chemistry] selected from, where in the formula, R c is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, halogen, -C(O)R 13 , or cyano, z is selected from 0, 1, 2, 3, or 4, and R 13 is selected from H, NH2, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl. Preferably, ring C is [Chemistry] selected from, where in the formula, R c is independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, bromopropyl, F, Cl, Br, -C(O)NH2, or cyano, z is selected from 0, 1, or 2, The dashed line between R1 and R2 represents connection or non-connection, When R1 and R2 are not connected, R1 is selected from H or D, and R2 is selected from O or S. Preferably, R1 is selected from H, and R2 is selected from O,​​​​​​​​​​​R4 is a single bond, -C(O)-, -NHC(O)-, -NH-, -CH2-(5-6 member heterocycloalkyl)-, 5-6 member heterocycloalkyl, -(C5-C6 cycloalkyl)-NHC(O)-, or -O-(C5-C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, or S (preferably 1 to 2 heteroatoms selected from N or O (e.g., N)), R 11 R4 is selected from H or C1-C3 alkyl, preferably R4 is a single bond, -C(O)-, -NHC(O)-, -NH- [ka] Selected from, R5 is H, R6, R7, R8, R9, and R 10 Each of these is independently H, R b Each is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, or bromopropyl (e.g., trifluoromethyl, trichloromethyl, or tribromomethyl), preferably R b Each of these is independently selected from H, F, Cl, methyl, ethyl, propyl, or trifluoromethyl. m is selected from 0 or 1. p is selected from 0, 1, or 2, preferably p is 0. p' is selected from 0, 1, or 2, preferably p' is 0. q is selected from 0, 1, or 2.

[0042] In some embodiments, the compound of formula (I) described above may be one of the compounds of the following general formulas. [ka] In the formula, R1, R2, R4, R6, R7, R8, R9, R 10 , R a , R b , R c z, m, q, k, n1, n2, X1, X2, X3, X4, X5, Y1, Y2, ring A, and ring C are defined in any one of the above definitions, Preferably, R6, R7, R8, R9, and R 10 Each of these is independently H.

[0043] In some embodiments, the compound of formula (I) above may be a compound of the following general formula: [ka] In the formula, ring A, ring B, ring C, R a , R b R4, m, and q are as defined above.

[0044] In some embodiments, the compound of formula (I-1) may be the compound of formula (I-1'), [ka] In the formula, X2, X3, X4, and X5 are each independently selected from C or N, with at least one of X3, X4, and X5 being N (preferably one or two of X3, X4, and X5 being N), and R4 is a single bond, -C(O)-, -NHC(O)-, -NH-, -CH2-(5-6 member heterocycloalkyl)-, 5-6 member heterocycloalkyl, -(C5-C6 cycloalkyl)-NHC(O)-, or -O-(C5-C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, or S (preferably 1 to 2 heteroatoms selected from N or O (e.g., N)), R 11 is selected from H or C1-C3 alkyl, R bEach of the elements is independently selected from H or C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), m is selected from 0, 1, or 2 (preferably m is 0 or 1), and the ring C is selected from a 5-membered heteroaryl or 5-membered heterocyclil containing 1-3 heteroatoms selected from N, O, or S, and this 5-membered heteroaryl or 5-membered heterocyclil may be substituted with one or more elements (e.g., 1-3, 1-2, or 1) selected from C1-C6 alkyl (preferably C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C1-C3 haloalkyl (e.g., C1-C3 fluoroalkyl, C1-C3 chloroalkyl, or C1-C3 bromoalkyl), halogen (preferably F, Cl, or Br), or -C(O)NH2.

[0045] In some embodiments, in the compound of formula (I-1'), X2 and X3 are N, X4 is C or N, X5 is , m is 0, and R4 is a single bond. [ka] The ring C is selected from a 5-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, or S (preferably N or S) (preferably, the ring C is [ka] (Selected from).

[0046] In some embodiments, in the compound of formula (I-2), ring A is [ka] Selected from, where at least one of X1 and X2 is N, and the other is optionally C or N, and n1 and n2 are each independently selected from 1 or 2, preferably ring A is [ka] Selected from, in the formula, * This indicates the connection point with R4. q is 0, R4 is a single bond, -C(O)-, -NHC(O)-, -NH-, -CH2-(5-6 member heterocycloalkyl)-, or -O-(C5-C6 cycloalkyl)-NR 11 Selected from C(O)-, this heterocycloalkyl contains 1-2 heteroatoms selected from N, O, or S (preferably 1-2 N atoms), R 11 is H, preferably R4 is a single bond, -C(O)-, -NHC(O)-, -NH- [ka] Selected from, Ring B is, [ka] Selected from, where X3, X4, and X5 are each independently selected from C or N, and at least one of X3, X4, and X5 is N, preferably, ring B is [ka] Selected from, in the formula, * This indicates the connection point with R4. R b The is selected from halogens, C1-C6 alkyls (preferably C1-C5 alkyls, C1-C4 alkyls, or C1-C3 alkyls), or C1-C3 haloalkyls (fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, or bromopropyl), and preferably R b It is selected from methyl, ethyl, propyl, or trifluoromethyl. m is selected from 0 or 1. Ring C is selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S (preferably N or S), and this 5-6 membered heteroaryl may be substituted with one or more selected from C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C3-C6 cycloalkyl (e.g., C3-C5 cycloalkyl or C3-C4 cycloalkyl), C1-C3 haloalkyl, or halogen, preferably, ring C is [ka] Selected from, in the formula, R c z is independently selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, or bromopropyl, and z is selected from 0 or 1.

[0047] In some embodiments, the following compounds are examples of compounds described in any one of the above provisions, pharmaceutically acceptable salts thereof, deuterated compounds thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof: [ka] [ka] [ka] [ka] [ka] [ka]

[0048] This application further includes embodiments obtained by any combination, deletion, or substitution of any of the above embodiments and preferred embodiments.

[0049] In another aspect, the present application provides the use of a compound, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof in the preparation of a medicament for the prevention and / or treatment of cereblon-mediated diseases. Alternatively, the present application provides a compound, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof for use in the prevention and / or treatment of cereblon-mediated diseases. Alternatively, the present application provides a method for the prevention and / or treatment of cereblon-mediated diseases, comprising the step of administering a compound, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof to a subject in need.

[0050] In some preferred embodiments, the cereblon-mediated diseases described above are transmitted by IKZF1 (Ikaros) and / or IKZF3 (Aiolos).

[0051] In some preferred embodiments, the cereblon-mediated disease is cancer, tumor, immune disease, or inflammatory disease.

[0052] In some preferred embodiments, the cereblon-mediated disease described above is an autoimmune disease.

[0053] In some preferred embodiments, the cereblon-mediated disease described above is a hematological malignancy.

[0054] In some preferred embodiments, the cerebron-mediated disease described above is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0055] In another aspect, the present application provides the use of a compound described in any one of the above provisions, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof in the preparation of an immunomodulator for a dual target of IKZF1 and IKZF3. Alternatively, the present application provides a compound described in any one of the above provisions, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof for use in immunomodulation of a dual target of IKZF1 and IKZF3. Alternatively, the present application provides a method for immunomodulating a dual target of IKZF1 and IKZF3, comprising the step of administering a compound described in any one of the above provisions, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof to a subject requiring it. [Modes for carrying out the invention]

[0056] To further clarify the purpose and technical solutions of this application, this application is described in more detail below, along with specific embodiments. It should be understood that these embodiments are used solely to illustrate this application and not to limit its scope. Furthermore, any specific experimental methods not described in the embodiments below are carried out in accordance with conventional experimental methods.

[0057] In this application, if there is a discrepancy between the chemical name and the structural formula, the structural formula shall take precedence unless the context suggests that the chemical name is correct rather than the structural formula.

[0058] The structure of the compound can be determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 It is determined by 1H NMR.

[0059] Proton nuclear magnetic resonance ( 1 The chemical shift (δ) of 1H NMR is given in parts per million (ppm). Nuclear magnetic resonance measurement ( 11H NMR) was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard. The chemical shift is 10 -6 given in units of (ppm).

[0060] Measurement by mass spectrometry (MS) was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm (Thermo), model: Finnigan LCQ advantage MAX).

[0061] As the silica gel for thin-layer chromatography, Yantai (Yantai) Huanghai (Huanghai) HSGF254 or Qingdao (Qingdao) GF254 silica gel plates are used.

[0062] As the carrier for column chromatography, usually, Yantai Huanghai silica gel, 200 - 300 mesh is used.

[0063] Definitions and general terms: Unless otherwise defined, all technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art to which this application belongs. When used in this specification, unless otherwise specified, the following terms have the meanings assigned to them below.

[0064] The term "substitution" in this application means that one or more (e.g., one, two, three, or four) hydrogens on a specified atom are replaced by a selection from a specified group, provided that the normal valence of the specified atom is not exceeded in the current case and this substitution forms a stable compound. Combinations of substituents and / or variables are only permitted if such combinations form stable compounds. It should be understood that other atoms such as hydrogen atoms or substituents described in this specification may be present as necessary to satisfy the valence of the atoms.

[0065] Where this application refers to several substituents, it means that the number of substituents on the base may be within the range of zero to the maximum possible number of substituents.

[0066] Where a connecting portion is not specifically defined in this application, it means that the connecting portion may be connected to any portion on the ring. For example, [ka] This indicates that the linking site may be attached to any site on ring C. For a group having two linking sites, for example, [ka] This indicates that the linkage configuration of the two linkage sites may be reversed, that is, the two side sites may be optionally bonded to the corresponding other group, preferably the left-side site representing the bond to the group at the left-side linkage site in the compound of the corresponding general formula. As used herein, [ka] This represents the base connection point.

[0067] If the substituted portion is not specifically indicated in this application, it indicates that any substituted portion has been substituted. For example, [ka] In R c teeth, [ka] This indicates that the substitution may occur at any site on the ring.

[0068] The term "independently" means that if multiple substituents are selected from many possible substituents, those substituents may be the same or different, or if one substituent occurs multiple times, each occurrence may be selected to be the same or different.

[0069] The terms “optional” or “optionally” mean that the events or circumstances described below may or may not occur, and that such descriptions include both cases in which the events or circumstances occur and cases in which they do not occur. Whenever a group is described as “may be substituted,” that group may be unsubstituted or substituted with one or more of the indicated substituents. Where substitutions are not specified, it means that the group may be optionally substituted with one or more groups selected, but not limited to, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, cyano, nitro, amino, or aminohydroxy groups. Preferably, "may be substituted" means that the substituent is independently selected from C1-C6 alkyl, haloalkyl, C3-C6 cycloalkyl, F, Cl, Br, hydroxy, alkoxy, cyano, amino, aryl, or heteroaryl substituents, including, but not limited to, methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, fluoro, chloro, methoxy, phenyl, naphthyl, pyridyl, and pyrazinyl substituents. If the composition "optionally" contains a particular component, the composition may or may not contain that component.

[0070] The term "C" in this application m ~C n " means that the number of carbon atoms is at least m and at most n (including both endpoints m and n), where m and n are non-zero integers, and m <nである。

[0071] In this application, the term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic group consisting of a carbon atom and one or more heteroatoms as optionally selected, including a bridging ring, fused ring, or spiro-ring structure, wherein the cyclic group may be saturated or unsaturated (including aromatic), and at least one ring has at least one heteroatom (O, S, or N). Accordingly, the term "heterocyclyl" encompasses heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, and heteroaryl groups. For example, "3-10 membered heterocyclyl" refers to a 3- to 10 membered ring composed of carbon atoms and heteroatoms. Specific non-limiting examples include, but are not limited to, aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazeto, 1,2-dihydrooxet, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydrotopyridine, 3,6-dihydro-2H-pyran, and 1,2,3,6-tetrahydropyridine. In this application, the term "heterocyclil" is intended to include "heteroaryl."

[0072] In this application, the term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclic group in which any two rings in the system share two indirectly bonded atoms, and the rings may have one or more double bonds, but none of the rings have a fully conjugated π-electron system, and the rings are N, O, S(O) m This refers to a ring cyclil having one or more heteroatoms selected from (m being an integer selected from 0 to 2), with the remaining ring atoms being carbon atoms. Depending on the number of rings, the bridging heterocyclil may be a bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclil, and preferably a bicyclic heterocyclil.

[0073] In this application, the term "condensed heterocyclyl" refers to a 5-20 membered polycyclic heterocyclic group in which each ring in the system shares pairs of adjacent atoms with other rings, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and the rings are N, O, S(O) m A condensed heterocyclyl has one or more heteroatoms as ring atoms selected from (m is an integer selected from 0 to 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings, the condensed heterocyclyl may be a bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl, and preferably a bicyclic or tricyclic condensed heterocyclyl.

[0074] In this application, the term “spiroheterocyl” refers to a 5-20 member polycyclic heterocyclic group in which the rings are linked via a common carbon atom (called a spiro atom), and the rings are composed of N, O and S(O). m A spiroheterocyclyl has one or more heteroatoms as ring atoms selected from (m is an integer selected from 0 to 2), the remaining ring atoms are carbon atoms, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Depending on the number of common spiroatoms, a spiroheterocyclyl may be a monospiroheterocyclyl, a disspiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl.

[0075] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic system, including spiro and fused ring structures, containing for example 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains heteroatoms selected from one or more of N, O, and S (preferably containing 1 to 3 heteroatoms), each ring system contains a ring composed of 5 to 7 atoms, and one or more linking sites are bonded to other parts of the molecule. For example, "5- to 10-membered heteroaryl" refers to 5- to 10-membered heteroaryl composed of carbon atoms and 1 or 3 heteroatoms independently selected from N, O or S. Non-limiting examples include, but are not limited to, furanyl, imidazolyl, pyridyl, pyrrolyl, thiazolyl, purinyl, quinolinyl, thienyl, isoxazolyl, oxazolyl, pyrazinyl, benzimidazolyl, benzofuranyl, benzothienyl, furopyridinyl, etc.

[0076] As used herein, the term "alkyl" when appearing alone or in combination refers to a straight or branched chain saturated hydrocarbon group composed of only carbon and hydrogen atoms, including but not limited to C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, and C1 alkyl. Non-limiting examples of alkyl may include the following straight or branched chain saturated hydrocarbon groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and its other 7 isomers, and n-hexyl and its 16 isomers. For example, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and all isomers thereof.

[0077] In this application, the term "cycloalkyl," appearing alone or in combination, refers to saturated monocyclic, bicyclic, or tricyclic alkyl groups, including monocyclic, fused, or spirocyclic structures, where each ring portion contains 3 to 12 carbon atoms as ring members. Non-limiting examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, etc. For example, non-limiting examples of "C3-C8 cycloalkyl groups" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and these cycloalkyl groups may be substituted.

[0078] In this application, the term "haloalkyl" refers to an alkyl group in which a hydrogen atom is substituted with a halogen, for example, substituted with F or Cl. For example, non-limiting examples of "C1-C6 haloalkyl" include, but are not limited to, -CF3, -CHCF2, -CH2CH2F, or -CH2CF3.

[0079] In this application, the terms "aryl" or "aromatic ring" refer to an aromatic monocyclic, carbocyclic, or polycyclic (e.g., fused ring or spirocycle) group having at least one aromatic ring and containing 6 to 12 carbon atoms, and specific non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl.

[0080] In this application, the term "alkoxy" refers to an "-O-alkyl" group. For example, the term "C1-C3 alkoxy" refers to a saturated linear or branched hydrocarbon moiety having at least one and at most three carbon atoms bonded by oxygen to an atom. Specific exemplary examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy.

[0081] In this application, the term "amino" refers to an optional -NH2 group that may or may not be substituted. When referred to as an optional amino, the amino is -NR'R'', where R' and R'' are independently any suitable substituent of choice. For example, in the specific examples of this application, "optional amino" means that the amino may be independently substituted with one or more substituents selected from H, C=O, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, F, Cl, Br, hydroxy, C1-C6 alkoxy, cyano, 5-6 membered aryl, or 5-6 membered heteroaryl.

[0082] In this specification, unless otherwise specifically defined, heteroatoms may be any atom other than C and H atoms commonly used in the art, such as N, O, S, P, Si, etc.

[0083] In this application, the term "halogen" refers to F, Cl, Br, or I.

[0084] In this application, the term "cyano" refers to the -CN group.

[0085] The alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups mentioned above may not be substituted, or may be optionally substituted with one or more substituents. For example, they may be substituted with the following substituents: alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, halogen, hydroxy, alkoxy, cyano, nitro, amino, or aminohydroxy groups. Preferably, they may be optionally substituted with substituents independently selected from C1-C6 alkyl, haloalkyl, C3-C6 cycloalkyl, halogen, hydroxy, hydroxy, alkoxy, cyano, amino, aryl, or heteroaryl groups. Specific exemplary examples include, but are not limited to, methyl, ethyl, propyl, F, Cl, trifluoromethyl, cyclopropyl, methoxy, phenyl, naphthyl, pyridyl, and pyrazinyl.

[0086] In this application, the term “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancer includes solid tumors (named according to the type of cells that make up the solid tumor), hematological cancers, myelomas, or lymphoid cancers. Examples of solid tumors include sarcomas and carcinomas. Examples of hematological cancers include, but are not limited to, leukemia, lymphoma, and myeloma. “Cancer” may also include “tumor.”

[0087] In this application, the term “tumor” means any mass of tissue caused by the growth or proliferation of excessive cells, which may be benign or malignant, including precancerous lesions. For example, a tumor may be breast cancer, gastric cancer, bladder cancer, brain tumor, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or splenic cancer.

[0088] Each of the compounds of this application contains one or more chiral centers, and both the compounds and intermediates of this application may exist in different tautomeristic forms, all of which are encompassed within the scope of protection of this application. This application includes all isomers of such structures (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)).

[0089] Of these, the term “stereoisomer” (also called “optical isomer”) refers to a stable isomer having an upright (perpendicular) asymmetric plane resulting from at least one chiral factor (including chiral centers, chiral axes, chiral planes, etc.) which may rotate plane-polarized light. A single stereoisomer in this application may be synthesized and prepared from an optically active starting material containing a desired chiral center, or it may be prepared and obtained by preparing a mixture of enantiomer products and then separating or resolving them by methods well known in the art, such as separation or recrystallization, chromatography, using chiral resolving agents, or direct separation of enantiomers on a chiral chromatography column after conversion to a mixture of diastereomers. Starting compounds having specific stereochemistry may be commercially available or may be prepared according to the methods described below and then resolving them by methods well known in the art. All stereoisomer forms of the compounds in this application are within the scope of this application.

[0090] The term "tautomer" (also called "tautomeristic form") refers to structural isomers with different energies that may interconvert across a low-energy barrier. For example, proton tautomers (also called proton-transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and amide-iminol isomerization.

[0091] In addition, each of the compounds of this application may contain one or more isotopic forms, namely, isotopic forms of any atom such as hydrogen isotopic forms D or T, or all isotopic forms of C or N. All isotopic forms of any C, N, or H in any of the optionally structured compounds of this application are included within the scope of protection of this application. In this application, the term “deuterated compound” refers to a compound of formula (I) of this application in which a hydrogen atom at any position is substituted with deuterium (i.e., D), and the amount of deuterium at that position is much greater than the naturally occurring abundance of deuterium (e.g., at least 1,000 times greater).

[0092] The terms “include,” “comprise,” and “comprising,” and their equivalents should be understood to have an additional, open, and non-exclusive meaning; that is, “included but not limited to these” and “listed but not limited to these” mean that, in addition to the listed elements, components, and processes, other unspecified elements, components, and processes may also be included.

[0093] The term "target" includes mammals such as humans, non-human primates (e.g., rhesus monkeys), pigs, cattle, horses, sheep, dogs, rabbits, mice, etc., and preferably humans.

[0094] In this specification, unless otherwise explicitly stated in the context, singular terms encompass multiple referents, and plural terms encompass singular referents. Similarly, unless otherwise explicitly stated in the context, the term "or" includes "and." Unless otherwise stated, parameter values ​​representing the quantity of a component, physicochemical properties, or reaction conditions should be understood in all cases as being modified by the term "about" or "approximately." Where the description in this application includes the terms "about" or "approximately," the terms "about" or "approximately" indicate the presence of an error value, for example, variation within ±5%, e.g., ±1%, or ±0.1% of a particular value.

[0095] Unless otherwise specified in this application, the solutions referred to in the reactions of this application are aqueous solutions.

[0096] In this application, the term "room temperature" refers to a temperature between 10°C and 25°C.

[0097] For explanatory and disclosure purposes, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided only for their disclosures prior to the filing date of this application. All statements relating to the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any endorsement of the accuracy of the dates of these documents or their contents. [Examples]

[0098] Intermediate 1: tert-butyl (S)-5-amino-4-(4-hydroxy-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka] Intermediate 1 was synthesized according to the method provided in the literature (Journal of Medicinal Chemistry, 2020, Vol. 63, No. 13, pp. 6648-6676).

[0099] Intermediate 2: 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine [ka] tert-butyl 4-(2-chloropyrimidine-4-yl)piperazine-1-formate [ka] 2,4-Dichloropyrimidine (8.4 g, 30 mmol, CAS: 3934-20-1) was dissolved in anhydrous N,N-dimethylformamide (50 mL), and triethylamine (6.3 mL, 45 mmol, d=0.728 g / mL) was added at room temperature, and the mixture was stirred for 30 minutes. Subsequently, a solution of 1-(tert-butoxycarbonyl)piperazine (6.14 g, 33 mmol, CAS: 57260-71-6) in N,N-dimethylformamide (50 mL) was slowly added dropwise to the above solution. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After TLC (petroleum ether / ethyl acetate = 1:1) was completed, the mixture was diluted with brine (200 mL), extracted three times with ethyl acetate (50 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (8.23 g, yield: 92%). LC-MS: m / z [M+H] + = 299.

[0100] tert-butyl 4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-carboxylate [ka] The above-mentioned tert-butyl 4-(2-chloropyrimidine-4-yl)piperazine-1-formate (6 g, 20 mmol), imidazole (1.91 g, 28 mmol), cuprous iodide (200 mg, 1 mmol), and cesium carbonate (7.82 g, 24 mmol) were added to a reaction tube. N,N-dimethylformamide (20 mL) was added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for half an hour. Next, the reaction solution was heated to 100 °C and stirred for 12 hours. After TLC (petroleum ether / ethyl acetate = 1:1) determined completion, the reaction solution was diluted with brine (100 mL), extracted three times with ethyl acetate (50 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (5.0 g, yield: 75%). LC-MS: m / z [M+H] + =331.

[0101] 2-(1H-imidazolyl)-4-(piperazine-1-yl)pyrimidine [ka] 5.0 g, 15 mmol of tert-butyl 4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-carboxylate was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then slowly heated to room temperature and stirred for 1 hour. The reaction solution was directly concentrated to obtain the title compound as a gray oily substance (6.1 g of crude product, TFA salt), which was used directly in the next step without further purification. LC-MS: m / z [M+H] + =231.

[0102] 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine [ka] 1,4-Bis(chloromethyl)benzene (7.9 g, 45 mmol, CAS: 623-25-6) was added to a 150 mL reaction flask, and anhydrous acetonitrile (50 mL) and N,N-dimethylformamide (50 mL) were added to the reaction flask using a syringe. This mixture was stirred at room temperature until 1,4-bis(chloromethyl)benzene was completely dissolved. N,N-diisopropylethylamine (6.0 mL, 45 mmol, d=0.782 g / mL) was slowly added dropwise to the reaction flask using a syringe. After the addition was complete, the reaction solution was stirred at room temperature for 30 minutes. Next, 2-(1H-imidazolyl)-4-(piperazin-1-yl)pyrimidine (6.1 g of crude product, TFA salt) was dissolved in a mixed solvent of acetonitrile (10 mL) and N,N-dimethylformamide (10 mL), and added dropwise to the above reaction solution at room temperature. The reaction mixture was stirred at 60°C for 2 hours. After TLC (petroleum ether / ethyl acetate = 1:1) indicated completion, brine (100 mL) was added to the reaction solution, and the reaction solution was extracted twice with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (2.0 g, yield: 36%). LC-MS: m / z [M+H] + =369.

[0103] Intermediate 3: 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Intermediate 3 was synthesized according to the method provided in brochure international publication no. 2020210630A1.

[0104] Intermediate 4: 2-Fluoro-6-(1H-imidazole-1-yl)pyridine [ka] 2,6-Difluoropyridine (345 mg, 3 mmol) and imidazole (136 mg, 2 mmol) were added to a reaction flask, followed by potassium carbonate (552 mg, 4 mmol) and dimethyl sulfoxide (10 mL). The mixture was stirred at 90°C for 6 hours. 50 mL of brine was added to the reaction solution, and this solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (228 mg, yield: 70%). LC-MS: m / z [M+H] + = 164.

[0105] As shown in the table below, the following intermediate 64 was prepared according to the preparation method of intermediate 4, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0106] [Table 1]

[0107] Intermediate 5: 2-(1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine [ka] 2-(1H-imidazole-1-yl)-4-(methylthio)pyrimidine [ka] 2-Chloro-4-methylthiopyrimidine (805 mg, 5 mmol, CAS: 49844-93-1), imidazole (510 mg, 7.5 mmol), cuprous iodide (181 mg, 1.0 mmol), and cesium carbonate (3.26 g, 10 mmol) were added to a 50 mL two-necked flask. Then, anhydrous N,N-dimethylacetamide (20 mL) was added under a nitrogen atmosphere, and the mixture was stirred overnight at 80°C. Salt water (100 mL) was added to the reaction solution, and this reaction solution was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (682 mg, yield: 71%). LC-MS: m / z [M+H] + = 193.

[0108] 2-(1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine [ka] 2-(1H-imidazole-1-yl)-4-(methylthio)pyrimidine (682 mg, 3.55 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (1.85 g, 10.65 mmol) was gradually added at 0°C. This mixture was stirred at the same temperature for 10 minutes, then heated to room temperature and stirred overnight. Saturated sodium thiosulfate solution (50 mL) was added to quench the mixture, and this mixture was extracted three times with dichloromethane (30 mL). The organic phases were combined, washed three times with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (604 mg, yield: 76%). LC-MS: m / z[M+H] + = 225.

[0109] As shown in the table below, intermediates 13, 15, 30, 32, 36, 40, 43, 45, 46, 48, 51, 52, 57, 71, 74, 75, 76, and 77 were prepared according to the preparation method for intermediate 5, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0110] [Table 2(1)] [Table 2(2)] [Table 2(3)]

[0111] Intermediate 6: 6-(1H-imidazole-1-yl)-2-picolinic acid [ka] Methyl 6-(1H-imidazole-1-yl)-2-picolinate [ka] Methyl 6-bromo-2-picolinate (6.48 g, 30 mmol, CAS: 26218-75-7), imidazole (6.13 g, 90 mmol), cuprous iodide (0.6 g, 3 mmol), and potassium carbonate (10.37 g, 75 mmol) were added to a reaction flask. The flask was purged with nitrogen three times, and N,N-dimethylformamide (100 mL) was added to the reaction flask via syringe. The reaction mixture was stirred overnight at 130°C. The reaction solution was diluted with water (300 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed three times with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (1.5 g, yield: 25%). LC-MS: m / z [M+H] + = 204.

[0112] 6-(1H-imidazole-1-yl)-2-picolinic acid [ka] Methyl 6-(1H-imidazole-1-yl)-2-picolinate (1.8 g, 8.9 mmol) was dissolved in a mixed solvent of tetrahydrofuran / methanol (20 mL / 20 mL), and 2 M aqueous lithium hydroxide solution (8.9 mL, 17.8 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred and allowed to react at 50°C for 2 hours. The reaction solution was directly concentrated. The residue was adjusted to pH ~2 with 2N hydrochloric acid, concentrated, and dried to obtain the title compound as a white solid (1.7 g crude product). LC-MS: m / z [M+H] + =190.

[0113] As shown in the table below, the following intermediate 14 was prepared according to the preparation method of intermediate 6, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0114] [Table 3]

[0115] Intermediate 7: 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid [ka] Intermediate 7 was synthesized according to the method provided in brochure international publication no. 2021207186A1.

[0116] Intermediate 8: 3-bromopiperidine-2,6-dione [ka] Piperidine-2,6-dione (5 g, 44 mmol, CAS: 1121-89-7) was dissolved in acetic acid (10 mL), and liquid bromine (2.3 mL, 45 mmol, d=3.119 g / mL) was slowly added dropwise. This reaction solution was refluxed at 130°C for 12 hours and then concentrated. The residue was neutralized with saturated sodium bicarbonate solution and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a grayish-white solid (5.50 g, yield: 65%). LC-MS: m / z [M+H] + = 192 / 194.

[0117] Intermediate 9: 1-(4-(chloromethyl)benzyl)-4-((di-tert-butoxycarbonyl)amino)piperidine [ka] Benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-formate [ka] 4-tert-butoxycarbonylaminopiperidine (3.72 g, 20 mmol, CAS: 73874-95-0) was added to the reaction flask, and anhydrous tetrahydrofuran (20 mL) was added to the reaction flask via syringe. Benzyl chloroformate (4.1 g, 24 mmol) was added gradually under ice bath conditions. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (100 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed three times with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (5.9 g, yield: 88%). LC-MS: m / z [M+H] + = 335.

[0118] Benzyl 4-((di-tert-butoxycarbonyl)amino)piperidine-1-formate [ka] Benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-formate (5.9 g, 17.6 mmol) was added to the reaction flask, and anhydrous tetrahydrofuran (20 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere. The temperature was lowered to -78°C, and a solution of 2 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (11 mL, 22 mmol) was added dropwise to the reaction solution, and the mixture was stirred at -78°C for 0.5 hours. Di-tert-butyl dicarbonate (7.68 g, 35.2 mmol, CAS:24424-99-5) was slowly added dropwise to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Saturated ammonium chloride solution (50 mL) was added dropwise to the reaction solution to quench the reaction, and the reaction solution was extracted three times with ethyl acetate (40 mL). The organic phases were combined, washed three times with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (5.7 g, yield: 75%). LC-MS: m / z [M+H] + = 435.

[0119] 4-((di-tert-butoxycarbonyl)amino)piperidine [ka] Benzyl 4-((di-tert-butoxycarbonyl)amino)piperidine-1-formate (5.7 g, 13.2 mmol) was added to the reaction flask. Methanol (15 mL), tetrahydrofuran (5 mL), and palladium hydroxide carbon (carbon-supported palladium hydroxide) catalyst (1.85 g) were added to the reaction flask via syringe. Hydrogen substitution was performed three times, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless liquid (3.96 g, yield: 100%). LC-MS: m / z [M+H] + =301.

[0120] 1-(4-(chloromethyl)benzyl)-4-((di-tert-butoxycarbonyl)amino)piperidine [ka] 4-((di-tert-butoxycarbonyl)amino)piperidine (3.96 g, 13.2 mmol) was added to the reaction flask. N,N-dimethylformamide (15 mL), acetonitrile (15 mL), and N,N-diisopropylethylamine (4.4 mL, 26.4 mmol, d=0.782 g / mL) were added to the reaction flask using a syringe. 1,4-bis(chloromethyl)benzene (5.18 g, 29.6 mmol) was added gradually while stirring. The mixture was stirred at room temperature for 30 minutes, then heated to 60°C for 1.5 hours. The reaction solution was diluted with brine (75 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed three times with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (3.8 g, yield: 65%). LC-MS: m / z [M+H] + = 439.

[0121] Intermediate 10: tert-butyl 4-((4-(4-(chloromethyl)benzyl)piperazine-1-yl)methyl)piperidine-1-formate [ka] Benzyl 4-((1-(tert-butoxycarbonyl)piperidine-4-yl)methyl)piperazine-1-carboxylate [ka] Benzyl piperazine-1-carboxylate (4.4 g, 20 mmol, CAS: 31166-44-6) and 1-tert-butoxycarbonylpiperidine-4-carboxyaldehyde (4.3 g, 20 mmol, CAS: 137076-22-3) were added to a round-bottom flask. Anhydrous dichloroethane (50 mL) was added under a nitrogen atmosphere, followed by the addition of acetic acid (0.9 mL, 40 mmol, d=1.05 g / mL). The mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (9 g, 40 mmol, CAS: 56553-60-7) was slowly added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium carbonate solution (50 mL) was added to the reaction solution to quench the reaction, and the reaction solution was extracted three times with dichloromethane (40 mL). The organic phase was combined, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a colorless oil (7.1 g, yield: 85%). LC-MS: m / z [M+H] + = 418.

[0122] tert-butyl 4-(piperazine-1-ylmethyl)piperidine-1-formate [ka] Benzyl 4-((1-(tert-butoxycarbonyl)piperidine-4-yl)methyl)piperazine-1-carboxylate (7.1 g, 17 mmol) and palladium carbon (1.1 g, 1.7 mmol) were added to tetrahydrofuran (5 mL) and methanol (10 mL) under a hydrogen atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless oil (5.1 g, yield: 106%). LC-MS: m / z [M+H] + = 284.

[0123] tert-butyl 4-((4-(4-(chloromethyl)benzyl)piperazine-1-yl)methyl)piperidine-1-formate [ka] 1,4-bis(chloromethyl)benzene (9.5 g, 51 mmol) was added to the reaction flask, and anhydrous acetonitrile (20 mL) and N,N-dimethylformamide (20 mL) were added to the reaction flask using a syringe. The mixture was stirred at room temperature until 1,4-bis(chloromethyl)benzene was completely dissolved. N,N-diisopropylethylamine (4.8 mL, 34 mmol, d=0.742 g / mL) was slowly added dropwise to the reaction flask using a syringe, and after the addition was complete, the reaction solution was stirred at room temperature for 30 minutes. Next, tert-butyl 4-(piperazine-1-ylmethyl)piperidine-1-formate (5.1 g, 17 mmol) was dissolved in a mixed solvent of acetonitrile (30 mL) and N,N-dimethylformamide (30 mL), and then added dropwise to the above reaction solution. The reaction solution was stirred at room temperature for 2 hours. Saltwater (200 mL) was added to the reaction solution, and this solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a white solid (3.08 g, yield: 43%). LC-MS: m / z [M+H] + = 422.

[0124] As shown in the table below, the following intermediate 41 was prepared according to the preparation method of intermediate 10, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0125] [Table 4]

[0126] Intermediate 11: 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] tert-butyl (1-(4-((2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)aminodicarboxylate [ka] 1-(4-(chloromethyl)benzyl)-4-((di-tert-butoxycarbonyl)amino)piperidine (3.8 g, 8.58 mmol, intermediate 9), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indole-2(1H)-one (2.1 g, 7.15 mmol, synthesized according to the method provided in the brochure for international patent application number 2020210630A1), Potassium phosphate (4.5 g, 21.5 mmol), tris(dibenzylideneacetone)dipalladium (363 mg, 0.36 mmol, CAS: 51364-51-3), and tri(2-methylphenyl)phosphine (218 mg, 0.715 mmol, CAS: 6163-58-2) were added to a reaction flask. Toluene (20 mL) and ethanol (10 mL) were added under a nitrogen atmosphere, and the mixture was heated at 100°C for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) yielded the title compound as a yellow solid (2.7 g, yield: 66%). LC-MS: m / z [M+H] + = 572.

[0127] tert-butyl (1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)aminodicarboxylate [ka] 2.7 g, 4.6 mmol) tert-butyl (1-(4-((2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)aminodicarboxylate and 30 mL of anhydrous tetrahydrofuran were added to a round-bottom flask. Sodium hydride (1.84 g, 46 mmol, stored in mineral oil at 60%) was added gradually at 0°C, and the mixture was stirred at 0°C for 20 minutes. 3-bromopiperidine-2,6-dione (7.0 g, 36.8 mmol, intermediate 8) was added at 0°C, and the reaction mixture was heated overnight at 70°C. 50 mL of brine was added to the reaction solution to quench the reaction, and 30 mL of ethyl acetate was added three times for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain the title compound as a yellow solid (1.4 g, yield: 45%). LC-MS: m / z [M+H] + = 683.

[0128] 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 683 mg, 1.0 mmol) of tert-butyl (1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)aminodicarboxylate and 8 mL of dichloromethane were added to a reaction flask, and 2 mL of trifluoroacetic acid was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 10 minutes, then heated to room temperature and stirred overnight. The reaction solution was concentrated directly under reduced pressure to obtain the title compound as a yellow solid (483 mg, yield: 81%, TFA salt). LC-MS: m / z [M+H] + = 483.

[0129] As shown in the table below, intermediates 12, 34, and 42 were prepared according to the preparation method for intermediate 11, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0130] [Table 5]

[0131] Intermediate 16: (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] tert-butyl (S)-5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka] tert-butyl (S)-5-amino-4-(4-hydroxy-1-oxoisoindorin-2-yl)-5-oxopentanoate (3.6 g, 10.8 mmol, intermediate 1), 1,4-bis(chloromethyl)benzene (5.67 g, 32.4 mmol, CAS: 623-25-6), and potassium carbonate (4.48 g, 32.4 mmol) were added to a reaction flask. Acetonitrile (90 mL) was added to the reaction flask through a syringe, and the reaction solution was stirred at 45°C for 13.5 hours. The reaction solution was filtered. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (4.1 g, yield: 80%). 1H NMR(400MHz,CDCl3) δ 7.45-7.39(m,6H),7.05(d,J=7.7Hz,1H),6.39(s,1H),5.46(s,1H),5.15(s,2H),4.92-4.88(m,1 H),4.61(s,2H),4.50(d,J=17.6Hz,1H),4.41(d,J=17.6Hz,1H),2.43-2.10(m,4H),1.41(s,9H).

[0132] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] tert-butyl (S)-5-amino-4-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)-5-oxopentanoate (3.8 g, 8.03 mmol) and benzenesulfonic acid (1.65 g, 10.4 mmol, CAS: 98-11-3) were added to a reaction flask, and acetonitrile (80 mL) was added to the reaction flask through a syringe. The reaction solution was stirred at 85°C for 23 hours. At 0°C, saturated sodium bicarbonate solution was added dropwise to the reaction solution until the pH reached 8, and the reaction solution was extracted twice with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (2.2 g, yield: 69%). 1 H NMR(400MHz,CDCl3) δ 8.18(s,1H),7.51(d,J=7.3Hz,1H),7.45-7.39(m,5H),7.08(d,J=7.9Hz,1H),5.23(dd,J=13.3,5.1Hz,1H),5.15(s,2H) ,4.60(s,2H),4.45(d,J=16.6Hz,1H),4.31(d,J=16.6Hz,1H),2.94-2.78(m,2H),2.41-2.29(m,1H),2.24-2.17(m,1H).

[0133] Intermediate 17: (2-(1H-imidazole-1-yl)pyrimidine-4-yl)(piperazine-1-yl)methanone hydrochloride [ka] tert-butyl 4-(2-(1H-imidazole-1-yl)pyrimidine-4-carbonyl)piperazine-1-carboxylate [ka] 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (209.2 mg, 1.1 mmol, intermediate 7), tert-butylpiperazine-1-carboxylate acetate (204.9 mg, 1.1 mmol, CAS: 143238-38-4), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (627.3 mg, 1.65 mmol, CAS: 148893-10-1) were added to a reaction flask. Anhydrous N,N-dimethylformamide (5 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere. N,N-diisopropylethylamine (355.0 mg, 2.75 mmol, CAS: 7087-68-5) was added while stirring, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was diluted with brine (30 mL) and extracted twice with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a yellow solid (230 mg, yield: 58%). 1 H NMR(400MHz,CDCl3) δ 8.83(d,J=5.0Hz,1H),8.58(s,1H),7.84(s,1H),7.48(d,J=4.8Hz,1H),7.17( s, 1H), 3.79-3.76 (m, 2H), 3.57-3.56 (m, 4H), 3.52-3.50 (m, 2H), 1.46 (s, 9H).

[0134] (2-(1H-imidazole-1-yl)pyrimidine-4-yl)(piperazine-1-yl)methanone hydrochloride [ka] 200.0 mg, 0.56 mmol of tert-butyl 4-(2-(1H-imidazole-1-yl)pyrimidine-4-carbonyl)piperazine-1-carboxylate was added to a reaction flask. 1 mL of ethyl acetate and 1 mL of dichloromethane were added to the reaction flask via syringe. A saturated solution of hydrogen chloride in ethyl acetate (5 mL) was added dropwise at 0°C, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered. The filter cake was washed with ethyl acetate (10 mL), collected, and dried to obtain the title compound as a white solid (140 mg, yield: 85%). LC-MS: m / z [M+H] + =259.

[0135] Intermediate 18: tert-butyl 4-((1R,4R)-4-aminocyclohexyl)piperazine-1-carboxylate [ka] tert-butyl 4-((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-1-carboxylate [ka] tert-butylpiperazine-1-carboxylate acetate (1.86 g, 10 mmol, CAS: 143238-38-4) and 4-N-benzyloxycarbonylaminocyclohexanone (2.47 g, 10 mmol, CAS: 16801-63-1) were added to a reaction flask. Dichloromethane (35 mL) was added to the reaction flask under a nitrogen atmosphere using a syringe, and acetic acid (240 mg, 4 mmol) was added to the reaction flask using a syringe while stirring. Next, sodium triacetoxyborohydride (6.4 g, 30 mmol, CAS: 56553-60-7) was added in three portions at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added dropwise to the reaction solution at 0°C until the pH was ~8, and the reaction solution was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound as a white solid (2.1 g, yield: 50%). 1 H NMR(400MHz,CDCl3) δ 7.38-7.30(m,5H),5.07(s,2H),4.61(d,J=7.7Hz,1H),3.48-3.40(m,5H),2.48(s,4H),2.27(t,J=11.8Hz ,1H),2.08(d,J=12.2Hz,2H),1.88(d,J=12.5Hz,2H),1.45(s,9H),1.40-1.30(m,2H),1.18-1.08(m,2H).

[0136] tert-butyl 4-((1R,4R)-4-aminocyclohexyl)piperazine-1-carboxylate [ka] 300 mg, 0.7 mmol of tert-butyl 4-((1R,4R)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-1-carboxylate was added to a reaction flask, and methanol (2 mL) was added to the reaction flask under a hydrogen atmosphere via a syringe, followed by the addition of palladium carbon (30 mg, CAS: 7440-05-3). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered through Celite. The filtrate was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (198 mg, yield: 100%). 1 H NMR(400MHz,CDCl3) δ 3.41-3.39(m,4H),2.69-2.62(m,1H),2.47(t,J=4.9Hz,4H),2.29-2.22(m,1H), 1.93(d,J=12.0Hz,2H),1.86(d,J=12.2Hz,2H),1.44(s,9H),1.35-1.07(m,4H).

[0137] Intermediate 19: 2-(1H-imidazole-1-yl)-N-((1R,4R)-4-(piperazine-1-yl)cyclohexyl)pyrimidine-4-carboxamide hydrochloride [ka] tert-butyl 4-((1R,4R)-4-(2-(1H-imidazole-1-yl)pyrimidine-4-carboxyamide)cyclohexyl)piperazine-1-carboxylate [ka] 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (88 mg, 0.46 mmol, intermediate 7), tert-butyl 4-((1R,4R)-4-aminocyclohexyl)piperazine-1-carboxylate (130 mg, 0.46 mmol, intermediate 18), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (262 mg, 0.69 mmol, CAS: 148893-10-1) were added to a reaction flask. Anhydrous N,N-dimethylformamide (5 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere, and N,N-diisopropylethylamine (149 mg, 1.15 mmol, CAS: 7087-68-5) was added while stirring. The reaction solution was stirred at room temperature for 11 hours. The reaction solution was diluted with brine (10 mL) and extracted twice with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a yellow solid (146 mg, yield: 70%). LC-MS: m / z [M+H] + = 456.

[0138] 2-(1H-imidazole-1-yl)-N-((1R,4R)-4-(piperazine-1-yl)cyclohexyl)pyrimidine-4-carboxamide hydrochloride [ka] 220 mg, 0.48 mmol of tert-butyl 4-((1R,4R)-4-(2-(1H-imidazole-1-yl)pyrimidine-4-carboxyamide)cyclohexyl)piperazine-1-carboxylate was added to a reaction flask. 3 mL of ethyl acetate was added to the reaction flask via syringe, and 10 mL of a saturated solution of hydrogen chloride in ethyl acetate was added dropwise at 0°C. The reaction solution was stirred at room temperature for 7 hours. The reaction solution was filtered. The filter cake was washed with 10 mL of ethyl acetate, collected, and dried to obtain the title compound as a white solid (150 mg, yield: 80%). LC-MS: m / z [M+H] += 356.

[0139] As shown in the table below, intermediates 20 and 22 were prepared according to the preparation method for intermediate 19, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0140] [Table 6]

[0141] Intermediate 21: 1-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine hydrochloride [ka] (1-(6-bromopyridine-2-yl)piperidine-4-yl)methanol [ka] 2-Bromo-6-fluoropyridine (1.5 g, 8.5 mmol, CAS: 144100-07-2) and 4-hydroxymethylpiperidine (982 mg, 8.5 mmol, CAS: 6457-49-4) were added to a reaction flask. 1,4-Dioxane (10 mL) was added to the reaction flask via syringe, and triethylamine (946 mg, 9.4 mmol) was added while stirring. The reaction solution was heated to 110°C and refluxed under stirring for 8 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound as a white solid (1.62 g, yield: 70%). 1 H NMR(400MHz,CDCl3) δ 7.27-7.23(m,1H),6.69(d,J=7.4Hz,1H),6.53(d,J=8.4Hz,1H),4.29(d,J=13.3Hz,2H),3.53( d,J=6.2Hz,2H),2.83(td,J=12.7,2.2Hz,2H),1.84-1.71(m,3H),1.26(qd,J=12.6,4.2Hz,2H).

[0142] 2-Bromo-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-yl)pyridine [ka] (1-(6-bromopyridine-2-yl)piperidine-4-yl)methanol (1.2 g, 4.4 mmol) and imidazole (452 ​​mg, 6.6 mmol) were added to a reaction flask. Dichloromethane (10 mL) was added to the reaction flask under a nitrogen atmosphere via syringe. A solution of tert-butyldimethylsilyl chloride (995 mg, 6.6 mmol, CAS: 18162-48-6) in dichloromethane (15 mL) was added dropwise to the reaction flask at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was filtered. The filtered cake was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (1.57 g, yield: 93%). LC-MS: m / z [M+H] + =385.

[0143] 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-yl)-6-(1H-imidazole-1-yl)pyridine [ka] 2-Bromo-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-yl)pyridine (1.1 g, 2.85 mmol), imidazole (972 mg, 14.3 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (148 mg, 0.14 mmol, CAS: 52522-40-4), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (109 mg, 0.26 mmol, CAS: 564483-19-8), and potassium phosphate (1.2 g, 5.7 mmol, CAS: 7778-53-2) were added to a reaction flask, and toluene (20 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere. The reaction solution was stirred at 110°C for 8 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtered cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain the title compound as a colorless oily liquid (977 mg, yield: 92%). 1 H NMR(400MHz,CDCl3) δ 8.64(s,1H),7.92(s,1H),7.87(t,J=8.0Hz,1H),7.48(s,1H),6.89(t,J=8.3Hz,2H),4.71(d,J=13.2Hz,2H),3.8 1(d,J=6.2Hz,2H),3.24-3.18(m,2H),2.18-2.05(m,3H),1.58(qd,J=12.4,4.4Hz,2H),1.23(s,9H),0.38(s,6H).

[0144] (1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methanol [ka] 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-yl)-6-(1H-imidazole-1-yl)pyridine (1.0 g, 2.68 mmol) was added to a reaction flask, and anhydrous tetrahydrofuran (15 mL) was added to the reaction flask under a nitrogen atmosphere via syringe. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (4 mL, 4 mmol, CAS: 429-41-4) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Salt water (50 mL) was added to the reaction solution, and the reaction solution was extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (597 mg, yield: 86%). 1 H NMR(400MHz,CDCl3) δ 8.30(s,1H),7.56-7.51(m,2H),7.13(s,1H),6.57-6.53(m,2H),4.38(d,J=13.2Hz,2H),3.53(d,J=6. 2Hz,2H), 2.89(td,J=12.9,2.2Hz,2H),2.44(s,1H),1.87-1.75(m,3H),1.28(qd,J=12.6,4.3Hz,2H).

[0145] (1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl-4-methylbenzene sulfonate [ka] (1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methanol (450 mg, 1.74 mmol) was added to the reaction flask, and anhydrous dichloromethane (6 mL) was added to the reaction flask under a nitrogen atmosphere via syringe. A solution of p-toluenesulfonyl chloride (498 mg, 2.61 mmol, CAS: 98-59-9) in anhydrous dichloromethane (8 mL) was added dropwise to the reaction flask at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered. The filtered cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow oil (413 mg, yield: 58%). 1 H NMR(400MHz,CDCl3) δ 8.27(s,1H),7.77(d,J=8.1Hz,2H),7.54-7.50(m,2H),7.34(d,J=8.1Hz,2H),7.12(s,1H),6.56(d,J=7.6Hz,1H),6.50(d,J=8.5Hz,1H),4.33 (d,J=13.2Hz,2H),3.87(d,J=6.5Hz,2H),2.83(t,J=12.7Hz,2H),2.43(s,3H),2.01-1.91(m,1H),1.77(d,J=12.7Hz,2H),1.28-1.18(m,2H).

[0146] 2-(4-(bromomethyl)piperidine-1-yl)-6-(1H-imidazole-1-yl)pyridine [ka] (1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl-4-methylbenzenesulfonate (300 mg, 0.72 mmol) and lithium bromide (126 mg, 1.45 mmol, CAS: 7550-35-8) were added to a reaction flask, and acetone (8 mL) was added to the reaction flask through a syringe. The reaction solution was stirred at 60°C for 17 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound as a yellow oily substance (202 mg, yield: 87%). LC-MS: m / z [M+H] + =321.

[0147] tert-butyl 4-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate [ka] 2-(4-(bromomethyl)piperidine-1-yl)-6-(1H-imidazole-1-yl)pyridine (450 mg, 1.44 mmol), tert-butylpiperazine-1-carboxylate acetate (322 mg, 1.73 mmol, CAS: 143238-38-4), and potassium carbonate (299 mg, 2.16 mmol) were added to a reaction flask, and acetonitrile (12 mL) was added to the reaction flask through a syringe. The reaction solution was stirred at 85°C for 17 hours. The reaction solution was filtered. The filtered cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a colorless oil (473 mg, yield: 77%). 1H NMR(400MHz,CDCl3) δ 8.31(s,1H),7.58(s,1H),7.49(t,J=8.0Hz,1H),7.13(s,1H),6.52(d,J=7.6Hz,1H),6.22(d,J=8.3Hz,1H),3.71(t,J=8.7Hz,1H), 3.63-3.59(m,1H),3.47-3.37(m,5H),3.05(t,J=9.3Hz,1H),2.45-2.27(m,7H),2.21-2.14(m,1H),1.72-1.61(m,3H),1.45(s,9H).

[0148] 1-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine hydrochloride [ka] 300 mg, 0.7 mmol of tert-butyl 4-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-carboxylate was added to a reaction flask. 1 mL of ethyl acetate and 1 mL of dichloromethane were added to the reaction flask via syringe, and a saturated solution of hydrogen chloride in ethyl acetate (5 mL) was added dropwise at 0°C. The reaction solution was stirred at room temperature for 22 hours. The reaction solution was filtered. The filter cake was washed with ethyl acetate (10 mL), collected, and dried to obtain the title compound as a yellow solid (241 mg, yield: 95%). LC-MS: m / z [M+H] + =327.

[0149] Intermediate 23: tert-butyl 4-(6-bromopyridine-2-yl)piperazine-1-carboxylate [ka] 2-Bromo-6-fluoropyridine (528 mg, 3 mmol, CAS: 144100-07-2) and tert-butylpiperazine-1-carboxylate acetate (559 mg, 3 mmol, CAS: 143238-38-4) were added to a reaction flask. 1,4-Dioxane (12 mL) was added to the reaction flask via syringe, and triethylamine (334 mg, 3.3 mmol) was added while stirring. The reaction solution was stirred at 105°C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain the title compound as a white solid (860 mg, yield: 84%). 1 H NMR (400MHz, CDCl3) δ 7.29(t,J=7.9Hz,1H),6.77(d,J=7.5Hz,1H),6.51(d,J=8.3Hz,1H),3.52(s,8H),1.47(s,9H).

[0150] Intermediate 24: 5-(6-(piperazine-1-yl)pyridine-2-yl)thiazole hydrochloride [ka] tert-butyl 4-(6-(thiazole-5-yl)pyridine-2-yl)piperazine-1-carboxylate [ka] tert-butyl 4-(6-bromopyridine-2-yl)piperazine-1-carboxylate (550 mg, 1.6 mmol, intermediate 23), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (407 mg, 1.9 mmol, CAS: 1086111-09-2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (141 mg, 0.19 mmol, CAS: 72287-26-4), and potassium carbonate (442 mg, 3.2 mmol) were added to a reaction flask, and 1,4-dioxane / water (16 mL, v / v 4:1) was added to the reaction flask through a syringe under a nitrogen atmosphere. The reaction solution was stirred at 95°C for 12 hours. Saltwater (20 mL) was added to the reaction solution, and this solution was extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a white solid (70 mg, yield: 70%). 1 H NMR (400MHz, CDCl3) δ 7.75(d,J=7.5Hz,1H),7.60(t,J=7.8Hz,1H),7.25(s,2H),6.66(d,J=8.4Hz,1H),3.62-3.57(m,8H),1.48(s,9H).

[0151] 5-(6-(piperazine-1-yl)pyridine-2-yl)thiazole hydrochloride [ka] 230 mg, 0.66 mmol of tert-butyl 4-(6-(thiazole-5-yl)pyridine-2-yl)piperazine-1-carboxylate was added to a reaction flask. 1 mL of ethyl acetate was added to the reaction flask via syringe, and a saturated solution of hydrogen chloride in ethyl acetate (7 mL) was added dropwise at 0°C. The reaction solution was stirred at room temperature for 22 hours. The reaction solution was filtered. The filter cake was washed with ethyl acetate (10 mL), collected, and dried to obtain the title compound as a yellow solid (180 mg, yield: 96%). LC-MS: m / z [M+H]+ =247.

[0152] As shown in the table below, the following intermediate 83 was prepared according to the preparation method for intermediate 24, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0153] [Table 7]

[0154] Intermediate 25: 3-(6-(4-((4-(2-chloropyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (240 mg, 0.5 mmol, intermediate 3), triethylamine (0.18 mL, 1.28 mmol, d=0.728 g / mL), and N,N-dimethylformamide (4 mL) were mixed with 2,4-dichloropyrimidine (95 mg, 0.64 mmol). The reaction solution was stirred at 20°C for 3 hours. The reaction solution was slowly added to water (20 mL) until a precipitate formed, and then filtered. The filter cake was washed once with water (5 mL), collected, and dried to obtain the title compound as a yellow solid (180 mg, yield: 62%). LC-MS: m / z[M+H] + = 581.

[0155] As shown in the table below, the following intermediate 26 was prepared according to the preparation method for intermediate 25, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0156] [Table 8]

[0157] Intermediate 27: 2-(6-chloropyridine-2-yl)-5-methyl-1,3,4-thiadiazole [ka] N'-acetyl-6-chloropyridinehydrazide [ka] At room temperature, 6-chloronicotinic acid (1 g, 6.35 mmol, CAS: 5326-23-8) was added to thionyl chloride (2.30 mL, 31.74 mmol, d=1.638 g / mL) and perfused under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated and then dissolved in dichloromethane (20 mL). 4-dimethylaminopyridine (77.58 mg, 0.64 mmol, CAS: 1122-58-3), triethylamine (2.64 mL, 19.05 mmol, d=0.728 g / mL), and acethydrazide (0.51 mL, 7.62 mmol, CAS: 1068-57-1) were added sequentially to the reaction solution. Next, this reaction solution was stirred overnight at room temperature under a nitrogen atmosphere. Water (20 mL) was slowly added to the reaction solution and stirred at room temperature for 2 hours. A solid precipitate formed, and the mixture was filtered. The filtered cake was collected and dried to obtain the title compound as a pale yellow solid (650 mg, yield: 48%). 1 H NMR(400MHz,CD3OD) δ 7.99(dd,J=7.7,0.9Hz,1H),7.86(t,J=7.8Hz,1H),7.44(dd,J=8.0,0.9Hz,1H),2.02(s,3H).

[0158] 2-(6-chloropyridine-2-yl)-5-methyl-1,3,4-thiadiazole [ka] At room temperature, Lawesson's reagent (1703.98 mg, 4.21 mmol, CAS: 19172-47-5) was gradually added to a solution of the above-mentioned N'-acetyl-6-chloropyridine hydrazide (600 mg, 2.81 mmol) in toluene (10 mL). Next, this reaction solution was heated to 90°C and stirred overnight under a nitrogen atmosphere. The reaction solution was filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1~3:1) to obtain the title compound as a yellow solid (250 mg, yield: 42%). 1 H NMR (400MHz, DMSO-d6) δ 8.23(dd,J=7.7,0.9Hz,1H),8.09(t,J=7.8Hz,1H),7.70(dd,J=8.0,0.9Hz,1H),2.80(s,3H).

[0159] Intermediate 28: 2-Chloro-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine [ka] Under a nitrogen atmosphere, cuprous oxide (167.67 mg, 1.16 mmol, CAS: 1317-39-1) and N1,N2-bis(furan-2-ylmethyl)oxalamide (287 mg, 1.28 mmol, CAS: 69010-90-8) were added to a mixed solution of 2,6-dichloropyridine (570 mg, 3.85 mmol, CAS: 2402-78-0), 3-methyl-1H-1,2,4-triazole (320 mg, 3.85 mmol, CAS: 7170-01-6), tripotassium phosphate (1460 mg, 6.88 mmol), and dimethyl sulfoxide (10 mL). This reaction solution was incubated at 145°C for 18 hours. The reaction solution was poured into water (50 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3:1) to obtain the title compound as a white solid (130 mg, yield: 17%). 1H NMR (400MHz, DMSO-d6) δ 9.19(s,1H),8.09(t,J=7.9Hz,1H),7.80(d,J=8.0Hz,1H),7.56(d,J=7.9Hz,1H),2.39(s,3H).

[0160] Intermediate 29: 2-Chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine [ka] 6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-amine (1 g, 4.9 mmol, CAS: 1448427-99-3) and benzyltriethylammonium chloride (216 mg, 9.8 mmol, CAS: 56-37-1) were dissolved in dichloromethane (20 mL), and tert-butyl nitrite (2.5 g, 24.6 mmol, CAS: 540-80-7) was slowly added at 0°C. After the addition was complete, the reaction solution was heated to 30°C and stirred overnight. The reaction solution was diluted with water (100 mL) and extracted twice with dichloromethane (60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a yellow oily substance (700 mg, yield: 64%). LC-MS: m / z [M+H] + =223.

[0161] Intermediate 31: 4-Cyclopropyl-1H-imidazole [ka] Formamidine acetate (3.12 g, 30 mmol, CAS: 3473-63-0) and sodium carbonate (3.18 g, 30 mmol) were added to the reaction flask, and the flask was purged with nitrogen three times. Anhydrous tetrahydrofuran (30 mL) was then added to the reaction flask using a syringe. The reaction mixture was stirred at 100°C for 3 hours and then filtered. 1-Cyclopropyl-2-bromoetanone (4.89 g, 30 mmol, CAS: 69267-75-0) was slowly added dropwise to the filtrate. The reaction solution was stirred at room temperature overnight. The reaction was quenched by adding saturated sodium bicarbonate solution (100 mL) to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (1.62 g, yield: 50%). LC-MS: m / z [M+H] + = 109.

[0162] Intermediate 33: tert-butyl ((1s,4s)-4-((1-(4-(chloromethyl)benzyl)piperidine-4-yl)oxy)cyclohexyl)aminodicarboxylate [ka] tert-butyl ((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)carbamate [ka] trans-4-(tert-butoxycarbonylamino)cyclohexanol (6.45 g, 30 mmol, CAS: 111300-06-2) and imidazole (4.08 g, 60 mmol) were placed in a reaction flask, and N,N-dimethylformamide (100 mL) was added to it using a syringe. Tert-butyldimethylsilyl chloride (9.04 g, 60 mmol, CAS: 18162-48-6) was added at 0°C. Next, this mixture was heated to room temperature and stirred for 2 hours to allow the reaction to proceed. Saturated ammonium chloride solution (200 mL) was added to the reaction solution, and this reaction solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated ammonium chloride solution (50 mL) and three times with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (9.9 g, yield: 100%). LC-MS: m / z [M+H] + =330.

[0163] tert-butyl ((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)dicarbamate [ka] The above tert-butyl ((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl) carbamate (9.9 g, 30 mmol) was added to the reaction flask, and anhydrous tetrahydrofuran (100 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere. The temperature was lowered to -78°C, and a 1.6 M solution of n-butyllithium in hexane (30 mL, 48 mmol) was added dropwise to the reaction solution, and the mixture was stirred at -78°C for 0.5 hours. Di-tert-butyl dicarbonate (9.8 g, 45 mmol, CAS:24424-99-5) was slowly added dropwise to the reaction solution. The mixture was stirred at -78°C for 3 hours, then heated to room temperature and allowed to react overnight. Saturated ammonium chloride solution (50 mL) was added dropwise to the reaction solution to quench the reaction, and the reaction solution was extracted three times with ethyl acetate (40 mL). The organic phases were combined, washed three times with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the title compound as a white solid (9.3 g, yield: 72%). LC-MS: m / z [M+H] + =430.

[0164] tert-butyl ((1R,4R)-4-hydroxycyclohexyl)aminodicarboxylate [ka] 6.45 g, 20 mmol of tert-butyl ((1R,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)aminodicarboxylate was placed in a reaction flask, and 50 mL of tetrahydrofuran was added to it using a syringe. Tetrabutylammonium fluoride (15.7 g, 60 mmol, CAS: 429-41-4) was added at 0°C. Next, the mixture was heated to room temperature and stirred for 2 hours to allow it to react. 50 mL of saturated ammonium chloride solution was added to the reaction solution, and this solution was extracted three times with ethyl acetate (40 mL). The organic phases were combined, washed twice with saturated ammonium chloride solution (50 mL) and once with brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (5.7 g, yield: 90%). LC-MS: m / z [M+H] + =316.

[0165] tert-butyl ((1s,4s)-4-(pyridine-4-yloxy)cyclohexyl)aminodicarboxylate [ka] 4-hydroxypyridine (6.48 g, 30 mmol, CAS: 626-64-2), tert-butyl ((1R,4R)-4-hydroxycyclohexyl)aminodicarboxylate (6.13 g, 30 mmol), and triphenylphosphine (11.8 g, 45 mmol, CAS: 603-35-0) were placed in a reaction flask, and the flask was purged with nitrogen three times. Tetrahydrofuran (60 mL) was added to the reaction flask using a syringe. At 0°C, diisopropyl azodicarboxylate (6.13 g, 45 mmol, CAS: 2446-83-5) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (8.2 g, yield: 70%). LC-MS: m / z [M+H] + =393.

[0166] 1-Benzyl-4-(((1s,4s)-4-((di-tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-1-ium bromide [ka] 6.45 g, 20 mmol of tert-butyl ((1s,4s)-4-(pyridine-4-yloxy)cyclohexyl)aminodicarboxylate was placed in a reaction flask, and 20 mL of dichloromethane was added to it using a syringe. 10 g, 60 mmol of benzyl bromide was then added. The reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound as a white solid (16.9 g of crude product).

[0167] tert-butyl ((1s,4s)-4-((1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)oxy)cyclohexyl)aminodicarboxylate [ka] 1-Benzyl-4-(((1s,4s)-4-((di-tert-butoxycarbonyl)amino)cyclohexyl)oxy)pyridine-1-ium bromide (16.9 g, 20 mmol) was placed in a reaction flask, methanol (20 mL) was added via syringe, and sodium borohydride (2.3 g, 60 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. The reaction was quenched by adding brine (100 mL) to the reaction solution, and the reaction solution was extracted five times with dichloromethane (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (4.4 g, yield in 2 steps: 45%). LC-MS: m / z [M+H] + = 487.

[0168] tert-butyl ((1s,4s)-4-(piperidine-4-yloxy)cyclohexyl)aminodicarboxylate [ka] tert-butyl ((1s,4s)-4-((1-benzyl-1,2,3,6-tetrahydropyridine-4-yl)oxy)cyclohexyl)aminodicarboxylate (4.4 g, 9 mmol) and palladium hydroxide carbon catalyst (0.7 g) were added to a reaction flask. Methanol (15 mL) and tetrahydrofuran (5 mL) were added to the reaction flask via syringe, and hydrogenation was performed three times. The mixture was stirred at 60°C for 24 hours. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a colorless liquid (3.2 g, yield: 89%). LC-MS: m / z [M+H] + =399.

[0169] tert-butyl ((1s,4s)-4-((1-(4-(chloromethyl)benzyl)piperidine-4-yl)oxy)cyclohexyl)aminodicarboxylate [ka] 3.2 g, 8.1 mmol of tert-butyl ((1s,4s)-4-(piperidine-4-yloxy)cyclohexyl)aminodicarboxylate was added to a reaction flask. 15 mL of N,N-dimethylformamide, 15 mL of acetonitrile, and 4 mL of N,N-diisopropylethylamine (16.2 mmol, d=0.782 g / mL) were added to the reaction flask via syringe, and 4.2 g, 24 mmol of 1,4-bis(chloromethyl)benzene was added gradually while stirring. The mixture was stirred at room temperature for 30 minutes, and then reacted at 60°C for 3 hours. The reaction solution was diluted with brine (75 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed three times with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (3.3 g, yield: 76%). LC-MS: m / z [M+H] + = 537.

[0170] Intermediate 35: 3-(6-(4-((4-(6-chloropyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (660 mg, 1.31 mmol, hydrochloride, intermediate 3), 2,6-dichloropyridine (300 mg, 2.03 mmol), triethylamine (600 mg, 5.93 mmol), and cesium fluoride (250 mg, 1.65 mmol) were added to dimethyl sulfoxide (12 mL), and this mixture was subjected to a microwave reaction at 135°C for 1 hour. The reaction solution was cooled to room temperature, poured into water (50 mL), and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 3:1) to obtain the title compound as a white solid (450 mg, yield: 59%). LC-MS: m / z [M+H] + = 580.

[0171] Intermediate 37: tert-butyl 4-(azetidine-3-yl)piperazine-1-carboxylate [ka] tert-butyl 4-(1-(benzyloxycarbonyl)azetidine-3-yl)piperazine-1-carboxylate [ka] 1-Benzyloxycarbonylazetidine-3-one (0.93 g, 5 mmol, CAS: 105258-93-3) and 1-(tert-butoxycarbonyl)piperazine (1.03 g, 5 mmol, CAS: 57260-71-6) were placed in a reaction flask, and the flask was purged with nitrogen three times. Dichloromethane (15 mL) and acetic acid (0.02 mL) were added to the reaction flask using a syringe. The reaction system was stirred at room temperature for 1 hour to allow the reaction to proceed. Then, sodium triacetoxyborohydride (1.6 g, 7.5 mmol, CAS: 56553-60-7) was added, and the reaction mixture was stirred at room temperature for 3 hours. Dichloromethane (50 mL) was added to the reaction solution, and the solution was washed twice with brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a white solid (1.5 g, yield: 80%). LC-MS: m / z [M+H] + =376.

[0172] tert-butyl 4-(azetidine-3-yl)piperazine-1-carboxylate [ka] 3.0 g, 8 mmol of tert-butyl 4-(1-(benzyloxycarbonyl)azetidine-3-yl)piperazine-1-carboxylate and 0.56 g, approximately 50% water content, CAS: 12135-22-7) were placed in a reaction flask. Hydrogen substitution was performed three times, and methanol (20 mL) and tetrahydrofuran (6 mL) were added to the reaction flask via syringe. The reaction system was stirred overnight at room temperature. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (1.8 g, yield: 93%). LC-MS: m / z [M+H] + = 242.

[0173] As shown in the table below, intermediates 50, 78, and 80 were prepared according to the preparation method for intermediate 37, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0174] [Table 9]

[0175] Intermediate 38: 4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzaldehyde [ka] Intermediate 38 was synthesized according to the method provided in brochure international publication no. 2020210630A1.

[0176] Intermediate 39: 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] tert-butyl 4-(1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)azetidine-3-yl)piperazine-1-carboxylate [ka] 4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzaldehyde (0.31 g, 0.78 mmol, intermediate 38) and tert-butyl 4-(azetidine-3-yl)piperazine-1-carboxylate (0.26 g, 1.09 mmol, intermediate 37) were dissolved in dichloromethane (8 mL), and acetic acid (0.09 mL) was slowly added dropwise. This mixture was stirred at room temperature for half an hour, and then sodium triacetoxyborohydride (0.33 g, 1.56 mmol, CAS: 56553-60-7) was gradually added to the reaction system, and the reaction mixture was stirred at room temperature for 3 hours. Dichloromethane (50 mL) was added to the reaction solution, and the reaction solution was washed twice with brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a white solid (0.35 g, yield: 72%). LC-MS: m / z [M+H] + = 624.

[0177] 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] tert-butyl 4-(1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)azetidine-3-yl)piperazine-1-carboxylate (0.35 g, 0.56 mmol) was dissolved in dichloromethane (8.5 mL), and trifluoroacetic acid (1.5 mL) was slowly added dropwise in an ice bath. The mixture was stirred and reacted at room temperature for 3 hours. The reaction solution was concentrated directly under reduced pressure to obtain the title compound as a white solid (357 mg, yield: 100%, TFA salt). LC-MS: m / z [M+H] + = 524.

[0178] As shown in the table below, the following intermediate 55 was prepared according to the preparation method of intermediate 39, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0179] [Table 10]

[0180] Intermediate 44: 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole [ka] tert-butyl 4-(2-chloro-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate [ka] 2,4-Dichloro-5-fluoropyrimidine (1.7 g, 10 mmol, CAS: 2927-71-1) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and triethylamine (2.1 mL, 15 mmol, d=0.728 g / mL) was slowly added. This reaction solution was stirred at 0°C for 30 minutes, and then 1-(tert-butoxycarbonyl)piperazine (2.0 g, 11 mmol, CAS: 57260-71-6) was slowly added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water (200 mL) and extracted three times with dichloromethane (100 mL). The organic phases were combined, washed twice with brine (50 mL), dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (2.82 g, yield: 89%). LC-MS: m / z [M+H] + =317.

[0181] tert-butyl 4-(2-cyano-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate [ka] 1.6 g, 5 mmol tert-butyl 4-(2-chloro-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate, 880 mg, 7.5 mmol zinc cyanide, and 0.25 mmol, 289 mg tetrakis(triphenylphosphine)palladium (CAS: 14221-01-3) were added to a Schlenk tube, and the tube was purged with nitrogen three times. Anhydrous N,N-dimethylformamide (5 mL) was then added under a nitrogen atmosphere. The reaction tube was then stirred at 160 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed twice with brine (20 mL), dried, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (1.2 g, yield: 71%). LC-MS: m / z [M+H] + = 308.

[0182] 4-(4-(tert-butoxycarbonyl)piperazine-1-yl)-5-fluoropyrimidine-2-carboxylic acid [ka] 1.2 g, 3.5 mmol of tert-butyl 4-(2-cyano-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate was added to a reaction flask, and 4.2 mL, 4.2 mmol of 1 M sodium hydroxide solution was slowly added dropwise at room temperature. The mixture was stirred overnight at room temperature. 1 N hydrochloric acid was slowly added dropwise to the reaction solution in an ice bath to adjust the pH to 3, and the reaction solution was extracted three times with 50 mL of dichloromethane. The organic phases were combined, washed twice with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (1.4 g, yield: 100%). LC-MS: m / z [M+H] + =327.

[0183] tert-butyl 4-(2-(2-acetylhydrazine-1-carbonyl)-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate [ka] 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluoropyrimidine-2-carboxylic acid (1.0 g, 3.0 mmol) and acetylhydrazine (333 mg, 4.5 mmol, CAS: 1068-57-1) were dissolved in anhydrous acetonitrile (30 mL), and diisopropylethylamine (0.63 mL, 3.6 mmol, d=0.782 g / mL) was slowly added dropwise at room temperature. The mixture was stirred at room temperature for half an hour. Next, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.4 g, 3.6 mmol, CAS: 94790-37-1, HBTU) was slowly added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with water (30 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (830 mg, yield: 72%). LC-MS: m / z [M+H] + =383.

[0184] tert-butyl 4-(5-fluoro-2-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl)piperazine-1-carboxylate [ka] 830 mg, 2.17 mmol of tert-butyl 4-(2-(2-acetylhydrazine-1-carbonyl)-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate was added to 20 mL of toluene, and Lawson's reagent (1.8 g, 4.34 mmol, CAS: 19172-47-5) was slowly added at room temperature. The mixture was stirred at 110 °C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (726 mg, yield: 44%). LC-MS: m / z [M+H] + =381.

[0185] 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole [ka] 726 mg (1.9 mmol) of tert-butyl 4-(5-fluoro-2-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl)piperazine-1-carboxylate was added to 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated directly under reduced pressure to obtain the title compound as a colorless oil (740 mg, yield: 99%, TFA salt). LC-MS: m / z [M+H] + =281.

[0186] Intermediate 47: 5-Chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-4-(piperazine-1-yl)pyrimidine [ka] tert-butyl 4-(2,5-dichloropyrimidine-4-yl)piperazine-1-carboxylate [ka] 2,4,5-Trichloropyrimidine (920 mg, 5 mmol, CAS: 5750-76-5) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and triethylamine (1.05 mL, 7.5 mmol, d=0.728 g / mL) was slowly added. The mixture was stirred at 0°C for 30 minutes. Next, 1-(tert-butoxycarbonyl)piperazine (1.02 g, 5.5 mmol, CAS: 57260-71-6) was slowly added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water (100 mL) and extracted three times with dichloromethane (100 mL). The organic phases were combined, washed twice with brine (50 mL), dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (1.43 g, yield: 86%). LC-MS: m / z [M+H] + =333.

[0187] tert-butyl 4-(5-chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-carboxylate [ka] 332 mg, 1 mmol of tert-butyl 4-(2,5-dichloropyrimidine-4-yl)piperazine-1-carboxylate, 92 mg, 1.1 mmol, CAS: 7170-01-6, cuprous iodide (40 mg, 0.2 mmol), and cesium carbonate (652 mg, 2 mmol) were added to a reaction flask. Anhydrous N,N-dimethylacetamide (5 mL) was then added under a nitrogen atmosphere, and the mixture was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature, brine (50 mL) was added, and then extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (231 mg, yield: 61%). LC-MS: m / z [M+H] + =380.

[0188] 5-Chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-4-(piperazine-1-yl)pyrimidine [ka] 231 mg, 0.61 mmol of tert-butyl 4-(5-chloro-2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-carboxylate (231 mg) was added to 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated directly under reduced pressure to obtain the title compound as a colorless oil (240 mg, yield: 100%, TFA salt). LC-MS: m / z [M+H] + =280.

[0189] As shown in the table below, intermediates 49 and 70 were prepared according to the preparation method for intermediate 47, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0190] [Table 11]

[0191] Intermediate 53: 4-Chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)pyrimidine [ka] 2-(3-methyl-1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-ol [ka] Cuprous iodide (0.67 g, 3.50 mmol) was added to a solution of 2-chloro-4-(methylthio)-6-(trifluoromethyl)pyrimidine (4 g, 17.50 mmol, intermediate 56), 3-methyl-1H-1,2,4-triazole (2.18 g, 26.24 mmol, CAS: 7170-01-6), and cesium carbonate (11.40 g, 34.99 mmol) in N,N-dimethylformamide (40 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours after three nitrogen purgings. The reaction solution was diluted with water (100 mL) and extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:100) to obtain the title compound as a white solid (1400 mg, yield: 33%). LC-MS: m / z [M+H] + = 246.

[0192] 4-Chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)pyrimidine [ka] 2-(3-methyl-1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)pyrimidine-4-ol (1.373 g, 5.60 mmol) was added to phosphorus oxychloride (5 mL), and the mixture was stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:10) to obtain the title compound as a pale yellow solid (630 mg, yield: 43%). LC-MS: m / z [M+H] + = 264.

[0193] Intermediate 54: tert-butyl 4-(azetidine-3-ylmethyl)piperazine-1-carboxylate [ka] Intermediate 54 was synthesized according to the method provided in brochure international publication no. 2021155321A2.

[0194] Intermediate 56: 2-Chloro-4-(methylthio)-6-(trifluoromethyl)pyrimidine [ka] 2,4-Dichloro-6-trifluoromethylpyrimidine (3.472 g, 16 mmol, CAS: 16097-64-6) was added to tetrahydrofuran (20 mL), and sodium thiomethoxide (6.16 g, 17.6 mmol, 20% aqueous solution, CAS: 5188-07-8) was slowly added dropwise at 0°C. The mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride solution to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (3.66 g, yield: 100%). LC-MS: m / z [M+H] + = 229.

[0195] Intermediate 58: 1-(6-(piperazine-1-yl)pyridine-2-yl)-1H-imidazole-4-carboxamide [ka] tert-butyl 4-(6-(4-(ethoxycarbonyl)-1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-carboxylate [ka] tert-butyl 4-(6-bromopyridine-2-yl)piperazine-1-carboxylate (860.0 mg, 2.5 mmol, intermediate 23), ethyl Imidazole-4-carboxylate (1.75 g, 12.5 mmol, CAS: 23785-21-9), tris(dibenzylideneacetone)dipalladium-chloroform adduct (388.2 mg, 0.375 mmol, CAS: 52522-40-4), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (286.6 mg, 0.675 mmol, CAS: 564483-19-8), and potassium phosphate (1.06 g, 36 mmol, CAS: 7778-53-2) were added to a reaction flask. Toluene (10 mL) was added to the reaction flask through a syringe under a nitrogen atmosphere, and the reaction mixture was stirred at 110°C for 12 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtered cake was washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a yellow solid (622.3 mg, yield: 62%). 1 H NMR(400MHz,CDCl3) δ 8.23(s,2H),7.58(t,J=8.0Hz,1H),6.67(d,J=7.6Hz,1H),6.57(d,J=8.5Hz,1H ),4.37(q,J=7.1Hz,2H),3.58-3.53(m,8H),1.46(s,9H),1.38(t,J=7.1Hz,3H).

[0196] tert-butyl 4-(6-(4-carbamoyl-1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-carboxylate [ka] 250.0 mg, 0.67 mmol of tert-butyl 4-(6-(4-(ethoxycarbonyl)-1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-carboxylate was added to a reaction flask. 6.8 mL of methanol was added to the reaction flask via syringe, and 2 mL of aqueous ammonia was added dropwise via syringe while stirring. The reaction mixture was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a white solid (135.8 mg, yield: 54%). 1 H NMR (400MHz, CDCl3) δ 8.25(d,J=5.5Hz,2H),7.60(t,J=8.0Hz,1H),6.68(d,J=7.6Hz,1H),6.58(d,J=8.5Hz,1H),3.59-3.54(m,8H),1.47(s,9H).

[0197] 1-(6-(piperazine-1-yl)pyridine-2-yl)-1H-imidazole-4-carboxamide [ka] 130.0 mg, 0.35 mmol of tert-butyl 4-(6-(4-carbamoyl-1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-carboxylate was added to a reaction flask. 1.5 mL of ethyl acetate was added to the reaction flask via syringe, and 8 mL of a 4 M solution of hydrogen chloride in ethyl acetate was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered. The filtered cake was washed with ethyl acetate (8 mL), collected, and dried to obtain the title compound as a yellow solid (113.5 mg, yield: 105%, hydrochloride). LC-MS: m / z [M+H] + =273.

[0198] Intermediate 59: 5-(4-(methylsulfonyl)pyrimidine-2-yl)thiazole [ka] 5-(4-(methylthio)pyrimidine-2-yl)thiazole [ka] 2-chloro-4-methylthiopyrimidine (1000 mg, 6.28 mmol, CAS: 49844-93-1), potassium carbonate (1811 mg, 12.56 mmol), tris(dibenzylideneacetone)dipalladium (56 mg, 0.06 mmol, CAS: 51364-51-3), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (35 mg, 0.12 mmol, CAS: 97739-46-3), and thiazole-5-boronic acid pinacol ester (1524 mg, 6.9 mmol, CAS: 1086111-09-2) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and the mixture was subjected to three nitrogen purging cycles and stirred overnight at 100°C. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (100 mg, yield: 8%). LC-MS: m / z [M+H] + =210.

[0199] 5-(4-(methylsulfonyl)pyrimidine-2-yl)thiazole [ka] 5-(4-(methylthio)pyrimidine-2-yl)thiazole (100 mg, 0.48 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperoxybenzoic acid (149 mg, 0.96 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was filtered. The filter cake was washed with dichloromethane (5 mL). The filtrate was sequentially washed twice with saturated sodium sulfite solution (20 mL) and once with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure until dry, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (50 mg, yield: 43%). LC-MS: m / z [M+H] + = 242.

[0200] As shown in the table below, intermediates 60, 61, 63, and 67 were prepared according to the preparation method for intermediate 59, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0201] [Table 12]

[0202] Intermediate 62: (1-methyl-2-(trifluoromethyl)-1H-imidazole-5-yl)boronic acid [ka] 1-Methyl-2-(trifluoromethyl)-1H-imidazole [ka] Iodomethane (0.69 mL, 11.02 mmol, d=2.28 g / mL) was added to a solution of 2-(trifluoromethyl)-1H-imidazole (1 g, 7.35 mmol, CAS: 66675-22-7) and cesium carbonate (7.18 g, 22.05 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a yellow oil (800 mg, yield: 72.5%). LC-MS: m / z[M+H] + = 151.

[0203] (1-methyl-2-(trifluoromethyl)-1H-imidazole-5-yl)boronic acid [ka] At -78°C under a nitrogen atmosphere, n-butyllithium (3.67 mL, 5.88 mmol, 1.6 M hexane solution) was slowly added dropwise to a solution of 1-methyl-2-(trifluoromethyl)-1H-imidazole (735 mg, 4.90 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at -78°C for 10 minutes. Next, triisopropyl borate (1.36 mL, 5.88 mmol, d=0.815 g / mL, CAS: 5419-55-6) was slowly added dropwise, and the reaction mixture was stirred at -78°C for 1 hour. The reaction was quenched by slowly adding saturated ammonium chloride solution (5 mL) dropwise to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by prep-HPLC (13-43% (v / v) acetonitrile and water, and 0.1% formic acid) to obtain the title compound as a white solid (420 mg, yield: 44%). LC-MS: m / z [M+H] + = 195.

[0204] Intermediate 65: 2-(6-fluoropyridine-2-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole [ka] 2-Fluoropyridine-6-boronic acid (141 mg, 1 mmol, CAS: 916176-61-9), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (82 mg, 0.1 mmol, CAS: 95464-05-4), and sodium carbonate (530 mg, 5 mmol) were added to a Schlenk tube, and the tube was purged with nitrogen three times. Dioxane (4 mL), water (1 mL), and 2-bromo-5-trifluoromethyl-1,3,4-thiazole (280 mg, 1.2 mmol, CAS: 37461-61-3) were added sequentially under a nitrogen atmosphere. The reaction tube was transferred to 100°C and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (110 mg, yield: 44%). LC-MS: m / z [M+H] + =250.

[0205] Intermediate 66: 4-(methylsulfonyl)-2-(pyridine-3-yl)pyrimidine [ka] 2-Chloro-4-(methylsulfonyl)pyrimidine [ka] 2-Chloro-4-methylthiopyrimidine (1.6 g, 10 mmol, CAS: 49844-93-1) was dissolved in anhydrous dichloromethane (20 mL), and m-chloroperbenzoic acid (5.2 g, 30 mmol) was slowly added under ice bath conditions. The mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate solution (20 mL) was slowly added to the reaction solution to quench the reaction, and the reaction solution was extracted three times with dichloromethane (100 mL). The organic phases were combined, washed twice with brine (50 mL), dried, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (1.6 g, yield: 84%). LC-MS: m / z [M+H] + = 193.

[0206] 4-(methylsulfonyl)-2-(pyridine-3-yl)pyrimidine [ka] 2-Chloro-4-(methylsulfonyl)pyrimidine (1.6 g, 8.3 mmol), pyridine-3-boronic acid (2.1 g, 17 mmol, CAS: 1692-25-7), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (680 mg, 0.83 mmol, CAS: 95464-05-4) were added to a Schlenk tube, and the tube was purged with nitrogen three times. Dioxane (8 mL) and water (2 mL) were added sequentially under a nitrogen atmosphere. The reaction tube was transferred to 100°C and stirred for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (605 mg, yield: 31%). LC-MS: m / z [M+H] + = 236.

[0207] Intermediate 68: 1-(4-(chloromethyl)benzyl)-4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine [ka] 2-Bromo-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine [ka] 2,6-Dibromopyridine (4.00 g, 17 mmol, CAS: 626-05-1), 3-methyl-1H-1,2,4-triazole (1.80 g, 22 mmol, CAS: 7170-01-6), cuprous iodide (1.30 g, 7 mmol), and cesium carbonate (11.00 g, 34 mmol) were added to N,N-dimethylformamide (40 mL), and the mixture was purged with nitrogen three times and stirred at 120 °C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4:1) to obtain the title compound as a white solid (2.16 g, yield: 53.5%). LC-MS: m / z [M+H] + = 239 / 241.

[0208] 1-(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine-2-yl)piperazine [ka] 2-Bromo-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine (2.10 g, 9 mmol) was dissolved in N,N-dimethylformamide (20 mL), and anhydrous piperazine (1.55 g, 18 mmol) and potassium carbonate (2.49 g, 18 mmol) were added. The mixture was stirred at 120 °C for 3.5 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted three times with a mixed solvent (dichloromethane / methanol = 20:1, 100 mL). The organic phases were combined, washed once with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a white solid (1.22 g, yield: 57%). LC-MS: m / z [M+H] + = 245.

[0209] 1-(4-(chloromethyl)benzyl)-4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine [ka] 1-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine (0.26 g, 1 mmol) and 4-(chloromethyl)benzaldehyde (0.15 g, 1 mmol, CAS: 73291-09-5) were added to toluene (10 mL), and the mixture was stirred at room temperature for half an hour. Next, sodium triacetoxyborohydride (0.68 g, 3.2 mmol) was added in three portions, each time for approximately 5 minutes, and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with water (100 mL) and extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed once with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a white solid (0.4 g, yield: 98%). LC-MS: m / z [M+H] + =383.

[0210] As shown in the table below, intermediates 72a, 72, 73a, 73, 79, 81, and 84 were prepared according to the preparation method for intermediate 68, except that the raw materials listed in the "Raw Materials" column were used in place of the corresponding raw materials.

[0211] [Table 13(1)] [Table 13(2)]

[0212] Intermediate 69: 5-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-2-methylthiazole [ka] tert-butyl 4-(5-fluoro-2-(2-methylthiazole-5-yl)pyrimidine-4-yl)piperazine-1-carboxylate [ka] 634 mg, 2 mmol) of tert-butyl 4-(2-chloro-5-fluoropyrimidine-4-yl)piperazine-1-carboxylate, 675 mg, 3 mmol, CAS: 1218791-01-5, potassium phosphate (1.272 g, 6 mmol), and tetrakis(triphenylphosphine)palladium (115.6 mg, 0.1 mmol) were added to toluene (10 mL), and the mixture was purged with nitrogen three times and stirred at 130 °C for 3 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (493 mg, yield: 65%). LC-MS: m / z [M+H] + =380.

[0213] 5-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-2-methylthiazole [ka] 493 mg (1.3 mmol) of tert-butyl 4-(5-fluoro-2-(2-methylthiazole-5-yl)pyrimidine-4-yl)piperazine-1-carboxylate was added to 8.5 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was slowly added dropwise at 0°C. The reaction solution was stirred at room temperature for 20 minutes. The reaction solution was concentrated directly under reduced pressure to obtain the title compound as a colorless oil (510 mg, yield: 100%, TFA salt). LC-MS: m / z [M+H] + =280.

[0214] Intermediate 82: 2-Chloro-6-(1-isopropyl-4,5-dihydro-1H-imidazole-2-yl)pyridine [ka] 6-Chloro-N-(2-(isopropylamino)ethyl)pyridinecarboxamide [ka] At room temperature, trimethylaluminum (8.74 mL, 8.74 mmol, 1 M hexane solution, CAS: 75-24-1) was slowly added to a solution of methyl 6-chloropyridine-2-carboxylate (1000 mg, 5.83 mmol, CAS: 6636-55-1) and N-isopropylethylenediamine (0.88 mL, 6.99 mmol, d=0.819 g / mL, CAS: 19522-67-9) in toluene (20 mL), and the mixture was refluxed overnight under a nitrogen atmosphere. Under ice bath conditions, water was added to the reaction solution to quench the reaction, and the reaction solution was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a pale yellow oil (1400 mg, yield: 99%). LC-MS: m / z[M+H] + = 242.

[0215] 2-Chloro-6-(1-isopropyl-4,5-dihydro-1H-imidazole-2-yl)pyridine [ka] At room temperature, 6-chloro-N-(2-(isopropylamino)ethyl)pyridinecarboxamide (600 mg, 2.48 mmol) was dissolved in phosphorus oxychloride (10 mL), and the mixture was stirred overnight at 110°C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by flash liquid chromatography (C18 chromatography column) to obtain the title compound as a white solid (130 mg, yield: 23%). LC-MS: m / z [M+H] + = 224.

[0216] Intermediate 85: 3-(2-oxo-6-(4-(piperazine-1-ylmethyl-d2)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Methyl 4-(((tert-butyldimethylsilyl)oxy)methyl benzoate [ka] To a solution of methyl 4-(hydroxymethyl)benzoate (5850 mg, 32.46 mmol, CAS: 6908-41-4) and imidazole (4100 mg, 60.22 mmol) in N,N-dimethylformamide (100 mL), tert-butyldimethylsilyl chloride (6100 mg, 40.47 mmol, CAS: 18162-48-6) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was slowly poured into a saturated aqueous solution of ammonium chloride (400 mL) and extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed once with brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / dichloromethane = 4:1) to obtain the title compound as a pale yellow liquid (9.1 g, yield: 95%). LC-MS: m / z [M+H] + =281.

[0217] (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-d2-ol [ka] At 0°C, a solution of lithium aluminum deuteride (2.1 g, 50.02 mmol, CAS: 14128-54-2) in tetrahydrofuran (100 mL) was slowly added dropwise to a solution of methyl 4-(((tert-butyldimethylsilyl)oxy)methyl benzoate (5.1 g, 17.32 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to -10°C, and sodium sulfate decahydrate (30 g) was added little by little. The mixture was then heated to room temperature and stirred for 30 minutes. The reaction solution was filtered. The filter cake was washed once with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed once with brine (100 mL). The organic phase was dried and concentrated under reduced pressure to obtain the title compound as a pale yellow liquid (3.1 g, yield: 70%).

[0218] (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-D2 methanesulfonate [ka] At 0°C, methylsulfonyl chloride (900 mg, 7.86 mmol, CAS: 124-63-0) was slowly added dropwise to a solution of (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-d2-ol (1.5 g, 5.90 mmol) and triethylamine (1.85 mL, 13.34 mmol, d=0.728 g / mL) in N,N-dimethylformamide (100 mL) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and washed once with water (100 mL). The organic phase was dried and concentrated under reduced pressure to obtain the title compound as a pale yellow solid (1.65 g, yield: 85%).

[0219] tert-butyl 4-(4-((((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-d2)piperazine-1-carboxylate [ka] To a solution of 1-(tert-butoxycarbonyl)piperazine (1500 mg, 8.05 mmol, CAS: 57260-71-6) and potassium carbonate (3000 mg, 21.71 mmol) in N,N-dimethylformamide (30 mL), (4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-d2 methanesulfonate (1600 mg, 4.81 mmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was slowly poured into water (150 mL) and extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed once with brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 10:1) to obtain the title compound as a pale yellow solid (2010 mg, yield: 99%). LC-MS: m / z [M+H] + = 423.

[0220] tert-butyl 4-((4-(hydroxymethyl)phenyl)methyl-d2)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-((((tert-butyldimethylsilyl)oxy)methyl)phenyl)methyl-d2)piperazine-1-carboxylate (2100 mg, 4.97 mmol) in tetrahydrofuran (20 mL), a 1N solution of tetrabutylammonium fluoride in tetrahydrofuran (10 mL, CAS: 429-41-4) was added, and the mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed once with brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 25:1) to obtain the title compound as a yellow liquid (1400 mg, yield: 91%). LC-MS: m / z [M+H] + =309.

[0221] tert-butyl 4-(4-(chloromethyl)phenyl)methyl-d2)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-((4-(hydroxymethyl)phenyl)methyl-d2)piperazine-1-carboxylate (1500 mg, 4.86 mmol) in dichloromethane (20 mL), thionyl chloride (1500 mg, 12.61 mmol) was slowly added, and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (25 mL) and washed once with brine (20 mL). The organic phase was dried and concentrated under reduced pressure to obtain the title compound as a yellow liquid (1300 mg, yield: 82%). LC-MS: m / z [M+H] + =327.

[0222] tert-butyl 4-((4-((2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)phenyl)methyl-d2)piperazine-1-carboxylate [ka] Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium (60 mg, 0.07 mmol, CAS: 51364-51-3) and tris(2-methylphenyl)phosphine (100 mg, 0.33 mmol, CAS: 6163-58-2) were dissolved in tert-butyl ethanol (8 mL) and toluene (20 mL). 4-(4-(chloromethyl)phenyl)methyl-d2)piperazine-1-carboxylate (1200 mg, 3.67 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indole-2(1H)-one (1200 mg, 4.07 mmol, synthesized according to the method provided in brochure International Publication No. 2020210630A1), and potassium phosphate (2500 mg, 11.78 mmol) were added to a mixed solution, and the reaction mixture was stirred at 100°C for 10 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtered cake was washed once with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (1150 mg, yield: 68%). LC-MS: m / z [M+H] + =460.

[0223] tert-butyl 4-((4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)phenyl)methyl-d2)piperazine-1-carboxylate [ka] At 55°C, sodium hydride (2500 mg, 62.50 mmol, stored in mineral oil at 60%) was gradually added to a solution of tert-butyl 4-((4-((2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)phenyl)methyl-d2)piperazine-1-carboxylate (1150 mg, 2.50 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 55°C for 30 minutes. Next, at the same temperature, 3-bromopiperidine-2,6-dione (2100 mg, 10.94 mmol, CAS: 62595-74-8) was gradually added, and the reaction mixture was heated at 70°C for 5 hours. The reaction solution was cooled to room temperature and slowly poured into a saturated ammonium chloride solution (150 mL), and extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed once with brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / ethyl acetate = 1:1) to obtain the title compound as a pale yellow solid (800 mg, yield: 56%). LC-MS: m / z [M+H] + = 571.

[0224] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl-d2)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-((4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)phenyl)methyl-d2)piperazine-1-carboxylate (750 mg, 1.31 mmol) in dichloromethane (10 mL), trifluoroacetic acid (1.5 mL) was slowly added dropwise, and the mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a yellow solid (800 mg, yield: 104%, TFA salt). LC-MS: m / z [M+H] + = 471.

[0225] Example 1 (S)-3-(4-((4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] tert-butyl (S)-4-(4-((4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)-5-amino-5-oxopentanoate [ka] 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (2.0 g, 5.4 mmol, intermediate 2) was dissolved in anhydrous N,N-dimethylformamide (20 mL), potassium carbonate (1.5 g, 10.8 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Subsequently, a solution of tert-butyl (S)-5-amino-4-(4-hydroxy-1-oxoisoindorin-2-yl)-5-oxopentanoate (1.8 g, 5.4 mmol, intermediate 1) in N,N-dimethylformamide (5 mL) was slowly added dropwise to the above solution, and the mixture was stirred at 45°C for 12 hours. Once TLC (dichloromethane / methanol = 20:1) was determined to be complete, brine (100 mL) was added to the reaction solution. This reaction solution was extracted three times with ethyl acetate (30 mL), and then purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a yellow oily substance (770 mg, yield: 21%). LC-MS: m / z [M+H] + = 667.

[0226] (S)-3-(4-((4-((4-((2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] tert-butyl (S)-4-(4-((4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)-5-amino-5-oxopentanoate (770 mg, 1.15 mmol) and benzenesulfonic acid (760 mg, 4.8 mmol) were added to a reaction flask, and anhydrous acetonitrile (50 mL) was added under a nitrogen atmosphere. The reaction solution was stirred at 85°C for 1 hour. When TLC (dichloromethane / methanol = 20:1) indicated completion, the reaction was quenched with saturated sodium bicarbonate solution (50 mL), and the reaction solution was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to obtain the title compound as a white solid (43 mg, yield: 6%). 1 H NMR(500MHz,CDCl3) δ 8.97(s,1H),8.51(s,1H),8.11(d,J=6.2Hz,1H),7.78(s,1H),7.49(d,J=7.5Hz,1 H),7.42(d,J=7.8Hz,1H),7.38(m,4H),7.09(m,2H),6.34(d,J=6.2Hz,1H),5.22( dd,J=13.3,5.1Hz,1H),5.13(s,2H),4.45(d,J=16.5Hz,1H),4.31(d,J=16.5Hz,1 H),3.70(s,4H),3.57(s,2H),2.85(m,2H),2.54(m,4H),2.32(m,1H),2.19(m,1H). LC-MS:m / z[M+H] + = 593.

[0227] Example 2: 3-(6-(4-((4-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 2-Fluoro-6-(1H-imidazole-1-yl)pyridine (326 mg, 1.28 mmol, intermediate 4) and 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (300 mg, 0.64 mmol, intermediate 3) were added to a 25 mL reaction flask, followed by the addition of potassium carbonate (265 mg, 1.92 mmol) and dimethyl sulfoxide (5 mL), and the mixture was reacted overnight at 90°C. Salt water (50 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (45 mg, yield: 11.5%). 1 H NMR(500MHz,CDCl3) δ 8.27(s,1H),8.23(s,1H),8.11(dd,J=19.7,7.6Hz,2H),7.70(dd,J=8.3,7.0Hz,1H),7.59-7.50(m,2H),7.24(s,2H) ,7.17(d,J=7.8Hz,2H),7.14(s,1H),6.70(d,J=7.3Hz,1H),6.59(d,J=7.6Hz,1H),6.49(d,J=8.5Hz,1H),5.33(dd,J =12.9,5.4Hz,1H),4.38(s,2H),3.57(t,J=5.0Hz,4H),3.52(s,2H),2.95(d,J=4.6Hz,1H),2.87(ddd,J=17.6,13.3, 5.1Hz,1H),2.73(qd,J=13.1,4.7Hz,1H),2.53(t,J=5.1Hz,4H),2.29(ddq,J=10.5,5.5,2.5Hz,1H);LC-MS:m / z[M+H] + = 612.

[0228] Example 3: 3-(6-(4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (234 mg, 0.5 mmol, intermediate 3), 2-(1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine (168 mg, 0.75 mmol, intermediate 5), and N,N-diisopropylethylamine (387 mg, 3 mmol) were added to a 50 mL one-neck flask, and isopropanol (5 mL) was then added. The mixture was stirred overnight at 100°C. The reaction solution was concentrated directly under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (45 mg, yield: 15%). 1 H NMR(500MHz,CDCl3) δ 8.50(s,1H),8.32(s,1H),8.13-8.08(m,3H),7.78(s,1H),7.72-7.68(m,1H),7.23(d,J=7.9Hz,3 H),7.17(d,J=8.1Hz,2H),7.09(s,1H),6.70(d,J=7.3Hz,1H),6.33(d,J=6.2Hz,1H),5.33(dd,J= 12.9,5.4Hz,1H),4.37(s,2H),3.67(s,4H),3.51(s,2H),2.96(dd,J=13.9,3.7Hz,1H),2.90-2.8 3(m,1H),2.73(qd,J=13.2,4.7Hz,1H),2.50(t,J=5.1Hz,4H),2.31-2.26(m,1H);LC-MS:m / z[M+H] + = 613.

[0229] Example 4 3-(6-(4-((4-(6-(1H-imidazole-1-yl)pyridine-2-carbonyl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (0.46g, 0.98mmol, intermediate 3), 6-(1H-imidazole-1-yl)-2-picolinic acid (0.19g, 0.98mmol, intermediate 6), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0. 28 g, 1.47 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (0.20 g, 1.47 mmol, CAS: 2592-95-2) were added to a 25 mL two-necked flask, then 10 mL of dichloromethane was added under a nitrogen atmosphere, and N-methylmorpholine (0.2 mL, 1.96 mmol, d=0.92 g / mL) was added via syringe. The mixture was stirred overnight at room temperature. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to obtain the title compound as a yellow solid (44 mg, yield: 7%). 1 H NMR(500MHz,CDCl3) δ 8.75(s,1H),8.35(s,1H),8.13(d,J=8.13Hz,1H),8.08(d,J=8.08Hz,1H),7.93(t,J=7.93Hz,1H),7.70(dd,J=8.3,7. 0Hz,1H),7.60-7.58(m,2H),7.39(d,J=8.2Hz,1H),7.24-7.21(t,J=7.3Hz,4H),7.16-7.18(m,2H),6.70(d,J=7.2Hz,1 H),5.34(dd,J=12.9,5.4Hz,1H),4.37(s,2H),3.83-3.82(m,2H),3.62-3.60(m,2H),3.52(s,2H),2.98-2.93(m,1H),2 .90-2.83(m,1H),2.77-2.69(m,1H),2.57(t,J=5.1Hz,2H),2.46(t,J=5.0Hz,2H),2.31-2.25(m,1H);LC-MS:m / z[M+H] + =640.

[0230] Example 5 3-(6-(4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (500 mg, 1.0 mmol, intermediate 3), 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (200 mg, 1.1 mmol, intermediate 7), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (290 mg, 1.5 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (202 mg, 1.5 mmol, CAS: 2592-95-2) were added to a 25 mL two-necked flask, then dichloromethane (10 mL) was added under a nitrogen atmosphere, and N-methylmorpholine (0.22 mL, 2 mmol, d=0.92 g / mL) was added via syringe. The mixture was stirred overnight at room temperature. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (53 mg, yield: 8%). 1H NMR(500MHz,CDCl3) δ 8.80(d,J=5.0Hz,1H),8.57(s,1H),8.38(s,1H),8.12(d,J=8.5Hz,1H),8.08(d,J=7.0Hz,1H),7.84(s,1H),7. 69(dd,J=8.3,7.0Hz,1H),7.44(d,J=5.0Hz,1H),7.21(d,J=7.8Hz,3H),7.16(m,3H),6.69(d,J=7.3Hz,1H),5.3 2(dd,J=13.0,5.4Hz,1H),4.36(s,2H),3.79(m,2H),3.55(m,2H),3.51(s,2H),2.95(ddd,J=17.4,4.8,2.6Hz, 1H),2.86(ddd,J=17.7,13.5,5.3Hz,1H),2.72(dd,J=13.1,4.7Hz,1H),2.55(m,2H),2.45(m,2H),2.27(m,1H). LC-MS:m / z[M+H] + =641.

[0231] Example 6: N-(1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)-6-(1H-imidazole-1-yl)pyridine-2-carboxamide [ka] 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (145 mg, 0.3 mmol, intermediate 11), 6-(1H-imidazole-1-yl)-2-picolinic acid (62 mg, 0.33 mmol, intermediate 6), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (61 mg, 0.45 mmol, CAS: 94790-37-1), and N,N-diisopropylethylamine (233 mg, 1.8 mmol) were added to dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (41 mg, yield: 21%). 1 H NMR (500MHz, acetone-d6) δ 9.98(s,1H),8.57(s,1H),8.40(d,J=10.0Hz,1H),8.28(d,J=10Hz,1H),8.14(t,J=10.0Hz,1H),8.04-8. 00(m,2H),7.95(s,1H),7.89(d,J=10.0Hz,1H),7.76(t,J=7.5Hz,1H),7.39(d,J=5.0Hz,1H),7.34-7.30( m,4H),7.10-7.07(m,2H),5.59(s,2H),5.44(dd,J=15.0,5.0Hz,1H),4.42(s,2H),4.07-4.05(m,1H),3. 95(br,2H),3.04-2.72(m,6H),2.29-2.24(m,1H),2.06-2.05(m,1H),1.97-1.89(m,2H);LC-MS:m / z[M+H] + = 654.

[0232] Example 7: N-(1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)-2-(1H-imidazole-1-yl)pyrimidine-4-carboxamide [ka] 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (483 mg, 1.0 mmol, intermediate 11), 2-(1H-imidazole-1-yl)pyrimidine-4-carboxylic acid (200 mg, 1.1 mmol, intermediate 7), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (202 mg, 1.5 mmol, CAS: 94790-37-1), and N,N-diisopropylethylamine (774 mg, 6.0 mmol) were added to dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (42 mg, yield: 6%). 1H NMR(500MHz,CDCl3) δ 8.87(d,J=5.0Hz,1H),8.61(s,1H),8.09(d,J=8.3Hz,1H),8.04(d,J=7.0Hz,1H),7.95(d,J=4.9Hz,1H),7.86(s,1H),7.72(d ,J=8.4Hz,1H),7.66(t,J=7.7Hz,1H),7.22(d,J=7.8Hz,2H),7.18(d,J=8.5Hz,2H),7.14(d,J=7.9Hz,2H),6.69(d,J=7.3Hz,1 H),5.31(dd,J=12.9,5.4Hz,1H),4.34(s,2H),4.07-3.93(m,1H),3.64(p,J=6.7Hz,1H),3.51(s,2H),3.06(q,J=7.4Hz,1H),2 .96-2.80(m,4H),2.71(qd,J=13.0,4.9Hz,1H),2.22(d,J=12.5Hz,2H),1.98(d,J=12.2Hz,2H),1.71(s,2H);LC-MS:m / z[M+H] + = 655.

[0233] Example 8: 3-(6-(4-((4-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 2-Fluoro-6-(1H-imidazole-1-yl)pyridine (410 mg, 2.5 mmol, intermediate 4) and 3-(2-oxo-6-(4-((4-(piperidine-4-ylmethyl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (900 mg, 1.3 mmol, intermediate 12) were dissolved in dimethyl sulfoxide (10 mL), then potassium carbonate (350 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Salt water (50 mL) was added to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (48 mg, yield: 5%). 1 H NMR(500MHz,CDCl3) δ 8.95(s,1H),8.29(s,1H),8.12(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.69(m,1H),7.54(s,1H),7.50(t,J=8.0Hz,1H),7 .21(dd,J=7.5,4.4Hz,3H),7.14(d,J=8.0Hz,3H),6.69(d,J=7.3Hz,1H),6.52(dd,J=14.7,8.0Hz,2H),5.32(dd,J=12.9,5 .4Hz,1H),4.35(s,2H),4.30(d,J=16.2Hz,2H),3.48(s,2H),2.94(m,1H),2.85(m,3H),2.72(q,J=14.7,13.9Hz,1H),2.45 (s,7H),2.26(m,1H),2.18(d,J=7.0Hz,2H)1.82(d,J=15.1Hz,2H),1.78-1.68(m,1H),1.23-1.12(m,2H);LC-MS:m / z[M+H] + = 709.

[0234] Example 9 3-(6-(4-((4-((2-((1H-imidazole-1-yl)pyrimidine-4-yl)amino)piperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(6-(4-((4-(2-chloropyrimidine-4-yl)amino)piperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (483 mg, 1.0 mmol, intermediate 11) and 2,4-dichloropyrimidine (298 mg, 2 mmol, CAS: 3934-20-1) were added to a reaction flask, followed by the addition of triethylamine (0.84 mL, 6 mmol, d=0.728 g / mL) and anhydrous N,N-dimethylacetamide (10 mL). The mixture was stirred at room temperature for 3 hours. Salt water (30 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (417 mg, yield: 70%). LC-MS: m / z [M+H] + = 595.

[0235] 3-(6-(4-((4-((2-((1H-imidazole-1-yl)pyrimidine-4-yl)amino)piperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(6-(4-((4-(2-chloropyrimidine-4-yl)amino)piperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (417 mg, 0.7 mmol), imidazole (110 mg, 1.4 mmol), cuprous iodide (27 mg, 0.14 mmol), and cesium carbonate (456 mg, 1.4 mmol) were added to a reaction flask, and then anhydrous N,N-dimethylacetamide (5 mL) was added under a nitrogen atmosphere. The mixture was stirred overnight at 80°C. Salt water (30 mL) was added to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (41 mg, yield: 9%). 1 H NMR(500MHz,CDCl3) δ 8.49(s,1H),8.13(d,J=8.3Hz,1H),8.08(d,J=7.1Hz,1H),7.77(s,1H),7.69(dd,J=8.3,7.0Hz,1H),7.21(dd,J=7.7, 6.2Hz,3H),7.16(d,J=7.9Hz,2H),7.09(s,1H),6.69(d,J=7.2Hz,1H),6.15(d,J=6.0Hz,1H),5.32(dd,J=12.9,5.4Hz, 1H),4.36(d,J=5.4Hz,2H),3.50(s,2H),2.98-2.87(m,1H),2.90-2.80(m,3H),2.72(qd,J=13.1,4.7Hz,1H),2.27(dt d,J=13.1,5.2,2.6Hz,1H),2.16(t,J=11.3Hz,2H),2.01(d,J=12.7Hz,2H),1.81(s,2H),1.56(s,4H);LC-MS:m / z[M+H] + = 627.

[0236] Example 10: 3-(6-(4-((4-(2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (234 mg, 0.5 mmol, intermediate 3), 2-(1H-imidazole-1-yl)-4-methyl-6-(methylsulfonyl)pyrimidine (179 mg, 0.75 mmol, intermediate 13), and N,N-diisopropylethylamine (387 mg, 3 mmol) were added to a 50 mL one-neck flask, and isopropanol (5 mL) was then added. The mixture was stirred overnight at 100°C. The reaction solution was concentrated directly under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (41 mg, yield: 13%). 1 H NMR(500MHz,CDCl3) δ 8.50(s,1H),8.43(s,1H),8.10(dd,J=16.1,7.6Hz,2H),7.79(s,1H),7.70(dd,J=8.3,7.0Hz,1H),7.23 (d,J=8.1Hz,3H),7.17(d,J=7.9Hz,2H),7.07(s,1H),6.70(d,J=7.3Hz,1H),6.18(s,1H),5.33(dd,J=1 3.0,5.4Hz,1H),4.37(s,2H),3.65(s,4H),3.51(s,2H),3.00-2.92(m,1H),2.92-2.81(m,1H),2.73(qd ,J=13.2,4.8Hz,1H),2.49(t,J=5.1Hz,4H),2.34(s,3H),2.28(dt,J=15.9,5.2Hz,1H);LC-MS:m / z[M+H] + = 627.

[0237] Example 11: 3-(6-(4-((4-(2-((1H-imidazole-1-yl)-6-methylpyrimidine-4-carbonyl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (0.46g, 0.98mmol, intermediate 3), 2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-carboxylic acid (0.2g, 0.98mmol, intermediate 14), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.28 g (1.47 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (0.20 g, 1.47 mmol, CAS: 2592-95-2) were added to a 25 mL two-necked flask, then 10 mL of dichloromethane was added under a nitrogen atmosphere, and N-methylmorpholine (0.2 mL, 1.96 mmol, d=0.92 g / mL) was added via syringe. The mixture was stirred overnight at room temperature. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 15:1) to obtain the title compound as a yellow solid (45 mg, yield: 7%). 1 H NMR(500MHz,CDCl3) δ 8.73(s,1H),8.58(s,1H),8.12(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.84(s,1H),7.69(dd,J=8.2,7 .1Hz,1H),7.29(s,1H),7.22-7.21(m,3H),7.17-7.15(m,3H),6.70(d,J=7.2Hz,1H),5.33(dd,J=13.0, 5.4Hz,1H),4.36(s,2H),3.80-3.78(m,2H),3.55(s,2H),3.51(s,2H),2.97-2.92(m,1H),2.90-2.83(m ,1H),2.77-2.68(m,1H),2.59(s,3H),2.55(t,J=5.2Hz,2H),2.45(t,J=4.8Hz,2H),2.30-2.24(m,1H). LC-MS:m / z[M+H] + = 655.

[0238] Example 12 N-(1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)-2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-carboxamide [ka] 3-(6-(4-((4-aminopiperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (473 mg, 0.9 mmol, intermediate 11), 2-(1H-imidazole-1-yl)-6-methylpyrimidine-4-carboxylic acid (205 mg, 1.0 mmol, intermediate 14), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (204 mg, 1.5 mmol, CAS: 94790-37-1), and N,N-diisopropylethylamine (774 mg, 6.0 mmol) were added to dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (50 mg, yield: 8%). 1H NMR(500MHz,CDCl3) δ 8.60(s,1H),8.33(s,1H),8.10(dd,J=19.4,7.6Hz,2H),7.87(s,1H),7.83(s,1H),7.72-7.63(m, 2H),7.25-7.20(m,3H),7.17(t,J=6.4Hz,3H),6.69(d,J=7.3Hz,1H),5.36-5.29(m,1H),4.37(s, 2H),4.00(d,J=8.4Hz,1H),3.51(s,2H),3.00-2.92(m,1H),2.91-2.80(m,2H),2.79-2.69(m,1H) ,2.64(s,3H),2.35-2.14(m,3H),1.99(d,J=14.1Hz,2H),1.68(d,J=10.9Hz,3H);LC-MS:m / z[M+H] + = 669.

[0239] Example 13: 3-(2-oxo-6-(4-((4-(2-(2-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (234 mg, 0.5 mmol, intermediate 3), 4-(methylsulfonyl)-2-(2-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (219 mg, 0.75 mmol, intermediate 15), and N,N-diisopropylethylamine (387 mg, 3 mmol) were added to a 50 mL one-neck flask, then isopropanol (5 mL) was added, and the mixture was stirred overnight at 100 °C. The reaction solution was concentrated directly under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (45 mg, yield: 13%). 1H NMR(500MHz,CDCl3) δ 8.21(s,1H),8.14(dd,J=13.9,7.2Hz,2H),8.09(d,J=7.0Hz,1H),7.90(s,1H),7.70(t,J=7.7Hz,1H),7.2 3(d,J=10.1Hz,3H),7.17(d,J=7.8Hz,2H),7.13(s,1H),6.70(d,J=7.2Hz,1H),6.40(d,J=6.2Hz,1H),5.33 (dd,J=12.9,5.3Hz,1H),4.37(s,2H),3.68(s,4H),3.50(s,2H),2.96(dt,J=17.0,3.9Hz,1H),2.90-2.83( m,1H),2.73(qd,J=13.2,4.7Hz,1H),2.49(t,J=5.1Hz,4H),2.28(dt,J=16.1,5.3Hz,1H);LC-MS:m / z[M+H] + = 681.

[0240] Example 14 (S)-3-(4-((4-((4-(2-(1H-imidazole-1-yl)pyrimidine-4-carbonyl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (91.7 mg, 0.23 mmol, intermediate 16) and (2-(1H-imidazole-1-yl)pyrimidine-4-yl)(piperazine-1-yl)methanone hydrochloride (70.0 mg, 0.27 mmol, intermediate 17) were added to a reaction flask, acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (71.0 mg, 0.7 mmol) was added while stirring. The reaction solution was stirred at room temperature for 60 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a white solid (34.3 mg, yield: 24%). 1H NMR(400MHz,CDCl3) δ 8.82(d,J=4.9Hz,1H),8.58(s,2H),7.86(s,1H),7.48(t,J=6.9Hz,2H),7.44-7.36(m, 5H),7.18(s,1H),7.09(d,J=8.0Hz,1H),5.22(dd,J=13.3,5.0Hz,1H),5.14(s,2H),4. 45(d,J=16.5Hz,1H),4.31(d,J=16.6Hz,1H),3.85(s,2H),3.62(s,4H),2.91-2.77(m, 2H),2.63(s,2H),2.54(s,2H),2.39-2.28(m,1H),2.23-2.18(m,1H);LC-MS:m / z[M+H] + = 621.

[0241] Example 15 N-((1R,4R)-4-(4-(4-(((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)cyclohexyl)-2-(1H-imidazole-1-yl)pyrimidine-4-carboxamide [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (40 mg, 0.1 mmol, intermediate 16) and 2-(1H-imidazole-1-yl)-N-((1R,4R)-4-(piperazine-1-yl)cyclohexyl)pyrimidine-4-carboxamide hydrochloride (43 mg, 0.12 mmol, intermediate 19) were added to a reaction flask. Acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (30 mg, 0.3 mmol) was added while stirring. The reaction solution was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a white solid (30.4 mg, yield: 42%). 1H NMR(400MHz,CDCl3) δ 8.90(d,J=4.9Hz,1H),8.72(s,1H),8.67(s,1H),7.99(d,J=4.9Hz,1H),7.90(s,1H),7.70(s,1H),7.48( d,J=7.6Hz,1H),7.41(t,J=7.7Hz,1H),7.37-7.33(m,4H),7.19(s,1H),7.09(d,J=8.0Hz,1H),5.21(dd, J=13.2,5.0Hz,1H),5.12(s,2H),4.43(d,J=16.5Hz,1H),4.32(d,J=16.7Hz,1H),3.97-3.90(m,1H),3.6 0(s,2H),2.92-2.71(m,10H),2.40-2.29(m,1H),2.20-2.13(m,5H),1.58-1.38(m,5H);LC-MS:m / z[M+H] + = 718.

[0242] Example 16 N-((1R,4R)-4-(4-(4-(((2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)cyclohexyl)-6-(1H-imidazole-1-yl)pyridine-2-carboxamide [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (40 mg, 0.1 mmol, intermediate 16) and 6-(1H-imidazole-1-yl)-N-((1R,4R)-4-(piperazine-1-yl)cyclohexyl)pyridine-2-carboxamide hydrochloride (43 mg, 0.12 mmol, intermediate 20) were added to a reaction flask, acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (30 mg, 0.3 mmol) was added while stirring. The reaction solution was stirred at room temperature for 11 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a white solid (30.5 mg, yield: 42.5%).1 H NMR(400MHz,CDCl3) δ 8.76(s,1H),8.34(s,1H),8.13(d,J=7.6Hz,1H),7.99(t,J=7.9Hz,1H),7.63-7.60(m,2H),7.50-7.4 6(m,2H),7.40(t,J=7.9Hz,1H),7.36-7.31(m,4H),7.22(s,1H),7.08(d,J=8.0Hz,1H),5.20(dd,J=13 .3,5.1Hz,1H),5.11(s,2H),4.42(d,J=16.6Hz,1H),4.30(d,J=16.6Hz,1H),3.96-3.86(m,1H),3.58( s,2H),2.92-2.68(m,10H),2.39-2.28(m,2H),2.20-2.10(m,5H),1.56-1.34(m,4H);LC-MS:m / z[M+H] + = 717.

[0243] Example 17 (S)-3-(4-((4-((4-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)pyridine-2,6-dione [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (55 mg, 0.14 mmol, intermediate 16) and 1-((1-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine hydrochloride (60 mg, 0.17 mmol, intermediate 21) were added to a reaction flask. Acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (43 mg, 0.42 mmol) was added while stirring. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a white solid (61 mg, yield: 63%). 1H NMR(400MHz,CDCl3) δ 8.70(d,J=22.0Hz,1H),8.32(s,1H),7.58(s,1H),7.51-7.41(m,3H),7.36-7.32(m,4H),7.14(s,1H),7 .11(d,J=8.0Hz,1H),6.52(d,J=7.4Hz,1H),6.22(d,J=8.3Hz,1H),5.22(dd,J=13.4,5.0Hz,1H),5.12( s,2H),4.42(d,J=16.6Hz,1H),4.31(d,J=16.7Hz,1H),3.74-3.69(m,1H),3.64-3.56(m,3H),3.43-3.3 6(m,1H),3.08-3.03(m,1H),2.92-2.77(m,2H),2.51-2.17(m,14H),1.72-1.62(m,3H);LC-MS:m / z[M+H] + = 689.

[0244] Example 18 (S)-N-(1'-(4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)-[1,4'-bipiperidine]-4-yl)-2-(1H-imidazole-1-yl)pyrimidine-4-carboxamide [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (56 mg, 0.14 mmol, intermediate 16) and N-([1,4'-bipiperidine]-4-yl)-2-(1H-imidazole-1-yl)pyrimidine-4-carboxamide hydrochloride (60 mg, 0.17 mmol, intermediate 22) were added to a reaction flask, acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (43 mg, 0.42 mmol) was added while stirring. The reaction solution was stirred at 40°C for 10 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a white solid (13.2 mg, yield: 13%). 1H NMR(400MHz,CDCl3) δ 8.90(d,J=4.9Hz,1H),8.73(brs,1H),8.64(s,1H),7.98(d,J=4.9Hz,1H),7.88(s,1H),7.77(d,J=9.1Hz,1H),7.48(d,J =7.5Hz,1H),7.43-7.33(m,5H),7.20(s,1H),7.09(d,J=8.0Hz,1H),5.21(dd,J=13.2,5.2Hz,1H),5.12(s,2H),4.45(d,J =16.6Hz,1H),4.31(d,J=16.5Hz,1H),4.08-4.01(m,1H),3.53(s,2H),3.03-1.97(m,4H),2.93-2.78(m,2H),2.52-2.48 (m,3H),2.41-2.29(m,1H),2.23-2.18(m,1H),2.09-2.00(m,4H),1.87-1.80(m,4H),1.73-1.64(m,2H);LC-MS:m / z[M+H] + = 718.

[0245] Example 19 (S)-3-(1-oxo-4-((4-((4-(6-(thiazole-5-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)oxy)isoindoline-2-yl)piperidine-2,6-dione [ka] (S)-3-(4-((4-(chloromethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (47 mg, 0.12 mmol, intermediate 16) and 5-(6-(piperazine-1-yl)pyridine-2-yl)thiazole hydrochloride (40 mg, 0.14 mmol, intermediate 24) were added to a reaction flask, acetonitrile (1 mL) was added to the reaction flask through a syringe, and triethylamine (36 mg, 0.36 mmol) was added while stirring. The reaction solution was stirred at room temperature for 28 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound as a white solid (31.5 mg, yield: 43%). 1H NMR(400MHz,CDCl3) δ 8.74(s,1H),8.23(s,1H),7.51-7.37(m,7H),7.09(d,J=8.1Hz,1H),7.00( d,J=8.2Hz,1H),6.54(d,J=8.5Hz,1H),5.17(dd,J=12.8,5.7Hz,1H),5.12( s,2H),4.44(d,J=16.9Hz,1H),4.31(d,J=16.5Hz,1H),3.58(s,5H),2.88- 2.75(m,2H),2.57(s,3H),2.37-2.26(m,1H),2.19(s,3H);LC-MS:m / z[M+H] + = 609.

[0246] Example 20: 3-(6-(4-((4-(2-(1-methyl-1H-imidazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Under a nitrogen atmosphere, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (30 mg, 0.10 mmol, CAS: 97739-46-3) and tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol, CAS: 51364-51-3) were subjected to 3-(6-(4-((4-(2-chloropyrimidine-4-yl)piperazin-1-yl)methyl)benzyl)-2- Oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (110 mg, 0.19 mmol, intermediate 25), 1-methylimidazole-5-boronic acid pinacol ester (61 mg, 0.29 mmol, CAS: 942070-72-6), cesium carbonate (185.30 mg, 0.57 mmol), and N,N-dimethylformamide (5 mL) were added to a mixed solution and reacted at 100°C for 3 hours. The reaction solution was purified by prep-HPLC (acetonitrile containing 0.1% ammonium bicarbonate and water) to obtain the title compound as a yellow solid (21.6 mg, yield: 18%). 1H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),8.34(d,J=8.3Hz,1H),8.19(d,J=6.2Hz,1H),8.08(d,J=6.9Hz,1H),7.81(t,J=7.6Hz,1H),7 .71(s,1H),7.60(s,1H),7.42(d,J=7.2Hz,1H),7.24(dd,J=16.1,7.9Hz,4H),7.11(d,J=7.3Hz,1H),6.62(d ,J=6.3Hz,1H),5.45(dd,J=12.4,4.9Hz,1H),4.39(s,2H),3.94(s,3H),3.60(s,4H),3.45(s,2H),3.08-2.8 7(m,1H),2.75(m=25.3,12.2Hz,1H),2.65(m=16.9Hz,1H),2.40(m,4H),2.17-2.00(m,1H);LC-MS:m / z[M+H] + = 627.

[0247] Example 21: 3-(6-(4-((4-(2-(2-(2-methylthiazole-5-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Under a nitrogen atmosphere, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (40.03 mg, 0.06 mmol, CAS: 95408-45-0) was converted to 3-(6-(4-((4-(2-chloro-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)- The mixture of piperidine-2,6-dione (200 mg, 0.31 mmol, intermediate 26), 2-methylthiazole-5-boronic acid pinacol ester (83.24 mg, 0.37 mmol, CAS: 1218791-01-5), cesium carbonate (424.22 mg, 1.30 mmol), and N,N-dimethylformamide (5 mL) was added and reacted at 100°C for 3 hours. The reaction solution was purified by prep-HPLC (acetonitrile containing 0.1% hydrochloric acid and water) to obtain the title compound as a yellow solid (15.6 mg, yield: 7%). 1 H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),10.36(s,1H),8.45-8.31(m,2H),8.14-8.04(m,1H),7.8 7-7.77(m,1H),7.50-7.37(m,5H),7.25(s,1H),7.16-7.08(m,1H),5.5 4-5.39(m,1H),4.50-4.39(m,2H),4.35-4.22(m,2H),3.47-3.44(m,4H ),3.17-3.03(m,2H),2.74-2.65(m,5H),2.33(s,2H);LC-MS:m / z[M+H] + = 712.

[0248] Example 22 3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (250 mg, 0.5 mmol, hydrochloride, intermediate 3), 2-(6-chloropyridine-2-yl)-5-methyl-1,3,4-thiadiazole (209.57 mg, 0.99 mmol, intermediate 27), triethylamine (250.47 mg, 2.48 mmol), and cesium fluoride (112.79 mg, 0.74 mmol) were added to dimethyl sulfoxide (10 mL) and subjected to a microwave reaction at 140°C for 1 hour. The reaction solution was cooled to room temperature, poured into water (30 mL), and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by prep-HPLC (acetonitrile containing 0.1% formic acid and water) to obtain the title compound as a yellow solid (98 mg, yield: 30%). 1 H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),8.34(d,J=8.2Hz,1H),8.08(d,J=7.0Hz,1H),7.82(t,J=7.6Hz,1H),7.70(t,J=7.9H z,1H),7.49-7.37(m,2H),7.25(q,J=8.1Hz,4H),7.12(d,J=7.3Hz,1H),6.95(d,J=8.6Hz,1H),5.4 5(dd,J=12.8,5.0Hz,1H),4.40(s,2H),3.55-3.50(m,4H),3.46(s,2H),3.00-2.90(m,1H),2.83-2 .75(m,1H),2.74(s,3H),2.70-2.61(m,1H),2.47-2.38(m,4H),2.15-2.05(m,1H);LC-MS:m / z[M+H] + = 644.

[0249] Example 23: 3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (250 mg, 0.5 mmol, hydrochloride, intermediate 3), 2-chloro-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine (96.34 mg, 0.50 mmol, intermediate 28), triethylamine (250 mg, 2.47 mmol), and cesium fluoride (90 mg, 0.59 mmol) were added to dimethyl sulfoxide (2.5 mL) and subjected to a microwave reaction at 135°C for 1 hour. The reaction solution was cooled to room temperature, poured into water (10 mL) until the solid precipitated, and then filtered. The filtered cake was washed once with 5 mL of water. The filtered cake was collected and dried to obtain the crude product. This crude product was purified by prep-HPLC (acetonitrile containing 0.1% formic acid and water) to obtain the title compound as a yellow solid (48 mg, yield: 15%). 1 H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),9.16(s,1H),8.34(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.88-7.76(m,1H),7.68(t,J=8.1Hz, 1H),7.41(d,J=7.4Hz,1H),7.24(q,J=8.2Hz,4H),7.11(d,J=7.3Hz,1H),6.96(d,J=7.6Hz,1H),6.76(d,J=8.5 Hz,1H),5.44(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.54(s,4H),3.45(s,2H),3.03-2.89(m,1H),2.76(dt,J=1 7.4,10.9Hz,1H),2.65(d,J=15.6Hz,1H),2.46-2.38(m,4H),2.34(s,3H),2.12-2.01(m,1H);LC-MS:m / z[M+H] + = 627.

[0250] Example 24 3-(6-(4-((4-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (468 mg, 1 mmol, intermediate 3) and 2-chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine (224 mg, 1 mmol, intermediate 29) were dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (515 mg, 5 mmol) was added. The reaction mixture was stirred at 130°C for 48 hours. The reaction solution was purified by prep-HPLC (acetonitrile containing 0.1% formic acid and water) to obtain the title compound as a yellow solid (10 mg, yield: 1.4%, FA salt). 1 H NMR(400MHz,DMSO-d6) δ 8.81(s,1H),8.34(d,J=8.3Hz,1H),8.23(d,J=1.7Hz,1H),8.08(d,J=7.0Hz,1H),7.81(dd,J=8.2,7.0Hz,1H),7.68(dd, J=8.6,7.4Hz,1H),7.42(d,J=7.3Hz,1H),7.35(d,J=7.3Hz,1H),7.24(q,J=8.1Hz,4H),7.11(d,J=7.3Hz,1H),6.92(d,J =8.6Hz,1H),5.41(ddd,J=25.4,13.1,6.0Hz,2H),4.39(s,2H),3.47(dd,J=11.1,6.0Hz,6H),3.00-2.86(m,1H),2.85-2 .70(m,1H),2.67(d,J=2.2Hz,1H),2.44(t,J=5.0Hz,5H),2.33(p,J=1.8Hz,1H),1.42(d,J=6.7Hz,6H);LC-MS:m / z[M+H] + = 655.

[0251] Example 25: 3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (234 mg, 0.5 mmol, intermediate 3), 4-(methylsulfonyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (219 mg, 0.75 mmol, intermediate 30), and N,N-diisopropylethylamine (387 mg, 3 mmol) were added to a 50 mL one-neck flask, then isopropanol (5 mL) was added, and the mixture was stirred overnight at 100 °C. The reaction solution was concentrated directly under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (60 mg, yield: 18%). 1 H NMR(500MHz,CDCl3) δ 9.03(s,1H),8.48(s,1H),8.11-8.08(m,3H),8.06(d,J=7.0Hz,1H),7.67(t,J=7.6Hz,1H) ,7.21(d,J=7.5Hz,3H),7.16(d,J=7.8Hz,2H),6.70(d,J=7.3Hz,1H),6.37(d,J=6.2Hz,1H ),5.31(dd,J=12.9,5.4Hz,1H),4.35(s,2H),3.66(s,4H),3.50(s,2H),2.95-2.80(m,2H) ,2.70(qd,J=13.1,4.9Hz,1H),2.49(t,J=5.0Hz,4H),2.28-2.20(m,1H);LC-MS:m / z[M+H] + = 681.

[0252] Example 26 3-(6-(4-((4-(2-(4-cyclopropyl-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (230 mg, 0.5 mmol, intermediate 3), 2-(4-cyclopropyl-1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine (200 mg, 0.75 mmol, intermediate 32), and N,N-diisopropylethylamine (320 mg, 2.5 mmol) were added to a 25 mL round-bottom flask, followed by the addition of isopropanol (15 mL), and the mixture was stirred at 100 °C for 5 hours. The reaction solution was concentrated directly under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (35 mg, yield: 11%). 1 H NMR(500MHz,CDCl3) δ 8.40(s,1H),8.37(s,1H),8.14(d,J=8.3Hz,1H),8.10(dd,J=6.6,3.3Hz,2H),7.72(dd,J=8.3,7.0Hz,1H),7.47(s ,1H),7.25(d,J=6.4Hz,2H),7.20(t,J=7.6Hz,3H),6.72(d,J=7.3Hz,1H),6.31(d,J=6.2Hz,1H),5.37-5.33(m,1H) ,4.39(s,2H),3.69(s,4H),3.53(s,2H),3.0-2.96(m,J=19.2,3.2Hz,1H),2.92-2.88(m,1H),2.79-2.70(m,1H),2 .52(t,J=5.0Hz,4H),2.32-2.28(m,1H),1.91-1.86(m,1H),0.89-0.85(m,2H),0.81-0.78(m,2H);LC-MS:m / z[M+H] + = 653.

[0253] Example 27 N-((1s,4s)-4-((1-(4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzyl)piperidine-4-yl)oxy)cyclohexyl)-6-(1H-imidazole-1-yl)pyridine-2-carboxamide [ka] 3-(6-(4-(4-((((1s,4s)-4-aminocyclohexyl)oxy)piperidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (0.46g, 0.98mmol, intermediate 34), 6-(1H-imidazole-1-yl)-2-picolinic acid (0.19g, 0.98mmol, intermediate 6), 1-ethyl-(3-dimethylaminopropyl)carbody Imidide hydrochloride (0.28 g, 1.47 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (0.20 g, 1.47 mmol, CAS: 2592-95-2) were added to a 25 mL two-necked flask. Then, dichloromethane (10 mL) was added under a nitrogen atmosphere, and N-methylmorpholine (0.2 mL, 1.96 mmol, d=0.92 g / mL) was added via syringe. The mixture was stirred overnight at room temperature. The reaction solution was diluted with brine (30 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain the title compound as a yellow solid (40 mg, yield: 5%). 1H NMR(500MHz,DMSO-d6) δ 11.11(s,1H),8.93(s,1H),8.62(d,J=8.4Hz,1H),8.29(d,J=8.4Hz,1H),8.23(s,1H),8.10(t,J=7.9Hz,1H),8.03(d,J=7.0Hz,1H) ),7.94(d,J=8.2Hz,1H),7.91(d,J=7.6Hz,1H),7.77(t,J=7.6Hz,1H),7.38(d,J=7.4Hz,1H),7.25-7.23(m,4H),7.11(s,1H),7.0 7(d,J=7.3Hz,1H),5.41(dd,J=12.9,5.2Hz,1H),4.34(s,2H),3.85-3.79(m,1H),3.57(s,1H),3.33-3.31(m,3H),2.95-2.88(m,1 LC-MS:m / z[M+H] + = 752.

[0254] Example 28 3-(6-(4-((4-(6-(3-methyl-4H-1,2,4-triazole-4-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Under a nitrogen atmosphere, cuprous oxide (100 mg, 0.69 mmol, CAS: 1317-39-1) and N1,N2-bis(furan-2-ylmethyl)oxalamide (120 mg, 0.48 mmol, CAS: 69010-90-8) were mixed with 3-(6-(4-((4-(6-chloropyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1( 2H)-yl)piperidine-2,6-dione (450 mg, 0.78 mmol, intermediate 35), 3-methyl-1H-1,2,4-triazole (95 mg, 1.14 mmol, CAS: 7170-01-6), tripotassium phosphate (600 mg, 2.83 mmol), and dimethyl sulfoxide (10 mL) were added to a mixed solution, and this reaction solution was subjected to a microwave reaction at 150°C for 1 hour. The reaction solution was poured into water (40 mL) until the solid precipitated, and then filtered. The filtered cake was washed once with 10 mL of water, collected, and dried to obtain the crude product. This crude product was purified by prep-HPLC (acetonitrile containing 0.1% formic acid and water) to obtain the title compound as a yellow solid (11.5 mg, yield: 2%). 1 H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),8.37(d,J=8.3Hz,1H),8.09(d,J=7.0Hz,1H),8.02(s,1H),7.82(t,J=7.8Hz,2H),7.48(t, J=8.2Hz,3H),7.42(d,J=7.9Hz,2H),7.13(t,J=7.2Hz,2H),6.93(d,J=8.4Hz,1H),5.45(dd,J=12.5,5.5 Hz,1H),4.44(s,2H),4.35(d,J=12.9Hz,2H),4.31-4.24(m,2H),3.40-3.28(m,4H),3.09-3.00(m,2H),2 .98-2.89(m,1H),2.82-2.73(m,1H),2.71(s,3H),2.68-2.60(m,1H),2.12-2.06(m,1H);LC-MS:m / z[M+H] + = 627.

[0255] Example 29 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (150 mg, 0.32 mmol, intermediate 3), 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (147 mg, 0.48 mmol, intermediate 36), and N,N-diisopropylethylamine (0.265 mL, 1.6 mmol, d=0.782 g / mL) were added to a 50 mL one-neck flask, then dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 120 °C for 5 hours. The reaction solution was purified by prep-HPLC (acetonitrile containing 0.1% formic acid and water) to obtain the title compound as a yellow solid (95 mg, yield: 43%). 1 H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.71(s,1H),8.63(t,J=1.5Hz,1H),8.33(d,J=8.3Hz,1H),8.08(d,J=7.0Hz ,1H),7.81(dd,J=8.3,7.0Hz,1H),7.42(d,J=7.4Hz,1H),7.25(q,J=8.0Hz,4H),7.12(d,J= 7.3Hz,1H),7.04(s,1H),5.45(dd,J=13.0,5.4Hz,1H),4.39(s,2H),3.70(s,4H),3.46(s,2 H),3.02-2.89(m,1H),2.85-2.60(m,2H),2.41(m,7H),2.13-2.06(m,1H);LC-MS:m / z[M+H] + = 695.

[0256] Example 30 (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Example 31 (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Chiral Separation: 27 g of 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Example 29) was separated into enantiomers by chiral normal-phase preparative high-performance liquid chromatography (HPLC). First, the preparative fractions were separately distilled off under reduced pressure to obtain solid substances. Next, these solid substances were suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. Next, the frozen mixture was freeze-dried in a freeze-dryer for 20 hours to obtain the (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (first elution peak, RT=1.659 min, tentatively designated as "S"ABS) (11. 5g, 99.37%ee) and (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (second elution peak, RT=2.133 min, tentatively designated as "R"ABS) (12.5g, 100%ee) were obtained.

[0257] Chiral analysis methods (analytical separation methods): Equipment: Shimadzu LC-20AB with PDA detector; Chromatography column: Chiralpak IC-3 100×4.6mm ID, 3μm; Mobile phase: A: Hexane (0.1% DEA), B: IPA:MeCN = 2:1; Isocratic elution: B: 60%; Flow rate: 1.0mL / min; Chromatography column temperature: 35°C; Wavelength: 254nm.

[0258] Kiral extraction method (extraction and separation method): Equipment: Shimadzu Corporation LC-A HPLC; クロマトグラフィーカラム: Chiralpak IC, 250×30mm, 10μm; Moving phase: A:DCM, B:IPA; Dissolution composition: B: 50%; Flow rate: 150 mL / min; クロマトグラフィーカラムTemperature:RT; Wavelengths: 220nm, 254nm; Sample preparation: Dissolve approximately 2,000mL of DCM / IPA into the sample; Injection volume: 200mL; サイクル time: 35 minutes.

[0259] Example 30: 1 H NMR (400MHz, DMSO-d6) δ 11.13(s,1H),8.71(s,1H),8.62(s,1H),8.33(d,J=8.4Hz,1H),8.08(d,J=6.8Hz,1H),7.81(dd,J=8 .4,7.2Hz,1H),7.42(d,J=7.6Hz,1H),7.26(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),7.11(d,J=7.2Hz ,1H),7.03(s,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.69(s,4H),3.46(s,2H),3.02-2.89( m,1H),2.81-2.70(m,1H),2.67-2.63(m,1H),2.43-2.38(m,7H),2.15-2.04(m,1H);LC-MS:m / z[M+H] + =695.

[0260] Example 31: 1H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),8.70(s,1H),8.62(s,1H),8.32(d,J=8.4Hz,1H),8.07(d,J=6.8Hz,1H),7.81(dd,J=8 .4,7.2Hz,1H),7.42(d,J=7.6Hz,1H),7.26(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),7.11(d,J=7.2Hz ,1H),7.03(s,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.69(s,4H),3.45(s,2H),3.02-2.89( LC-MS:m / z[M+H] + = 695.

[0261] Example 32 3-(6-(4-(3-(4-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-6-(4-((3-(piperazin-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (357 mg, 0.56 mmol, intermediate 39), 2-fluoro-6-(1H-imidazole-1-yl)pyridine (180 mg, 1.12 mmol, intermediate 4), and potassium carbonate (230 mg, 1.68 mmol) were added to dimethyl sulfoxide (5 mL), and the mixture was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with water (mL) and once with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (0.33 g, yield: 89%). 1 H NMR(500MHz,CDCl3) δ 9.20(s,1H),8.28(s,1H),8.08(t,J=7.7Hz,2H),7.68(dd,J=8.3,7.0Hz,1H),7.56-7.53(m,2H), 7.22-7.19(m,3H),7.16-7.14(m,3H),6.68(d,J=7.3Hz,1H),6.61(d,J=7.6Hz,1H),6.50(d,J=8. 4Hz,1H),5.33(dd,J=13.0,5.4Hz,1H),4.35(s,2H),3.68(s,2H),3.60-3.58(m,6H),3.05(s,3H) ,2.96-2.82(m,2H),2.76-2.67(m,1H),2.39(t,J=5.0Hz,4H),2.29-2.24(m,1H);LC-MS:m / z[M+H] + = 667.

[0262] Example 33 (S)-3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Example 34 (R)-3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Chiral Separation: 480 mg of 3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Example 25) was separated into enantiomers by chiral normal-phase preparative HPLC. First, the preparative fractions were separately removed by vacuum distillation to obtain solid substances. Next, these solid substances were suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. Next, the frozen mixture was freeze-dried in a freeze-dryer for 20 hours to obtain the (S)-3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (first elution peak, RT=3.360 min, tentatively designated as "S"ABS) (194.4 mg, 99. (58% ee, yellow solid) and (R)-3-(2-oxo-6-(4-((4-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (second elution peak, RT=3.997 min, tentatively designated as "R"ABS) (190.1 mg, 98.99% ee, yellow solid) were obtained.

[0263] The chiral analysis method was the same as in Examples 30 and 31, except that the mobile phase was adjusted to "A: MeCN, B: MeOH (0.05% DEA)" and the fixed-composition elution was performed with 50% B. The chiral preparation method was the same as in Examples 30 and 31, except for the following adjustments. Mobile phase: A: MeCN, B: MeOH; Isocratic elution: B: 65%; Flow rate: 120mL / min; Sample preparation: Dissolve the sample in approximately 30 mL of DCM / MeOH; Injection volume: 10mL.

[0264] Example 33: 1 H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.68(s,1H),8.46(s,1H),8.34(d,J=8.4Hz,1H),8.21(d,J=6.4Hz,1H),8.08(d,J=6.8Hz,1 H),7.81(t,J=7.6Hz,1H),7.42(d,J=7.2Hz,1H),7.27(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.12(d,J= 7.2Hz,1H),6.81(d,J=6.4Hz,1H),5.46(dd,J=13.2,5.6Hz,1H),4.39(s,2H),3.70(t,J=5.0Hz,4H),3.46 (s,2H),3.04-2.90(m,1H),2.83-2.60(m,2H),2.40(t,J=5.0Hz,4H),2.16-2.03(m,1H);LC-MS:m / z[M+H] + = 681.

[0265] Example 34: 1H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.68(s,1H),8.46(s,1H),8.34(d,J=8.3Hz,1H),8.21(d,J=6.2Hz,1H),8.08(d,J=7.0Hz,1 H),7.81(dd,J=8.3,7.0Hz,1H),7.42(d,J=7.3Hz,1H),7.27(d,J=7.9Hz,2H),7.23(d,J=8.0Hz,2H),7.12( d,J=7.3Hz,1H),6.81(d,J=6.3Hz,1H),5.46(dd,J=13.0,5.3Hz,1H),4.39(s,2H),3.92-3.55(m,4H),3.4 6(s,2H),3.04-2.90(m,1H),2.83-2.60(m,2H),2.40(t,J=5.0Hz,4H),2.16-2.03(m,1H);LC-MS:m / z[M+H] + = 681.

[0266] Example 35 (S)-3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Example 36 (R)-3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Chiral Separation: 550 mg of 3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Example 22) was separated into enantiomers by chiral normal-phase preparative HPLC. First, the preparative fractions were separately removed by vacuum distillation to obtain solid substances. Next, these solid substances were suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. Next, the frozen mixture was freeze-dried in a freeze-dryer for 20 hours to obtain the (S)-3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (first elution peak, RT=5.265 min, tentatively designated as "S"ABS) (101 mg, 99 (0.02% ee, yellow solid) and (R)-3-(6-(4-((4-(6-(5-methyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (second elution peak, RT=6.465 min, tentatively designated as "R"ABS) (95 mg, 99.19% ee, yellow solid) were obtained.

[0267] The chiral analysis method was the same as in Examples 33 and 34, except that the detection wavelength was adjusted to 220 nm. The chiral preparation method was the same as in Examples 33 and 34, except that the sample was dissolved in approximately 250 mL of DCM / MeOH and the injection volume was adjusted to 15 mL.

[0268] Example 35: 11H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.43 (dd, J = 10.4, 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 7.3 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.45 (dd, J = 12.8, 5.4 Hz, 1H), 4.39 (s, 2H), 3.52 (t, J = 4.4 Hz, 4H), 3.45 (s, 2H), 3.02 - 2.90 (m, 1H), 2.81 - 2.76 (m, 1H), 2.73 (s, 3H), 2.69 - 2.61 (m, 1H), 2.43 (t, J = 4.4 Hz, 4H), 2.16 - 2.03 (m, 1H); LC-MS: m / z [M + H] + = 644.

[0269] Example 36: 1 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.43 (dd, J = 10.4, 8.4 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 7.3 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 5.45 (dd, J = 12.8, 5.4 Hz, 1H), 4.39 (s, 2H), 3.52 (t, J = 4.4 Hz, 4H), 3.45 (s, 2H), 3.02 - 2.90 (m, 1H), 2.81 - 2.76 (m, 1H), 2.73 (s, 3H), 2.69 - 2.61 (m, 1H), 2.43 (t, J = 4.4 Hz, 4H), 2.16 - 2.03 (m, 1H); LC-MS: m / z [M + H] + = 644.

[0270] Example 37 (S)-3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Example 38 (R)-3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Chiral Separation: 500 mg of 3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (Example 23) was separated into enantiomers by chiral normal-phase preparative HPLC. First, the preparative fractions were separately distilled off under reduced pressure to obtain solid substances. Next, these solids were suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. Next, the frozen mixture was freeze-dried in a freeze-dryer for 20 hours to obtain the (S)-3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (first elution peak, RT=4.269 min, tentatively designated as "S"ABS) (185 mg, 98. (37% ee, yellow solid) and (R)-3-(6-(4-((4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (second elution peak, RT=5.211 min, tentatively designated as "R"ABS) (195 mg, 98.90% ee, yellow solid) were obtained.

[0271] The chiral analysis method and chiral preparative method were the same as those in Examples 33 and 34.

[0272] Example 37: 11H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.17 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.45 (dd, J = 12.8, 5.2 Hz, 1H), 4.39 (s, 2H), 3.54 (t, J = 4.4 Hz, 4H), 3.45 (s, 2H), 3.01 - 2.89 (m, 1H), 2.84 - 2.61 (m, 2H), 2.42 (t, J = 4.4 Hz, 4H), 2.35 (s, 3H), 2.15 - 2.05 (m, 1H); LC-MS: m / z [M+H] + = 627。

[0273] Example 38: 1 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.17 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.45 (dd, J = 12.8, 5.2 Hz, 1H), 4.39 (s, 2H), 3.54 (t, J = 4.4 Hz, 4H), 3.45 (s, 2H), 3.01 - 2.89 (m, 1H), 2.84 - 2.61 (m, 2H), 2.42 (t, J = 4.4 Hz, 4H), 2.35 (s, 3H), 2.15 - 2.05 (m, 1H); LC-MS: m / z [M+H] + = 627。

[0274] Example 39 3-(2-oxo-6-(4-((4-(2-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(methylsulfonyl)-2-(2-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 15) with 4-(methylsulfonyl)-2-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 40) and using the same method as in Example 13. 1 H NMR(500MHz,CDCl3) δ 9.12(s,1H),8.66(s,1H),8.21(d,J=6.2Hz,1H),8.10(d,J=8.3Hz,1H),8.07(d,J=7.0H) z,1H),7.68(t,J=7.6Hz,1H),7.22(t,3H),7.17(d,J=7.8Hz,2H),6.70(d,J=7.3Hz,1H) ,6.47(d,J=6.2Hz,1H),5.32(dd,J=12.9,5.4Hz,1H),4.35(s,2H),3.76(s,4H),3.53(s ,2H),2.95-2.81(m,2H),2.71(qd,1H),2.53(s,4H),2.28-2.23(m,1H);LC-MS:m / z[M+H] + = 682.

[0275] Example 40: 3-(2-oxo-6-(4-((4-(1-(2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-((4-(piperidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 42) using the same method as in Example 25. 1 H NMR(500MHz,CDCl3) δ 8.80(s,1H),8.52(s,1H),8.13-8.10(m,2H),8.06(d,J=4.8Hz,2H),7.68-7.65(m,1H ),7.22(d,J=7.8Hz,2H),7.15(dd,J=16.5,7.6Hz,3H),6.67(d,J=7.2Hz,1H),6.41(d ,J=6.3Hz,1H),5.32-5.28(m,1H),4.32(s,2H),3.73(s,2H),2.96-2.71(m,16H),2.2 7(dd,J=7.9,5.2Hz,1H),1.99(d,J=11.8Hz,2H),1.55-1.48(m,2H);LC-MS:m / z[M+H] + = 764.

[0276] Example 41 3-(6-(4-((4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine (intermediate 29) with 2-(3-methyl-1H-1,2,4-triazole-1-yl)-4-(methylsulfonyl)pyrimidine (intermediate 43) using the same method as in Example 24. 1H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),9.20(s,1H),8.33(d,J=8.2Hz,1H),8.20(d,J=6.2Hz,1H),8.08(d,J=7.0Hz,1H),7.81(t ,J=7.6Hz,1H),7.42(d,J=7.4Hz,1H),7.24(dd,J=17.0,8.1Hz,4H),7.11(d,J=7.3Hz,1H),6.78(d,J=6 .3Hz,1H),5.45(dd,J=13.0,5.2Hz,1H),4.39(s,2H),3.67(m,4H),3.46(s,2H),3.10-2.89(m,1H),2.8 7-2.71(m,1H),2.71-2.65(m,1H),2.41-2.37(m,4H),2.34(s,3H),2.14-1.95(m,1H);LC-MS:m / z[M+H] + = 628.

[0277] Example 42 3-(6-(4-((4-(5-fluoro-2-(5-methyl-1,3,4-thiadiazole-2-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (740 mg, 1.9 mmol, TFA salt, intermediate 44) and 4-((1-(2,6-dioxopiperidine-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)methyl)benzaldehyde (797 mg, 2 mmol, intermediate 38) were added to 1,2-dichloroethane (5 mL) and acetic acid (230 mg, 3.8 mmol), and the mixture was stirred at room temperature for 20 minutes. Next, sodium triacetoxyborohydride (805 mg, 3.8 mmol, CAS: 56553-60-7) was added, and the reaction mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate solution (50 mL) was added to the reaction solution to quench the reaction, and the reaction solution was extracted three times with dichloromethane (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain the title compound as a yellow solid (81 mg, yield: 7%). 1 H NMR(500MHz,CDCl3) δ 8.31(s,1H),8.12(t,J=7.6Hz,2H),8.08(d,J=7.0Hz,1H),7.74-7.64(m,1H),7.2 2(d,J=7.8Hz,3H),7.16(d,J=8.0Hz,2H),6.70(d,J=7.3Hz,1H),5.33(dd,J=12.9, 5.3Hz,1H),4.37(s,2H),3.87(s,4H),3.50(s,2H),2.94(s,1H),2.91-2.81(m,1H) ,2.79(s,3H),2.78-2.67(m,1H),2.53(s,4H),2.34-2.21(m,1H);LC-MS:m / z[M+H] + = 663.

[0278] Example 43 3-(6-(4-((4-(2-(4-chloro-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine (intermediate 29) with 2-(4-chloro-1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine (intermediate 45) using the same method as in Example 24. 1 H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),8.48(d,J=1.4Hz,1H),8.33(d,J=8.3Hz,1H),8.17(d,J=6.3Hz,1H),8.08(d,J=7.0Hz,1H),7.9 4(d,J=1.4Hz,1H),7.81(dd,J=8.0,7.2Hz,1H),7.42(d,J=7.4Hz,1H),7.24(dd,J=17.9,8.1Hz,4H),7.11(d, J=7.3Hz,1H),6.76(d,J=6.3Hz,1H),5.45(dd,J=12.8,5.3Hz,1H),4.39(s,2H),3.67(s,4H),3.45(s,2H),3. 02-2.88(m,1H),2.83-2.71(m,1H),2.69-2.59(m,1H),2.44-2.34(m,4H),2.15-2.04(m,1H);LC-MS:m / z[M+H] + =647.

[0279] Example 44 3-(6-(4-((4-(2-(4-cyano-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine (intermediate 29) with 2-(4-cyano-1H-imidazole-1-yl)-4-(methylsulfonyl)pyrimidine (intermediate 46) using the same method as in Example 24. 1H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.86(d,J=1.2Hz,1H),8.71(d,J=1.3Hz,1H),8.34(d,J=8.3Hz,1H),8.21(d,J=6.3Hz,1H), 8.08(d,J=7.0Hz,1H),7.81(dd,J=8.2,7.0Hz,1H),7.42(d,J=7.4Hz,1H),7.30-7.17(m,4H),7.12(d,J=7. 3Hz,1H),6.83(d,J=6.3Hz,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.73(s,4H),3.46(s,2H),3.0 1-2.90(m,1H),2.82-2.71(m,1H),2.63(s,1H),2.39(t,J=5.0Hz,4H),2.14-2.06(m,1H);LC-MS:m / z[M+H] + = 638.

[0280] Example 45 3-(6-(4-((4-(5-chloro-2-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 44) with 5-chloro-2-(3-methyl-1H-1,2,4-triazole-1-yl)-4-(piperazin-1-yl)pyrimidine (intermediate 47) using the same method as in Example 42. 1H NMR(500MHz,CDCl3) δ 8.90(s,1H),8.36(s,1H),8.24(s,1H),8.10(dd,J=16.6,7.6Hz,2H),7.74-7.65(m,1H) ,7.23(d,J=7.1Hz,3H),7.17(d,J=8.1Hz,2H),6.69(d,J=7.3Hz,1H),5.33(dd,J=13.0, 5.4Hz,1H),4.37(s,2H),3.85(s,4H),3.51(s,2H),2.94(s,1H),2.92-2.80(m,1H),2.7 3(dd,J=13.2,4.6Hz,1H),2.55(s,4H),2.49(s,3H),2.34-2.23(m,1H);LC-MS:m / z[M+H] + = 662.

[0281] Example 46 (S)-3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] Example 47 (R)-3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] 3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-chloro-6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine (intermediate 29) with 2-methyl-4-(3-methyl-1H-1,2,4-triazole-1-yl)-6-(methylsulfonyl)pyrimidine (intermediate 48) using the same method as in Example 24. Chiral separation: 150 mg of 3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione was separated into enantiomers by chiral normal-phase preparative HPLC. First, the preparative fractions were separately removed by vacuum distillation to obtain solid substances. Next, this solid was suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. Then, the frozen mixture was freeze-dried in a freeze-dryer for 20 hours to obtain the (S)-3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (first elution peak, RT=2.254 min, tentatively designated as "S"ABS) (24 mg, 97. (56% ee, yellow solid) and (R)-3-(6-(4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (second elution peak, RT=2.920 min, tentatively designated as "R"ABS) (17 mg, 97.52% ee, yellow solid) were obtained.

[0282] The chiral analysis method was the same as in Examples 30 and 31, except that a fixed composition elution of 80% B was performed. The chiral preparative method was the same as in Examples 30 and 31, except for the following adjustments. Mobile phase: A: ヘキサン, B:IPA:MeCN=2:1 (0.1% NH3·H2O); Dissolution composition: B: 80%; Flow rate: 80 mL / min; Sample preparation: Dissolve approximately 30mL of DCM / IPA into the sample; Injection volume: 3 mL.

[0283] Example 46: 1 H NMR (400MHz, DMSO-d6) δ 11.15(s,1H),9.14(s,1H),8.33(d,J=8.4Hz,1H),8.08(d,J=6.8Hz,1H),7.81(t,J=7.8 Hz,1H),7.42(d,J=7.2Hz,1H),7.26(d,J=7.8Hz,2H),7.22(d,J=7.8Hz,2H),7.11(d,J=7 .6Hz,1H),6.78(s,1H),5.52-5.39(m,1H),4.39(s,2H),3.64(s,4H),3.43(s,2H),2.99- 2.91(m,1H),2.84-2.63(m,2H),2.41-2.33(m,10H),1.36-1.24(m,1H);LC-MS:m / z[M+H] + =642.

[0284] Example 47: 1 H NMR (400MHz, DMSO-d6) δ 11.15(s,1H),9.14(s,1H),8.33(d,J=8.4Hz,1H),8.08(d,J=6.8Hz,1H),7.81(t,J=7.8 Hz,1H),7.42(d,J=7.2Hz,1H),7.26(d,J=7.8Hz,2H),7.22(d,J=7.8Hz,2H),7.11(d,J=7 .6Hz,1H),6.78(s,1H),5.52-5.39(m,1H),4.39(s,2H),3.64(s,4H),3.43(s,2H),2.99- 2.91(m,1H),2.84-2.63(m,2H),2.41-2.33(m,10H),1.36-1.24(m,1H);LC-MS:m / z[M+H] + =642.

[0285] Example 48 3-(6-(4-((3-(4-(2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 39), and replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-methyl-4-(3-methyl-1H-1,2,4-triazole-1-yl)-6-(methylsulfonyl)pyrimidine (intermediate 48), using the same method as in Example 29. 1 H NMR(400MHz,DMSO-d6) δ 11.11(s,1H),9.13(s,1H),8.31(d,J=8.2Hz,1H),8.07(d,J=6.9Hz,1H),7.80(t,J=7.5Hz, 1H),7.40(d,J=7.2Hz,1H),7.21(d,J=7.6Hz,2H),7.16(d,J=7.8Hz,2H),7.10(d,J=7.2Hz,1 H),6.81(s,1H),5.44(dd,J=12.8,5.1Hz,1H),4.37(s,2H),3.64(s,5H),3.49(s,2H),3.01- 2.65(m,7H),2.41(s,3H),2.37(s,3H),2.28(s,4H),2.10(d,J=5.4Hz,1H);LC-MS:m / z[M+H] + = 697.

[0286] Example 49 3-(6-(4-((3-(4-(5-fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 44) with 4-(4-(azetidine-3-yl)piperazin-1-yl)-5-fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 50) using the same method as in Example 42. 1 H NMR(500MHz,CDCl3) δ 9.03(s,1H),8.86(s,1H),8.06(q,3H),7.66(t,1H),7.19(t,3H),7.14(d,J=7.9H z,2H),6.67(d,J=7.3Hz,1H),5.31(dd,J=13.0,5.4Hz,1H),4.33(s,2H),3.86(t, J=4.9Hz,4H),3.67(s,2H),3.55(s,2H),3.05(s,3H),2.94-2.83(m,2H),2.74-2. 65(m,1H),2.47(s,3H),2.40(t,J=5.0Hz,4H),2.31-2.21(m,1H);LC-MS:m / z[M+H] + = 701.

[0287] Example 50 3-(6-(4-((4-(6-(-4-chloro-1H-imidazole-1-yl)-2-methylpyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 4-(4-chloro-1H-imidazole-1-yl)-2-methyl-6-(methylsulfonyl)pyrimidine (intermediate 51) using the same method as in Example 29. 1 H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.51(d,J=1.5Hz,1H),8.33(d,J=8.3Hz,1H),8.12-8.05(m,2H),7.81(t,J=7.6Hz ,1H),7.42(d,J=7.4Hz,1H),7.24(q,J=8.0Hz,4H),7.11(d,J=7.2Hz,1H),6.90(s,1H),5.45(dd, J=12.9,5.4Hz,1H),4.39(s,2H),3.67(s,4H),3.45(s,2H),2.96(ddd,J=16.9,13.1,5.3Hz,1H), 2.82-2.70(m,1H),2.69-2.61(m,1H),2.39(d,J=4.5Hz,7H),2.13-2.05(m,1H);LC-MS:m / z[M+H] + =661.

[0288] Example 51 3-(6-(4-((4-(6-(-4-cyano-1H-imidazole-1-yl)-2-methylpyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 4-(4-cyano-1H-imidazole-1-yl)-2-methyl-6-(methylsulfonyl)pyrimidine (intermediate 52) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.11(s,1H),8.88(d,J=1.3Hz,1H),8.73(d,J=1.3Hz,1H),8.32(d,J=8.3Hz,1H),8.07(d,J=7 .0Hz,1H),7.81(dd,J=8.3,7.0Hz,1H),7.41(d,J=7.4Hz,1H),7.24(q,J=8.0Hz,4H),7.11(d,J= 7.3Hz,1H),7.01(s,1H),5.44(dd,J=12.9,5.4Hz,1H),4.39(s,2H),3.69(s,4H),3.46(s,2H),3 .01-2.90(m,1H),2.83-2.62(m,2H),2.41(d,J=5.8Hz,7H),2.14-2.06(m,1H);LC-MS:m / z[M+H] + = 652.

[0289] Example 52 3-(6-(4-((3-(4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 4-chloro-2-(3-methyl-1H-1,2,4-triazole-1-yl)-6-(trifluoromethyl)pyrimidine (intermediate 53), and replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 39), using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),9.31(s,1H),8.32(d,J=8.2Hz,1H),8.07(d,J=7.0Hz,1H),7.84-7.78(m,1H),7.41(d,J=7.4 Hz,1H),7.29(s,1H),7.22(d,J=8.1Hz,2H),7.16(d,J=8.1Hz,2H),7.11(d,J=7.2Hz,1H),5.50-5.39(m,1H) ),4.37(s,2H),3.92(s,2H),3.69(s,2H),3.49(s,2H),3.30(d,J=6.0Hz,2H),3.00-2.91(m,1H),2.90-2.7 1(m,4H),2.66(d,J=10.6,8.8Hz,1H),2.36(s,3H),2.33-2.28(m,4H),2.13-2.04(m,1H);LC-MS:m / z[M+H] + = 751.

[0290] Example 53 3-(6-(4-((3-(4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-chloro-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine (intermediate 28), and replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 39), using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.11(s,1H),9.17(s,1H),8.32(d,J=8.2Hz,1H),8.07(d,J=7.0Hz,1H),7.81(t,J=7.7Hz,1H),7.70(t,J=8.1H) z,1H),7.41(d,J=7.2Hz,1H),7.23(d,J=8.2Hz,2H),7.18(d,J=8.0Hz,2H),7.10(d,J=7.3Hz,1H),6.97(d,J=7. 5Hz,1H),6.80(d,J=8.7Hz,1H),5.51-5.36(m,1H),4.37(s,2H),3.55(s,6H),3.37(s,2H),2.97(d,J=12.2Hz,1 H),2.91(s,3H),2.79-2.71(m,1H),2.67(s,1H),2.35(s,3H),2.31(s,4H),2.15-2.03(m,1H);LC-MS:m / z[M+H] + = 682.

[0291] Example 54 3-(6-(4-((3-(4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-((3-(piperazine-1-yl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 39) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.11(s,1H),8.71(s,1H),8.63(s,1H),8.32(d,J=8.2Hz,1H),8.07(d,J=7.0Hz,1H),7.81(t,1H),7.41(d,J= 7.4Hz,1H),7.22(d,J=8.0Hz,2H),7.16(d,J=8.0Hz,2H),7.10(d,J=7.3Hz,1H),7.05(s,1H),5.44(dd,J=13.0 ,5.5Hz,1H),4.37(s,2H),3.70(s,4H),3.51(s,2H),3.40(s,1H),3.31(s,1H),3.01-2.92(m,1H),2.90-2.82( LC-MS:m / z[M+H] + =750.

[0292] Example 55 3-(6-(4-((3-((4-(6-(1H-imidazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)azetidine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 3-(2-oxo-6-(4-((4-((piperidine-4-ylmethyl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 12) with 3-(2-oxo-6-(4-((3-(piperazine-1-ylmethyl)azetidine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 55) using the same method as in Example 8. 1H NMR(500MHz,CDCl3) δ 8.31(s,1H),8.11(d,J=8.3Hz,1H),8.07(d,J=7.0Hz,1H),7.68(m,1H),7.53(t,J=8 .0Hz,2H),7.17(m,7H),6.68(d,J=7.3Hz,1H),6.58(d,J=7.6Hz,1H),6.47(d,J=8.5 Hz,1H),5.32(dd,J=12.7,5.2Hz,1H),4.35(t,J=11.9Hz,2H),3.54(m,8H),2.89(m, 4H),2.75(m,2H),2.58(d,J=6.7Hz,2H),2.46(m,4H),2.25(m,1H);LC-MS:m / z[M+H] + = 681.

[0293] Example 56 3-(2-oxo-6-(4-((4-(6-(trifluoromethyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(methylsulfonyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 30) with 4-(methylsulfonyl)-6-(trifluoromethyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 57) using the same method as in Example 25. 1H NMR(500MHz,CDCl3) δ 8.86(s,1H),8.49(s,1H),8.11(d,J=1.4Hz,1H),8.09(d,J=8.3Hz,1H),8.06(d,J=7.0 Hz,1H),7.70-7.64(m,1H),7.22-7.20(m,3H),7.17(d,J=7.9Hz,2H),6.70(d,J=8.5Hz ,2H),5.33(dd,J=13.0,5.4Hz,1H),4.35(s,2H),3.93(s,2H),3.52(s,4H),2.95-2.83 (m,2H),2.76-2.66(m,1H),2.53(t,J=5.1Hz,4H),2.28-2.21(m,1H);LC-MS:m / z[M+H] + = 749.

[0294] Example 57 (S)-1-(6-(4-(4-((((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)pyridine-2-yl)-1H-imidazole-4-carboxamide [ka] The title compound was synthesized by replacing 5-(6-(piperazin-1-yl)pyridine-2-yl)thiazole hydrochloride (intermediate 24) with 1-(6-(piperazin-1-yl)pyridine-2-yl)-1H-imidazole-4-carboxamide (intermediate 58) using the same method as in Example 19. 1H NMR(400MHz,DMSO-d6) δ 10.97(s,1H),8.51(s,1H),8.31(s,1H),7.67(t,J=8.1Hz,1H),7.48-7.43(m,4H),7 .36-7.30(m,4H),7.23(s,1H),7.06(d,J=7.6Hz,1H),6.76(d,J=8.7Hz,1H),5.21(s, 2H),5.09(dd,J=13.6,4.9Hz,1H),4.40(d,J=17.7Hz,1H),4.23(d,J=17.5Hz,1H),3. 54(s,5H),2.93-2.84(m,1H),2.57-2.37(m,7H),1.98-1.92(m,1H);LC-MS:m / z[M+H] + = 635.

[0295] Example 58: 3-(2-oxo-6-(4-((4-(2-(thiazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 5-(4-(methylsulfonyl)pyrimidine-2-yl)thiazole (intermediate 59) and using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),9.14(s,1H),8.50(s,1H),8.34(d,J=8.4Hz,1H),8.20(d,J=6.0Hz,1H),8.08(d,J=6.4H z,1H),7.84-7.78(m,1H),7.42(d,J=6.4Hz,1H),7.26(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.11(d ,J=7.6Hz,1H),6.71(d,J=6.4Hz,1H),5.45(dd,J=13.0,5.6Hz,1H),4.39(s,2H),3.65(s,4H),3.46(s ,2H),3.00-2.91(m,1H),2.81-2.66(m,2H),2.40(t,J=5.1Hz,4H),2.13-2.06(m,1H);LC-MS:m / z[M+H] + = 630.

[0296] Example 59 3-(2-oxo-6-(4-((4-(2-(thiazole-5-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 5-(4-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine-2-yl)thiazole (intermediate 60) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),9.14(s,1H),8.50(s,1H),8.34(d,J=8.4Hz,1H),8.20(d,J=6.0Hz,1H),8.08(d,J=6.4H z,1H),7.84-7.78(m,1H),7.42(d,J=6.4Hz,1H),7.26(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.11(d ,J=7.6Hz,1H),6.71(d,J=6.4Hz,1H),5.45(dd,J=13.0,5.6Hz,1H),4.39(s,2H),3.65(s,4H),3.46(s ,2H),3.00-2.91(m,1H),2.81-2.66(m,2H),2.40(t,J=5.1Hz,4H),2.13-2.06(m,1H);LC-MS:m / z[M+H] + = 630.

[0297] Example 60 3-(6-(4-((4-(5-fluoro-2-(thiazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 5-(5-fluoro-4-(methylsulfonyl)pyrimidine-2-yl)thiazole (intermediate 61) and using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),9.14(s,1H),8.50(s,1H),8.34(d,J=8.4Hz,1H),8.20(d,J=6.0Hz,1H),8.08(d,J=6.4H z,1H),7.84-7.78(m,1H),7.42(d,J=6.4Hz,1H),7.26(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.11(d ,J=7.6Hz,1H),6.71(d,J=6.4Hz,1H),5.45(dd,J=13.0,5.6Hz,1H),4.39(s,2H),3.65(s,4H),3.46(s ,2H),3.00-2.91(m,1H),2.81-2.66(m,2H),2.40(t,J=5.1Hz,4H),2.13-2.06(m,1H);LC-MS:m / z[M+H] + = 630.

[0298] Example 61 3-(6-(4-((4-(2-(1-methyl-2-(trifluoromethyl)-1H-imidazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-(1-methyl-2-(trifluoromethyl)-1H-imidazole-5-yl)-4-(methylsulfonyl)pyrimidine (intermediate 63) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),8.34(d,J=8.3Hz,1H),8.26(d,J=6.2Hz,1H),8.08(d,J=7.0Hz,1H),7.81(dd,J=8.2,7.0 Hz,1H),7.71(s,1H),7.42(d,J=7.4Hz,1H),7.25(q,J=8.0Hz,4H),7.11(d,J=7.3Hz,1H),6.75(d,J=6.3 Hz,1H),5.45(dd,J=12.8,5.4Hz,1H),4.39(s,2H),4.12(s,3H),3.63(s,4H),3.45(s,2H),3.01-2.90( m,1H),2.83-2.70(m,1H),2.69-2.61(m,1H),2.40(t,J=5.0Hz,4H),2.14-2.05(m,1H);LC-MS:m / z[M+H] + = 695.

[0299] Example 62 3-(2-oxo-6-(4-((4-(6-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-fluoro-6-(1H-imidazole-1-yl)pyridine (intermediate 4) with 2-fluoro-6-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyridine (intermediate 64) using the same method as in Example 2. 1H NMR(500MHz,CDCl3) δ 9.04(s,1H),8.76(s,1H),8.10(d,J=8.3Hz,1H),8.07(d,J=7.0Hz,1H),7.67(t,J=7.6Hz,1H),7.60(t,J=8.0Hz ,1H),7.24(d,J=8.0Hz,2H),7.21(d,J=7.3Hz,1H),7.17(d,J=7.8Hz,2H),7.13(d,J=7.6Hz,1H),6.70(d,J=7.3 Hz,1H),6.60(d,J=8.5Hz,1H),5.33(dd,J=12.9,5.4Hz,1H),4.35(s,2H),3.58(t,J=5.1Hz,4H),3.52(s,2H),2 .91-2.84(m,2H),2.71(qd,J=13.1,4.9Hz,1H),2.55(q,J=5.2,4.4Hz,4H),2.27-2.23(m,1H);LC-MS:m / z[M+H] + = 681.

[0300] Example 63: 3-(2-oxo-6-(4-((4-(6-(5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-fluoro-6-(1H-imidazole-1-yl)pyridine (intermediate 4) with 2-(6-fluoropyridine-2-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (intermediate 65) using the same method as in Example 2. 1H NMR(500MHz,CDCl3) δ 8.42(s,1H),8.12(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.73-7.67(m,1H),7.64(d,J=7.2Hz ,1H),7.60(t,J=7.8Hz,1H),7.26-7.21(m,3H),7.17(d,J=7.9Hz,2H),6.75(d,J=8.3Hz,1H),6 .70(d,J=7.2Hz,1H),5.33(dd,J=12.9,5.3Hz,1H),4.37(s,2H),3.64-3.54(m,4H),3.52(s,2H) ),3.03-2.80(m,2H),2.79-2.63(m,1H),2.59-2.49(m,4H),2.34-2.21(m,1H);LC-MS:m / z[M+H] + = 698.

[0301] Example 64: 3-(2-oxo-6-(4-((4-(2-(pyridin-3-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(methylsulfonyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 30) with 4-(methylsulfonyl)-2-(pyridine-3-yl)pyrimidine (intermediate 66) using the same method as in Example 25. 1H NMR(500MHz,CDCl3) δ 9.53(s,1H),8.66(s,1H),8.59(d,J=8.1Hz,1H),8.29(d,J=6.2Hz,2H),8.11(dd,J=18.3,7.6Hz, 2H),7.76-7.66(m,1H),7.39-7.33(m,1H),7.24-7.13(m,5H),6.70(d,J=7.1Hz,1H),6.42(d,J=6. 2Hz,1H),5.33(dd,J=13.0,5.5Hz,1H),4.38(s,2H),3.73(s,4H),3.53(s,2H),3.02-2.93(m,1H) ,2.92-2.83(m,1H),2.81-2.66(m,1H),2.53(d,J=7.3Hz,4H),2.36-2.21(m,1H);LC-MS:m / z[M+H] + = 624.

[0302] Example 65 3-(6-(4-((4-(2-(3,5-dimethylisoxazole-4-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(methylsulfonyl)-2-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 30) with 3,5-dimethyl-4-(4-(methylsulfonyl)pyrimidine-2-yl)isoxazole (intermediate 67) using the same method as in Example 25. 1H NMR(500MHz,CDCl3) δ 8.48(s,1H),8.23(d,J=6.2Hz,1H),8.09(dd,J=12.6,6.9Hz,2H),7.73-7.70(m,1H),7.24(d,J=6. 9Hz,3H),7.18(d,J=8.0Hz,2H),6.71(d,J=7.3Hz,1H),6.39(d,J=6.7Hz,1H),6.33(d,J=6.2Hz,1H) ,5.34(dd,J=12.9,5.4Hz,1H),4.38(s,2H),3.65(s,3H),3.52(s,2H),2.99-2.92(m,1H),2.91-2. 84(m,1H),2.75(s,1H),2.72(s,3H),2.53(s,3H),2.50(s,4H),2.32-2.27(m,1H);LC-MS:m / z[M+H] + = 642.

[0303] Example 66 (S)-3-(4-((4-((4-(6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 1-(4-(chloromethyl)benzyl)-4-(6-(3-methyl-1H-1,2,4-triazole-1-yl)pyridine-2-yl)piperazine (intermediate 68) using the same method as in Example 1. 1H NMR(400MHz,DMSO-d6) δ 10.98(s,1H),9.29(s,1H),7.82(dd,J=8.5,7.6Hz,1H),7.62(d,J=8.0Hz,2H),7.56(d,J=8.1Hz,2H),7.50(t,J=7.8Hz,1H),7 .35(dd,J=7.8,6.0Hz,2H),7.09(d,J=7.7Hz,1H),6.91(d,J=8.5Hz,1H),5.33(s,2H),5.13(dd,J=13.3,5.1Hz,1H),4.56(d,J= 13.7Hz,2H),4.48-4.37(m,3H),4.29(d,J=17.4Hz,1H),3.41(d,J=11.6Hz,2H),3.22(d,J=13.7Hz,2H),3.13(s,2H),2.93(dd d,J=17.4,13.6,5.4Hz,1H),2.64-2.55(m,1H),2.44(dd,J=13.2,4.5Hz,1H),2.37(s,3H),2.05-1.97(m,1H);LC-MS:m / z[M+H] + = 607.

[0304] Example 67 3-(6-(4-((4-(5-fluoro-2-(2-methylthiazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 44) with 5-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-2-methylthiazole (intermediate 69) using the same method as in Example 42. 1H NMR(500MHz,CDCl3) δ 8.40(s,1H),8.19(s,H),8.12(d,J=8.3Hz,1H),8.09(d,J=7.0Hz,1H),8.00(d,J=6.6Hz,1H) ,7.70(t,1H),7.23(t,3H),7.17(d,J=7.9Hz,2H),6.70(d,J=7.3Hz,1H),5.33(dd,J=13.0,5. 4Hz,1H),4.37(s,2H),3.82(s,4H),3.50(s,2H),2.98-2.93(m,1H),2.86(ddd,J=17.5,13.3, 5.0Hz,1H),2.77-2.72(m,1H),2.70(s,3H),2.52(s,4H),2.30-2.25(m,1H);LC-MS:m / z[M+H] + = 662.

[0305] Example 68 3-(6-(4-((4-(5-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 44) with 5-fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)-4-(piperazin-1-yl)pyrimidine (intermediate 49) using the same method as in Example 42. 1H NMR(500MHz,CDCl3) δ 8.85(s,1H),8.25(s,1H),8.10(dd,J=15.4,7.6Hz,2H),8.05(d,J=6.1Hz,1H),7.70(t,1H ),7.22(d,J=8.8Hz,3H),7.17(d,J=7.9Hz,2H),6.69(d,J=7.2Hz,1H),5.33(dd,J=12.9,5 .4Hz,1H),4.37(s,2H),3.86(t,4H),3.50(s,2H),2.99-2.94(m,1H),2.90-2.83(m,1H),2 .77-2.69(m,1H),2.53(t,J=4.9Hz,4H),2.48(s,3H),2.31-2.26(m,1H);LC-MS:m / z[M+H] + = 646.

[0306] Example 69 3-(6-(4-((4-(2-(3-methyl-1H-1,2,4-triazole-1-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(5-fluoro-4-(piperazin-1-yl)pyrimidine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 44) with 2-(3-methyl-1H-1,2,4-triazole-1-yl)-4-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidine (intermediate 70) using the same method as in Example 42. 11H NMR (500MHz, CDCl3) δ 9.02(s,1H),8.18(s,1H),8.10(dd,J=13.1,7.7Hz,2H),7.76-7.65(m,1H),7.2 4-7.20(m,3H),7.18(d,J=7.9Hz,2H),6.70(m,2H),5.33(dd,J=13.0,5.4Hz,1H ),4.38(s,2H),3.97(s,2H),3.52(s,4H),3.04-2.92(m,1H),2.88(d,J=5.2Hz, 1H),2.79-2.66(m,1H),2.57-2.45(m,7H),2.32-2.21(m,1H);LC-MS:m / z[M+H] + = 696.

[0307] Example 70 3-(6-(4-((4-(2-methyl-6-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-methyl-4-(methylsulfonyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 71) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),9.60(s,1H),8.34(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.81(dd,J=8.3,7.0H z,1H),7.42(d,J=7.4Hz,1H),7.25(q,J=7.9Hz,4H),7.12(d,J=7.3Hz,1H),6.92(s,1H),5.45(d d,J=13.1,5.3Hz,1H),4.39(s,2H),3.68(s,4H),3.45(s,2H),3.02-2.90(m,1H),2.82-2.73(m, 1H),2.71-2.63(m,1H),2.45(s,3H),2.41(d,J=6.0Hz,4H),2.15-2.05(m,1H);LC-MS:m / z[M+H] + = 696.

[0308] Example 71 (S)-3-(4-((4-((4-(2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 72) using the same method as in Example 1. 11H NMR (400MHz, DMSO-d6) δ 10.98(s,1H),9.15(s,1H),7.53-7.42(m,3H),7.40-7.29(m,4H),6.82(s,1H) ),5.25(s,2H),5.12(dd,J=13.2,5.1Hz,1H),4.43(d,J=17.5Hz,1H),4.27(d, J=17.5Hz,1H),3.68(s,4H),3.54(s,2H),2.92(ddd,J=17.3,13.6,5.4Hz,1H ),2.63-2.54(m,1H),2.51-2.37(s,11H),2.03-1.93(m,1H);LC-MS:m / z[M+H] + = 622.

[0309] Example 72 (S)-3-(4-((4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 73) using the same method as in Example 1. 1H NMR(400MHz,DMSO-d6) δ 10.97(s,1H),8.72(s,1H),8.64-8.64(m,1H),7.51-7.46(m,3H),7.38-7.33(m,4 H),7.06(s,1H),5.25(s,2H),5.14-5.10(m,1H),4.45-4.41(d,J=17.5Hz,1H),4.2 9-4.25(d,J=17.5Hz,1H),3.74(s,4H),3.55(s,2H),2.91-2.89(m,1H),2.60-2.56 (m,1H),2.51-2.50(m,4H),2.47-2.42(m,4H),2.01-1.98(m,1H);LC-MS:m / z[M+H] + = 675.

[0310] Example 73 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)pyrimidine (intermediate 74) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.12(s,1H),8.81(s,1H),8.33(d,J=8.4Hz,1H),8.07(d,J=7.0Hz,1H),7.81(dd,J=8.3,7.0 Hz,1H),7.42(d,J=7.3Hz,1H),7.30-7.19(m,5H),7.11(d,J=7.3Hz,1H),5.44(dd,J=12.9,5.4 Hz,1H),4.39(s,2H),3.71(s,4H),3.46(s,2H),2.95(ddd,J=17.0,13.2,5.2Hz,1H),2.78(td, J=12.8,4.2Hz,1H),2.72-2.61(m,1H),2.48-2.37(m,7H),2.14-2.06(m,1H);LC-MS:m / z[M+H] + = 696.

[0311] Example 74 3-(6-(4-((4-(2-(4-chloro-1H-imidazole-1-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-(4-chloro-1H-imidazole-1-yl)-4-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (intermediate 75) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),8.51(d,J=1.3Hz,1H),8.34(s,1H),8.08(d,J=7.0Hz,1H),7.98(d,J=1.4Hz,1H),7. 86-7.72(m,1H),7.42(d,J=7.3Hz,1H),7.27(d,J=8.0Hz,2H),7.22(d,J=7.8Hz,3H),7.11(d,J=7.3 Hz,1H),5.45(dd,J=12.2,5.1Hz,1H),4.39(s,2H),3.93(s,2H),3.68(s,2H),3.47(s,2H),3.03-2 .89(m,1H),2.82-2.72(m,1H),2.70-2.60(m,1H),2.41(s,4H),2.16-2.02(m,1H);LC-MS:m / z[M+H] + = 715.

[0312] Example 75 3-(6-(4-((4-(2-(4-cyano-1H-imidazole-1-yl)-6-(trifluoromethyl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-(4-cyano-1H-imidazole-1-yl)-4-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (intermediate 76) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.14(s,1H),8.88(s,1H),8.73(s,1H),8.33(d,J=8.3Hz,1H),8.08(d,J=7.0Hz,1H),7.8 7-7.75(m,1H),7.42(d,J=7.3Hz,1H),7.33-7.17(m,5H),7.11(d,J=7.3Hz,1H),5.45(dd, J=12.6,5.0Hz,1H),4.39(s,2H),3.95(s,2H),3.69(s,2H),3.48(s,2H),3.03-2.89(m,1H ),2.82-2.72(m,1H),2.70-2.60(m,1H),2.42(s,4H),2.16-2.03(m,1H);LC-MS:m / z[M+H] + = 706.

[0313] Example 76 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-2H-1,2,3-triazole-2-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 36) with 2-methyl-4-(methylsulfonyl)-6-(4-(trifluoromethyl)-2H-1,2,3-triazole-2-yl)pyrimidine (intermediate 77) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),9.14(s,1H),8.46(s,1H),8.34(d,J=8.0Hz,1H),8.27(d,J=6.8Hz,1H),8.08(d,J=6.8 Hz,1H),7.81(dd,J=8.4,7.2Hz,1H),7.42(d,J=7.2Hz,1H),7.27(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2 H),7.11(d,J=7.2Hz,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.75(t,J=4.8Hz,4H),3.45(s, 2H),3.01-2.89(m,1H),2.82-2.63(m,2H),2.46(t,J=4.8Hz,4H),2.14-2.04(m,1H);LC-MS:m / z[M+H] + = 648.

[0314] Example 77 (S)-3-(4-((4-((3-(4-(2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 4-(4-(1-(4-(chloromethyl)benzyl)azetidine-3-yl)piperazin-1-yl)-2-methyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 79) using the same method as in Example 1. 1H NMR(400MHz,DMSO-d6) δ 10.99(s,1H),7.58(d,J=8.2Hz,2H),7.53(d,J=7.8Hz,2H),7.49(s,1H),7.38-7.29(m ,3H),6.93(d,J=32.2Hz,1H),5.30(s,2H),5.13(dd,J=13.3,5.2Hz,1H),4.46(s,2H),4 .42(d,J=4.6Hz,3H),4.28(d,J=17.4Hz,2H),4.20-3.99(m,6H),3.73(s,4H),2.97-2. 85(m,1H),2.78(s,2H),2.60(d,J=17.8Hz,1H),2.45(d,J=7.2Hz,6H);LC-MS:m / z[M+H] + = 677.

[0315] Example 78 (S)-3-(4-((4-((3-(4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 4-(4-(1-(4-(chloromethyl)benzyl)azetidine-3-yl)piperazin-1-yl)-2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine (intermediate 81) using the same method as in Example 1. 1H NMR(400MHz,DMSO-d6) δ 10.99(s,1H),8.74(s,1H),8.66(s,1H),7.71-7.43(m,5H),7.40-7.25(m,2H),7.11 (s,1H),5.30(s,2H),5.13(dd,J=5.1,13.2Hz,1H),4.52-4.35(m,3H),4.28(d,J=17 .6Hz,1H),4.17-4.05(m,5H),3.76(br.s.,4H),3.31(d,J=6.8Hz,1H),3.03-2.85(m ,1H),2.59(d,J=16.9Hz,1H),2.50-2.38(m,7H),2.08-1.94(m,1H);LC-MS:m / z[M+H] + = 730.

[0316] Example 79 3-(6-(4-((4-(6-(1-isopropyl-4,5-dihydro-1H-imidazole-2-yl)pyridine-2-yl)piperazine-1-yl)methyl)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 2-(6-chloropyridine-2-yl)-5-methyl-1,3,4-thiadiazole (intermediate 27) with 2-chloro-6-(1-isopropyl-4,5-dihydro-1H-imidazole-2-yl)pyridine (intermediate 82) using the same method as in Example 22. 1H NMR(400MHz,DMSO-d6) δ 11.13(s,1H),10.43(s,1H),10.23(s,1H),8.35(d,J=8.3Hz,1H),8.09(d,J=7.0Hz,1H),7.93-7.85(m,1H),7.82(dd,J=8.3 ,7.0Hz,1H),7.50-7.34(m,5H),7.26(d,J=8.6Hz,1H),7.20-7.09(m,2H),5.45(dd,J=13.0,5.4Hz,1H),4.60(s,1H),4.43(s ,2H),4.31(br.s.,4H),4.05(dd,J=12.1,8.5Hz,2H),3.93(dd,J=12.5,8.8Hz,2H),3.40(br.s.,2H),3.21(br.s.,2H),3.05 (s,2H),3.03-2.89(m,1H),2.83-2.71(m,1H),2.67-2.63(m,1H),2.13-2.06(m,1H),1.22(d,J=6.7Hz,6H);LC-MS:m / z[M+H] + = 656.

[0317] Example 80 (S)-3-(1-oxo-4-((4-((4-((2-(thiazole-5-yl)pyrimidine-4-yl)piperazine-1-yl)methyl)benzyl)oxy)isoindoline-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 5-(6-(piperazin-1-yl)pyridine-2-yl)thiazole hydrochloride (intermediate 24) with 5-(4-(piperazin-1-yl)pyrimidine-2-yl)thiazole hydrochloride (intermediate 83) using the same method as in Example 19. 1H NMR(400MHz,CDCl3) δ 8.82(s,1H),8.59(s,1H),8.32(s,1H),8.21(d,J=6.2Hz,1H),7.51(d,J=7.5Hz,1H),7.41(d ,J=19.0Hz,5H),7.10(d,J=8.0Hz,1H),6.37(d,J=6.3Hz,1H),5.23(dd,J=13.2,5.1Hz,1H), 5.15(s,2H),4.47(d,J=16.5Hz,1H),4.33(d,J=16.5Hz,1H),3.72(s,4H),3.59(s,2H),2.93 -2.78(m,2H),2.56(s,4H),2.35(qd,J=13.0,5.1Hz,1H),2.23-2.19(m,1H);LC-MS:m / z[M+H] + =610.

[0318] Example 81 (S)-3-(4-((4-((3-(4-(5-Fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)azetidine-1-yl)methyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-2-(1H-imidazole-1-yl)pyrimidine (intermediate 2) with 4-(4-(1-(4-(chloromethyl)benzyl)azetidine-3-yl)piperazin-1-yl)-5-fluoro-2-(3-methyl-1H-1,2,4-triazole-1-yl)pyrimidine (intermediate 84) using the same method as in Example 1. 1H NMR(400MHz,DMSO-d6) δ 11.15-10.87(m,1H),9.27-9.08(m,1H),8.36(t,J=8.3Hz,1H),7.84-7.45(m,2H), 7.45-7.26(m,3H),7.26-7.08(m,1H),6.98(s,1H),5.11(d,J=13.8Hz,2H),4.42-4 .17(m,3H),4.06(d,J=13.0Hz,2H),3.94(d,J=17.4Hz,4H),3.82(s,9H),3.09(s,2) H),2.94(d,J=12.4Hz,1H),2.40-2.21(m,3H),2.08-1.90(m,1H);LC-MS:m / z[M+H] + = 681.

[0319] Example 82 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazole-1-yl)pyrimidine-4-yl)piperazine-1-yl)methyl-d2)benzyl)-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione [ka] The title compound was synthesized by replacing 3-(2-oxo-6-(4-(piperazine-1-ylmethyl)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 3) with 3-(2-oxo-6-(4-(piperazine-1-ylmethyl-d2)benzyl)benzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (intermediate 85) using the same method as in Example 29. 1H NMR(400MHz,DMSO-d6) δ 11.15(s,1H),8.71(s,1H),8.63(s,1H),8.32(d,J=8.2Hz,1H),8.08(d,J=7.0Hz,1H),7.81(dd ,J=8.2,7.2Hz,1H),7.42(d,J=7.2Hz,1H),7.24(q,J=8.2Hz,4H),7.11(d,J=7.2Hz,1H),7.03(s ,1H),5.45(dd,J=12.8,5.4Hz,1H),4.39(s,2H),3.69(s,4H),3.01-2.90(m,1H),2.76(tt,J=1 7.2,8.6Hz,1H),2.65(d,J=16.8Hz,1H),2.44-2.36(m,7H),2.12-2.06(m,1H);LC-MS:m / z[M+H] + = 697.

[0320] Examples of biological activity tests Test Example 1. Cell Titer-GLO (CTG) assay for NCI-H929 cell proliferation. 1. Experimental objective: To determine the inhibitory activity of the compound against NCI-H929 multiple myeloma cells.

[0321] 2. Experimental method: NCI-H929 cells purchased from Nanjing Cobioer Biotechnology Co., Ltd. were cultured in RPMI1640 medium (Viva, C3010-0500) containing 10% fetal bovine serum (Viva, C04002-500) and 1% penicillin-streptomycin at 37°C, 5% CO2, and saturated humidity.

[0322] Logarithmically growing cells were plated in 96-well plates at a rate of 5000 cells per well. After incubation overnight, compounds at concentrations of 0.00512 nM, 0.0256 nM, 0.128 nM, 0.64 nM, 3.2 nM, 16 nM, 80 nM, and 400 nM were added to the plates using two overlapping wells at each dose. The cells were incubated at 37°C in 5% CO2 for 72 hours. After incubation, the plates were left at room temperature for half an hour, and then 50 μL of Cell Titer-Glo® (Promega, G7573) was added. The plates were shaken for 2 minutes for homogenization and then left in the dark at room temperature for 10 minutes. Brightness signals were measured using SpectraMax Paradigm (Molecular Devices).

[0323] Cell activity inhibition rate (%) = 100 - (RLU) 化合物 -RLU ブランク ) / (RLU 対照 -RLU ブランク ) × 100%. In the formula, the control refers to the 0.1% DMSO-treated group, and the blank refers to the culture medium control. The IC50 values ​​and maximum inhibition rates of the compounds were calculated using the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0.

[0324] [Table 14]

[0325] Conclusion: The compounds in the examples of this application exhibit good cell proliferation inhibitory activity against NCI-H929 cells.

[0326] Test Example 2. Proteolytic assay (In-cell Western chemistry) NCI-H929 cells were inoculated into 96-well plates at a rate of 100,000 cells / well and cultured overnight. Compounds at concentrations of 1600 nM, 400 nM, 100 nM, 25 nM, 6.25 nM, 1.56 nM, 0.39 nM, and 0.1 nM were administered into double wells, and the cells were incubated in a 37°C incubator for 24 hours. After incubation, the supernatant was removed by centrifugation, and 150 μL of 4% paraformaldehyde was added. After incubating the cells at room temperature for 20 minutes, 200 μL of washing solution (0.1% TritonX-100, Beyotime; ST1722) was added, and the cells were incubated at room temperature on a shaker. After washing four times, 150 μL of Licor INTERCEPT blocking solution (Lico, catalog no. 927-7001) was added, and the cells were incubated on a shaker at room temperature for 1.5 hours. Antibodies IKZF1 (Cell Signaling; catalog no. 14859S), IKZF3 (Cell Signaling; catalog no. 15103S), GSPT1 (Proteintech, catalog no. 10763-1-AP), CK1α (Thermo; 7117067), and SALL4 (Abcam, ab22675) were diluted 1:100 with antibody diluent (Intercept Blocking Buffer, LI-COR, 211114), and 50 μL of each diluted primary antibody was added to a 96-well plate. The cells were incubated overnight on a shaker at 4°C. The primary antibody was removed, and the mixture was washed four times with PBST. Then, 50 μL of diluted secondary antibody (Licor, catalog number 926-68070) was added, and 0.5 μL each of IRDye800CW and IRDye680CW were added simultaneously. The secondary antibody was aspirated and removed, PBST was added, and the mixture was washed four times at room temperature using a shaker. The signal intensity was then detected using an infrared laser imaging system (Lico, Odyssey-CLx).

[0327] [Table 15]

[0328] Conclusion: The compounds in the examples of this application showed good degradation effects on the target protein IKZF1 / 3 and showed no apparent degradation effects on other non-target proteins such as GSPT1, CK1α, and SALL4 with good selectivity (for example, the DC50 values ​​determined for these proteins were greater than 10,000 nM).

[0329] Test Example 3. IKZF1 Proteolysis Assay (HiBiT) The degrading activity of compounds against the target protein was detected using the constructed K562-HiBiT-IKZF1 cell line (in which the HiBiT tag was added to the endogenous target protein IKZF1) (this cell line was constructed by WuXi AppTec). K562-HiBiT-IKZF1 cells were cultured in IMDM (GIBCO, 12440053) culture medium containing 10% FBS. Cells in the logarithmic growth phase were plated at 10,000 cells / well in 96 wells and cultured at 37°C and 5% CO2 at 100% relative humidity. Compounds at concentrations of 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.0137 μM, 0.0046 μM, and 0.0015 μM were administered with 0.2% DMSO as the final concentration. Cells were cultured in an incubator for 24 hours, and detection was performed according to the instructions for the Promega Nano-Glo® HiBiT Lytic Detection System assay kit (Promega, catalog number N3050). Specifically, the plate was left at room temperature for 30 minutes. After removing the supernatant, 25 μL of PBS and 25 μL of 2× detection reagent (1 mL of lysis buffer + 20 μL of Nano-Glo® HiBiT lysis substrate + 10 μL of LgBiT protein) were added to each well, and the plate was then shaken on an orbital shaker at 300 rpm for 3 minutes. After standing for 10 minutes, the HiBiT luminescence signal was detected using a 2104 EnVision plate reader (PerkinElmer). Target protein degradation rate (DR): DR(%) = (1 - (RLU) 化合物 -RLU ブランク対照 ) / (RLU ビヒクル対照-RLU ブランク対照 )) × 100%.

[0330] Conclusion: The compounds in the examples of this application exhibit good degradation activity against the target protein IKZF1, and in some examples, the compounds can achieve up to 10 times the degradation activity of compound CC-92480.

[0331] Test Example 4. CRBN Binding Assay (HTRF) The binding activity between CRBN and the compound was detected by an HTRF competitive assay using a CRBN binding kit (Cisbio, 64BDCRBNPEG). First, the reagents in the kit were equilibrated to room temperature, diluted 1-fold with double-distilled water, and then thoroughly vortexed both the reagents and the sample for later use to ensure homogeneity. Europium-labeled specific GST antibody and XL665-labeled thalidomide-red reagent (Cisbio, catalog no. 64BDCRBNPEG) were pre-mixed in equal volumes and then added to a 384-well white microplate at a rate of 10 μL / well. 5 μL of GST-labeled CRBN WT protein (Cisbio, catalog number 64BDCRBNPEG) was added to each well and mixed uniformly. Then, the concentrations of the test compound were set to 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.013 μM, and 0.0044 μM, respectively. The concentrations of the standard substances were set to 200 μM, 40 μM, 8 μM, 1.6 μM, 0.32 μM, 0.064 μM, and 0.0128 μM, respectively. 5 μL of the test compound, standard substance (provided in the kit), positive control CC-92480, and negative control (diluent) were added to each well. After uniform mixing, the contents of the 384-well plate were sealed and incubated in the dark at room temperature for 3 hours. A 384-well white microplate was placed in a microplate reader and fluorescence (ex: 320nm, em: 620nm / 665nm) was detected. The HTRF ratio = (signal at 665nm / signal at 620nm) × 10000. This represents the binding strength of each compound.

[0332] [Table 16]

[0333] Conclusion: Compared to CC-92480, the compounds in the examples of this application exhibit good binding activity to CRBN.

[0334] Test Example 5. Inhibitory activity of compounds against JJN3, RPMI-8226, TMD8, and Mino cells. JJN3, RPMI-8226, TMD8, and Mino cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. RPMI-8226, TMD8, and Mino cells were cultured in RPMI1640 medium (Viva, catalog number C3010-0500). JJN3 cells were cultured in IMDM medium (Procell, catalog number PM150510). All media contained 10% fetal bovine serum (Viva, catalog number C04002-500) and 1% penicillin-streptomycin. Cells were cultured in an incubator at 37°C, 5% CO2, and saturated humidity. Logarithmic growth phase cells were inoculated into 96-well plates at a rate of 5000 cells / well and cultured overnight. Compounds at concentrations of 0.00512 nM, 0.0256 nM, 0.128 nM, 0.64 nM, 3.2 nM, 16 nM, 80 nM, and 400 nM were administered with 0.2% DMSO as the final concentration. Cells were cultured in a 37°C, 5% CO2 incubator for 72 hours. After incubation, the plates were left at room temperature for half an hour, then 50 μL of Cell Titer-Glo® (Promega, catalog no. G7573) was added, and the plates were placed on a shaker for 2 minutes to ensure homogeneity. Subsequently, the plates were incubated in the dark at room temperature for 10 minutes, and the brightness signal was measured using SpectraMax Paradigm (Molecular Devices). Cell activity inhibition rate (%) = 100 - (RLU) 化合物 -RLU ブランク ) / (RLU 対照 -RLU ブランク) × 100%. In the formula, the control refers to the 0.2% DMSO-treated group, and the blank refers to the culture medium control. The IC50 values ​​and maximum inhibition rates of the compounds were calculated using the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0.

[0335] Conclusion: The compounds in the examples of this application exhibit good cell proliferation inhibitory activity against JJN3, RPMI-8226, TMD8, and Mino cells, etc.

[0336] Test Example 6. Liver Microsome Stability Test Phase I metabolic stability studies were performed by simulating the physiological conditions of liver microsomes using an in vitro liver microsome incubation system and adding the redox coenzyme NADPH for the relevant reactions. First, 445 μL of mouse or human liver microsome working solution (mouse: catalog number M1000, Xenotech; human: catalog number 452117, Corning) was added separately to two 96-well plates at a concentration of 0.56 mg / mL, and these were named the T60 incubation plate (with NADPH addition) and the non-cofactor (NCF) 60 incubation plate (without NADPH addition).

[0337] The incubation plate described above was pre-incubated in a 37°C water bath for approximately 10 minutes, and then 5 μL of the test compound or control compound (testosterone, diclofenac, and propafenone) was added at a concentration of 100 μM. 50 μL of potassium phosphate buffer was added to each well of the NCF60 incubation plate to start the reaction. One 96-well T0 termination plate was prepared, and 180 μL of termination solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) and 6 μL of NADPH regeneration system working solution (a 10 mM NADPH solution prepared by dissolving NADPH powder in a 10 mM MgCl2 solution) were added. 54 μL of the sample was removed from the T60 incubation plate and added to the T0 termination plate (to prepare the T0 sample). The reaction was initiated by adding 44 μL of NADPH regeneration system working solution to each well of a T60 incubation plate. Only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of termination solution were added to the blank plate. Consequently, in the test compound or control compound samples, the final reaction concentrations of the compound, testosterone, diclofenac, and propafenone were 1 μM, the liver microsome concentration was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively. After incubation for an appropriate time (e.g., 5, 15, 30, 45, and 60 minutes), 180 μL of termination solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to each sample well of the termination plate, and then 60 μL of the sample was removed from the T60 incubation plate to terminate the reaction. All sample plates were mixed uniformly and centrifuged at 3,220 g for 20 minutes. Next, 80 μL of the supernatant was taken from each well and diluted with 240 μL of pure water for liquid chromatography-tandem mass spectrometry.

[0338] Conclusion: The compounds in the embodiments of this application exhibit good liver microsomal stability.

[0339] Test Example 7. CYP450 Enzyme Inhibition Test This experiment was conducted to determine the potential of the compound to inhibit human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). First, human liver microsomes stored in a refrigerator at below -60°C were thawed on ice (Corning, catalog no. 452117). After complete thawing, the human liver microsomes were diluted with potassium phosphate buffer (PB) to prepare a working solution of a certain concentration (0.253 mg / mL). 20.0 μL of a substrate mixture (10 μM phenacetin, 5 μM diclofenac, 30 μM S-mephenytoin, 5 μM dextromethorphan, and 2 μM midazolam) was added to a reaction plate, followed by the addition of 158 μL of human liver microsome working solution to the reaction plate. The reaction plate was then placed on ice, and 2.00 μL of test compounds and specific inhibitors at various concentrations (5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150, and 0.00500 mM) were added. After pre-incubating in a 37°C water bath for 10 minutes, 20.0 μL of coenzyme factor (10 mM NADPH) solution was added to the reaction plate, and the reaction plate was placed in a water bath and incubated at 37°C for 10 minutes. Next, 400 μL of pre-cooled acetonitrile solution (containing an internal standard of 200 ng / mL tolbutamide and labetalol) was added to stop the reaction. The reaction plate was placed on a shaker and shaken for 10 minutes to ensure uniform mixing. Then, it was centrifuged at 4°C and 4,000 rpm for 20 minutes. 200 μL of the supernatant was collected and added to 100 μL of water for sample dilution. Finally, the plate was sealed and shaken for 10 minutes to ensure uniform mixing, followed by LC / MS / MS detection.

[0340] Conclusion: The compounds in the examples of this application do not have any clear inhibitory effect on the isozymes of human liver microsomal cytochrome P450.

[0341] Test Example 8. hERG potassium ion channel action test The HEK293 cell line (catalog number K1236) that stably expresses hERG ion channels used in this experiment was purchased from Invitrogen. These cells were cultured in DMEM medium (Thermofisher, catalog number 10569044) containing 10% fetal bovine serum (Shanghai Bohan, catalog number BS-0005-500). A small slide containing HEK293 cells was placed in the perfusion tank of the micromanipulation table, the tip of the glass electrode was determined and positioned in the center of the field of view, and then the electrode was adjusted to approach the cells, while the micromanipulator was fine-tuned to allow the electrode to gradually approach the cell surface. In voltage clamp mode, transient capacitance current (C) fast The negative pressure was compensated for, and then the membrane was repeatedly ruptured by applying short bursts of negative pressure to finally form a whole-cell recording mode. With the membrane potential clamped to -60mV, a slow capacitive current (C) was applied. slow ), cell membrane capacitance (C mThe input membrane resistance (Ra) was compensated for. After the cells stabilized, the clamp voltage was changed to -90mV, the sampling frequency to 20kHz, and the filter frequency to 10kHz. The leakage current detection condition was to change the clamp voltage to -80mV for a duration of 500ms. hERG current test method: A depolarization command voltage was applied for 4.8 seconds to depolarize the membrane potential from -80mV to +30mV, and then immediately a repolarization voltage was applied for 5.2 seconds to lower the membrane potential to -50mV to remove channel inactivation, and the hERG tail current was observed. The peak value of the tail current was defined as the magnitude of the hERG current. The hERG current for detecting the test compound was continuously recorded for 120 seconds before administration, and the stability of the hERG current generated by the test cells was evaluated. Only stable cells within the acceptable evaluation range were included in subsequent compound tests. Testing the inhibitory effect of the test compound on hERG current: First, the hERG current measured in an extracellular solution containing 0.1% DMSO was used as the detection baseline. After the hERG current remained stable for at least 5 minutes, the solution containing the test compound was sequentially perfused around the cells from low to high concentrations. After each perfusion was completed, a waiting period of approximately 5 minutes was allowed for the compound to fully act on the cells, and the hERG current was recorded simultaneously. After the recorded current stabilized, the last five hERG current values ​​were recorded, and their average value was used as the final current value at a given concentration. After testing the compound, 450 nM dofetilide was added to the same cells to completely inhibit their current and serve as a positive control for the cells. Meanwhile, the positive compound dofetilide was tested synchronously before and after the drug testing assay using the same patch-clamp system to ensure the reliability and sensitivity of the entire detection system. The above test procedure was repeated in two separate test cells (n=2).

[0342] Conclusion: The compounds in the examples of this application do not have any significant inhibitory effect on the hERG potassium ion channel current.

[0343] Test Example 9. In vitro growth inhibition test for PBMCs PBMC cells were purchased from Milecell Biotechnology Co., Ltd. These PBMC cells were resuspended in RPMI-1640 (Solarbio, 11965) medium (containing 10% FBS: Solarbio, S903) and cultured overnight in an incubator at 37°C and 5% CO2. After overnight incubation, the cells were stained with AOPI and counted using a cell counter. A viable cell percentage of over 80% was required for this count. The above cells were inoculated into 96-well plates at a concentration of 20,000 cells / well, and compounds at concentrations of 10,000 nM, 2,500 nM, 625 nM, 156.25 nM, 39 nM, 9.8 nM, 2.4 nM, 0.6 nM, and 0.15 nM were administered with 0.2% DMSO as the final concentration. Each compound was tested in a double well. The 96-well plate was placed in an incubator and incubated at 37°C with 5% CO2 for 72 hours. Then, 50 μL of Cell Titer-Glo® (Promega, catalog number G7573) was added and homogeneously mixed, followed by incubation in the dark for 10 minutes, and the luminance signal value was read using SpectraMax Paradigm (Molecular Devices).

[0344] Conclusion: The compounds in the examples of this application do not have any clear inhibitory effect on PBMCs.

[0345] Test Example 10. Pharmacokinetic study in mice A clear solution of the test compound was administered to ICR mice (fasted overnight) by tail vein injection, or to ICR mice (feeding) by gastric tube feeding (force-feeding). The intravenous and oral doses were 1 mg / kg and 1 mg / kg, respectively. For intravenous administration, 50 μL of blood was collected by buccal puncture at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an anticoagulant tube containing heparin sodium, and the mixture was thoroughly vortexed at 4°C and centrifuged at 6,000 rpm for 3 minutes. For administration via oral gastric tube feeding, blood was collected by buccal puncture at 0 hours (before administration) and at 0.083, 0.25, 1, 2, 4, 6, 8, and 24 hours post-administration. The blood was placed in an anticoagulant tube containing heparin sodium, thoroughly vortexed, and centrifuged at 6,000 rpm for 3 minutes. Plasma drug concentrations were determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the Phoenix WinNonlin 8.2.0 pharmacokinetic software with a linear logarithmic trapezoidal model using a non-compartmental model. The intravenous administration vehicle was either 15% DMA + 50% PEG400 + 35% D5W, or 10% DMSO + 15% Solutol + 75% physiological saline. The oral (gastric tube feeding) vehicle was either 0.25% Tween80 + 99.75% (0.5% CMC aqueous solution) or 10% DMSO + 15% Solutol + 75% physiological saline.

[0346] Conclusion: The compounds in the embodiments of this application exhibit good oral absorption in mice.

[0347] Test Example 11. Pharmacokinetic study in cynomolgus monkeys The medical-grade (washed-out) cynomolgus monkeys (not naive) used in this experiment were provided by Shanghai ChemPartner. The animals were at least 3 years old, male, weighing 3-5 kg, and the weight of all animals used in the experiment was within ±20% of the average weight of their respective sexes. All cynomolgus monkeys were fasted overnight before administration. The intravenous and oral doses were 0.1 mg / kg and 1 mg / kg, respectively. At 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, approximately 300 μL of blood samples were collected by puncture from the radial cutaneous vein of the forelimb or the saphenous vein of the hindlimb into an anticoagulant centrifuge tube containing K2-EDTA. Within 15 minutes of collection, the samples were centrifuged (3,000 g and 4°C for 5 minutes) to obtain plasma. The concentration of compounds in the plasma of cynomolgus monkeys was determined by the LC-MS / MS internal standard method, and data analysis was performed using WinNonlin 8.2 software, with peak concentration (C max ), time to peak (T max ), half-life (t 1 / 2 Pharmacokinetic parameters such as clearance rate (Cl), steady-state apparent volume of distribution (Vss), area under the concentration-time curve (AUC), mean residence time (MRT), and bioavailability (F) were calculated using a non-compartment model. The intravenous administration vehicle was 10% DMSO + 15% Solutol + 75% saline. The oral (gastric tube feeding) administration vehicle was 10% DMSO + 15% Solutol + 75% saline.

[0348] Conclusion: The compounds in the embodiments of this application exhibit good oral absorption in cynomolgus monkeys.

[0349] Test Example 12. In vivo efficacy experiment in mice The NOD / SCID mice used in this experiment were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., were female, weighed 18-22g, and were 6-8 weeks old. Upon arrival, the animals were quarantined and allowed to acclimate to the experimental environment for 7 days before the start of the experiment. NCI-H929 cells in the logarithmic growth phase (added with Matrigel, Corning, and BD356230 in a 1:1 volume ratio) were subcutaneously inoculated into the right back of the mice. The average tumor volume was approximately 100-150 mm². 3 Once the target was reached, group division and administration were carried out. Oral QD administration was performed continuously for 21 days, and tumor measurements and weighing were performed three times a week. Tumor volume was measured using calipers. The formula is TV = 0.5 × a × b 2 In the formula, a is the longest diameter of the tumor and b is the shortest diameter of the tumor. Tumor weight was measured at the end of the experiment. The antitumor efficacy of the compound was evaluated by TGI(%). TGI(%) reflects the tumor growth inhibition rate, and TGI(%) = [(1-(mean tumor volume at the end of administration in the treatment group - mean tumor volume at the start of administration in the treatment group) / (mean tumor volume at the end of treatment in the vehicle control group - mean tumor volume at the start of treatment in the vehicle control group))] × 100%.

[0350] Conclusion: The compounds in the examples of this application have a good inhibitory effect on the proliferation of the NCI-H929 transplanted tumor model in mice.

[0351] The above examples are merely illustrative of embodiments of the present application. However, the scope of protection of this application is not limited to the above embodiments and examples. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and scope of this application should be included within the scope of protection.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, 【Chemistry 1】 During the ceremony, Ring A is selected from a 3-10 member monocyclic heterocycline, a 6-13 member bridged heterocycline, or a 6-13 member condensed heterocycline. Ring B is selected from a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl. Ring C is selected from a substituted or substituted 5- to 10-membered heteroaryl or a substituted or substituted 5- to 10-membered heterocyclyl. R １ and R ２ The dashed line between them indicates connection or disconnection. R １ and R ２ If they are not connected, R １ is selected from H or D, R ２ is selected from O, NH, or S, R １ and R ２ When they are linked, R １ and R ２ together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic ring which may be substituted, R ３ It is selected from H, D, or halogen. R ａ These are H and C, respectively, independently. １ ~C ６ Alkyl, cyano, C １ ~C ６ Haloalkyl or C ３ ~C １０ Selected from cycloalkyl, the C １ ~C ６ Alkyl and C ３ ~C １０ Each cycloalkyl group may be substituted with one or more of H, halogen, hydroxyl, or cyano, or two R groups bonded to the same carbon atom. ａ Along with the carbon atoms to which they are bonded, C ３ ~C ６ Forming a cycloalkyl or 4-6 membered heterocycline, R ４ This is a single bond, -C(O)-, -NR １１ C(O)-, -NR １１ -, -CR １１ R １２ , -CR １１ R １２ - (4-6 member heterocyclyl) -, 4-6 member heterocyclyl, - (C ３ ~C ６ Cycloalkyl)-NR １１ C(O)-, or -O-(C ５ ~C ６ Cycloalkyl)-NR １１ Selected from C(O)-, the heterocyclyl and cycloalkyl are H, halogen, and C, respectively. １ ~C ６ Alkyl, or C １ ~C ６ It may be substituted with one or more selected from haloalkyls, or R ４ and any one of R ａ C ３ ~C ８ Forming a cycloalkyl or 4-6 membered heterocycline, R ５ H, C １ ~C ６ Alkyl, C １ ~C ６ Selected from haloalkyl or halogen, R ６ , R ７ , R ８ , R ９ , and R １０ Each is independently selected from H or D, R １１ and R １２ These are, independently, H or C １ ~C ６ Selected from alkyl groups, or R １１ and R １２ Along with the carbon atoms to which they are bonded, C ３ ~C ８ Forming a cycloalkyl or 4-6 membered heterocycline, R ｂ H, halogen, C １ ~C ６ Alkyl, C １ ~C ３ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Selected from alkoxy, optionally substituted amino, or cyano, or two adjacent R ｂ These, along with the carbon atoms to which they are bonded, are C ３ ~C ６ Forming cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or 5-6 membered aryl, m is selected from 0, 1, 2, or 3. p is selected from 0, 1, 2, 3, or 4. p' is selected from 0, 1, 2, or 3. q is selected from 0, 1, 2, 3, or 4. Compounds, pharmaceutically acceptable salts thereof, deuterated compounds thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof.

2. The ring A is selected from a 4-6 member monocyclic heterocycline or a 6-8 member bridged heterocycline. Preferably, the ring A is 【Chemistry 2】 Selected from, X １ and X ２ At least one of them is N, and the other may be C or N. n1, n2, and k are each independently selected from 1 or 2. More preferably, the ring A is 【Transformation 3】 A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

3. R ａ is, independently of each other, H, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, or C ３ ~C ６ cycloalkyl, and the C １ ~C ６ alkyl may be substituted with one or more of H, halogen, hydroxy, or cyano, or two Rs bonded to the same carbon atom together with the carbon atom to which they are bonded form C ａ ~C ３ ~C ６ cycloalkyl, Preferably, R ａ is, independently of one another, H, C １ to C ３ alkyl, or C １ to C ３ haloalkyl, and said C １ to C ３ alkyl or C １ to C ３ haloalkyl may each be substituted with one or more of H, hydroxy, or cyano, and R ａ is more preferably selected from H, -CH ２ OH, -CH ２ CH ２ OH, -CN, or -CH ２ CN, Preferably, two R atoms bonded to the same carbon atom ａ C ３ ~C ６ Forms a cycloalkyl group, and more preferably a cyclopropyl group. A compound according to claim 1 or claim 2, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

4. The aforementioned ring B is selected from a 6-membered heteroaryl, Preferably, the ring B is 【Chemistry 4】 Selected from, in the formula, X ３ , X ４ , and X ５ Each is independently selected from C or N, and X ３ , X ４ , and X ５ At least one of them is N, More preferably, the ring B is 【Transformation 5】 A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

5. R ｂ These are H, halogen, and C, respectively, independently. １ ~C ６ Alkyl, C １ ~C ３ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Selected from alkoxy, optionally substituted amino, or cyano, where m is selected from 0, 1, 2, or 3. Preferably, R ｂ Each of the following is independently selected from H, F, Cl, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl, and m is selected from 0 or 1. A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

6. The ring C is selected from a substituted or substituted 5-6 member heteroaryl or substituted or 5-6 member heterocyclyl. Preferably, the ring C is 【Transformation 6】 Selected from, in the formula, R ｃ H and C are independent of each other. １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ３ Haloalkyl, halogen, -C(O)R １３ , or selected from cyano, z is selected from 0, 1, 2, 3, or 4, Y １ is selected from S or N, Y ２ is selected from C or N, R １３ H, NH ２ , C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, or C １ ~C ３ Selected from haloalkyls, More preferably, the ring C is 【Transformation 7】 Selected from, in the formula, R ｃ These are independently H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, F, Cl, -C(O)NH ２ , or selected from cyano, z is selected from 0, 1, or 2, More preferably, the ring C is 【Transformation 8】 Selected from, in the formula, R ｃ These are independently H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, F, Cl, -C(O)NH ２ Selected from , or cyano, where z is selected from 0, 1, or 2. A compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

7. R ４ These are single bonds, -C(O)-, -NHC(O)-, -NH-, -CH ２ - (5-6 member heterocycline) -, 5-6 member heterocycline, - (C ５ ~C ６ Cycloalkyl)-NHC(O)-, or -O-(C ５ ~C ６ Selected from cycloalkyl)-NHC(O)-, Preferably, R ４ These are single bonds, -C(O)-, -NHC(O)-, -NH-, 【Chemistry 9】 Selected from, More preferably, R ４ It is selected from single bonds. A compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

8. The compound of formula (I) is a compound of the following general formula: 【Chemistry 10】 A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

9. The ring A is selected from a 4-8 member monocyclic heterocycloalkyl or a 6-10 member bridged heterocycloalkyl containing 1-3 heteroatoms selected from N, O, or S. The ring B is selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S. The ring C is selected from a 5-6 membered heteroaryl or 5-6 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, or S, and the 5-6 membered heteroaryl or 5-6 membered heterocyclyl contains H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ３ Haloalkyl, halogen, -C(O)R １３ R may be substituted with one or more selected from cyano, １３ H, NH ２ , C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, or C １ ~C ３ Selected from haloalkyls, R １ and R ２ The dashed line between them indicates connection or disconnection. R １ and R ２ If they are not connected, R １ is selected from H or D, R ２ It is selected from O or S, R １ and R ２ If they are connected, R １ and R ２ Together with the carbon atoms to which they are bonded, they form a benzene ring. R ３ It is selected from H or D, R ａ These are H and C, respectively, independently. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl or C ３ ~C ６ Selected from cycloalkyl, the C １ ~C ６ The alkyl group may be substituted with one or more of H, halogen, hydroxyl, or cyano, or with two R groups bonded to the same carbon atom. ａ Along with the carbon atoms to which they are bonded, C ３ ~C ６ Forming a cycloalkyl group, R ４ This is a single bond, -C(O)-, -NR １１ C(O)-, -NR １１ -, -CR １１ R １２ , -CR １１ R １２ -(4-6 member heterocycloalkyl)-, 4-6 member heterocycloalkyl, -(C ３ ~C ６ Cycloalkyl)-NR １１ C(O)-, or -O-(C ５ ~C ６ Cycloalkyl)-NR １１ Selected from C(O)-, the heterocycloalkyl or cycloalkyl is H or C １ ~C ３ It may be substituted with one or more alkyl groups, and the heterocycloalkyl group contains one to three heteroatoms selected from N, O, or S, and R １１ and R １２ These are, independently, H or C １ ~C ３ Selected from alkyl groups, R ５ H is, R ６ , R ７ , R ８ , R ９ , and R １０ Each of these is independently H, R ｂ These are H, halogen, and C, respectively, independently. １ ~C ６ Alkyl, C １ ~C ３ Haloalkyl, C ３ ~C ６ Selected from cycloalkyl, amino, or cyano, m is selected from 0, 1, or 2. p is selected from 0, 1, or 2. p' is selected from 0, 1, or 2. q is selected from 0, 1, or 2. A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

10. The aforementioned ring A is 【Chemistry 11】 Selected from, in the formula, X １ and X ２ At least one of them is N, and the other may be C or N, and n1, n2, and k are each independently selected from 1 or 2. The aforementioned ring B is, 【Chemistry 12】 Selected from, in the formula, X ３ , X ４ , and X ５ Each is independently selected from C or N, and X ３ , X ４ , and X ５ At least one of them is N, The aforementioned ring C is 【Chemistry 13】 Selected from, in the formula, R ｃ H and C are independent of each other. １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ３ Haloalkyl, halogen, -C(O)R １３ , or selected from cyano, z is selected from 0, 1, 2, 3, or 4, R １３ H, NH ２ , C １ ~C ３ Alkyl, C ３ ~C ６ Cycloalkyl, or C １ ~C ３ Selected from haloalkyls, R １ and R ２ The dashed line between them indicates connection or disconnection. R １ and R ２ If they are not connected, R １ is selected from H or D, R ２ It is selected from O or S, R １ and R ２ If they are connected, R １ and R ２ Together with the carbon atoms to which they are bonded, they form a benzene ring. R ３ It is selected from H or D, R ａ These are, independently, H or C １ ~C ６ Selected from alkyl, the C １ ~C ６ The alkyl group may be substituted with one or more hydroxyl or cyano compounds, or with two R compounds bonded to the same carbon atom. ａ Along with the carbon atoms to which they are bonded, C ３ ~C ６ Forming a cycloalkyl group, R ４ These are single bonds, -C(O)-, -NHC(O)-, -NH-, -CH ２ -(5-6 member heterocycloalkyl)-, 5-6 member heterocycloalkyl, -(C ５ ~C ６ Cycloalkyl)-NHC(O)-, or -O-(C ５ ~C ６ Cycloalkyl)-NR １１ Selected from C(O)-, the heterocycloalkyl comprises 1 to 3 heteroatoms selected from N, O, or S, and R １１ is H or C １ ~C ３ Selected from alkyl groups, R ５ H is, R ６ , R ７ , R ８ , R ９ , and R １０ Each of these is independently H, R ｂ Each of these is independently selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, bromomethyl, bromoethyl, or bromopropyl. m is selected from 0 or 1. p is selected from 0, 1, or 2. p' is selected from 0, 1, or 2. q is selected from 0, 1, or 2. A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

11. The aforementioned compound, 【Chemistry 14】 A compound according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

12. The aforementioned compound, 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, selected from among.

13. A compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, for use in the prevention and / or treatment of cereblon-mediated diseases, Preferably, the disease is cancer, tumor, immune disease, or inflammatory disease. Preferably, the aforementioned immune disease is an autoimmune disease. Preferably, the disease is a hematological malignancy. Preferably, the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma. Compounds for use, pharmaceutically acceptable salts thereof, deuterated compounds thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof.

14. The disease is mediated by IKZF1 and / or IKZF3, and the compound for use according to claim 13, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

15. Compounds according to any one of claims 1 to 12, pharmaceutically acceptable salts thereof, deuterated compounds thereof, stereoisomers thereof, tautomers thereof, or mixtures thereof for use in the immunomodulation of dual targets of IKZF1 and IKZF3.

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