Bicyclic substituted glutarimide celecoxib binder

Abstract

The present invention provides a degron compound that binds to cereblon, which is a component of the E3 ubiquitin ligase. The degrons provided herein can be used, either alone or covalently linked to a tail, to modulate the activity of cereblon. Alternatively, the degron can be linked to a targeting ligand that binds to a target protein for proteolysis.

Description

【Technical Field】 【0001】 [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 349,509, filed Jun. 6, 2022, the entire disclosure of which is incorporated herein by reference for all purposes. 【0002】 The present invention provides degron compounds that bind to cereblon, a component of the E3 ubiquitin ligase. The degrons provided herein can be used, alone or covalently linked to a tail, to modulate the activity of cereblon. Alternatively, the degron can be linked to a targeting ligand that binds to a target protein for proteolysis. 【Background Art】 【0003】 Proteolysis is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excessive proteins is achieved by the ubiquitin - proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neurodegeneration and myopathy, the morphogenesis of neural circuitry, the regulation of cell - surface receptors, ion channels, and the secretory pathway, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection. 【0004】 The covalent attachment of multiple ubiquitin molecules to the terminal lysine residue by an E3 ubiquitin ligase labels the protein for proteasomal degradation, and the protein is digested into small peptides and ultimately its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with various clinical disorders, including, in particular, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer. 【0005】 Drugs such as thalidomide and its analogs lenalidomide and pomalidomide have attracted attention as immunomodulatory agents and anti-cancer agents, particularly in multiple myeloma (Non-Patent Documents 1, 2, 3, 4, and 5). The exact mechanism of action of thalidomide, lenalidomide, and pomalidomide in treatment is unknown, but the compounds exhibit activity. Thalidomide and its analogs have been shown to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Non-Patent Document 6). Cereblon is part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1, forms an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (known as RBX1), and functions as a substrate receptor for selecting proteins for ubiquitination. Binding of lenalidomide to cereblon promotes subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and proteasomal degradation (see Non-Patent Documents 7 and 8). 【0006】 With the discovery that thalidomide binds to the cereblon E3 ubiquitin ligase, research has been conducted to investigate the incorporation of thalidomide and certain derivatives into compounds for the destruction of targeted proteins. Celgene has disclosed imides for similar uses, including those in Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27. 【0007】 Patent applications describing compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation filed by C4 Therapeutics, Inc. include the following: Patent Document 28, titled "Neurotrophic Tyrosine Receptor Kinase (NTRK) Degrading Compounds"; Patent Document 29, titled "Selected Compounds for Targeted Degradation of BRD9"; Patent Document 30, titled "Compounds for Targeting Degradation of IRAK4 Proteins"; Patent Document 31, titled "Compounds for Targeting Degradation of IRAK4 Proteins"; Patent Document 32, titled "EGFR Degraders to Treat Cancer Metastasis to the Brain or CNS"; Patent Document 33, titled "Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins"; Patent Document 34, titled "Tricyclic Compounds to Degrade Neosubstrates for Medical Therapy"; Patent Document 35, titled "Tricyclic Ligands for Degradation of IKZF2 or IKZF4"; Patent Document 36, titled "Advantageous Therapies for Disorders Mediated by Ikaros or Aiolos".Patent Document 37, title: "Heterobifunctional Compounds as Degraders of BRAF"; Patent Document 38, title: "BRAF Degraders"; Patent Document 39, title: "Compounds for Targeted Degradation of BRD9"; Patent Document 40, title: "Isoindolinone And Indazole Compounds For The Degradation Of EGFR"; Patent Document 41, title: "Bifunctional Compounds"; Patent Document 42, title: "Bifunctional Compounds for the Treatment of Cancer"; Patent Document 43, title: "Tricyclic Degraders of Ikaros and Aiolos"; Patent Document 44, title: "Heterocyclic Compounds for Medical Treatment"; Patent Document 45, title: "Targeted Protein Degradation"; Patent Document 46, title: "Spirocyclic Compounds"; Patent Document 47, title: "Compounds for the degradation of BRD9 or MTH1"; Patent Document 48, title: "Cereblon binders for the Degradation of Ikaros"; Patent Document 49, title: "Spirocyclic Compounds"; Patent Document 50, title: "Degraders and Degrons for Targeted Protein Degradation";Patent Document 51, title "N / O-Linked Degrons and Degronimers for Protein Degradation"; Patent Document 52, title "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation"; Patent Document 53, title "Heterocyclic Degronimers for Target Protein Degradation"; Patent Document 54, title "Spirocyclic Degronimers for Target Protein Degradation"; Patent Document 55, title "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and Patent Document 56, title "Bromodomain Targeting Degronimers for Target Protein Degradation".; 【0008】 Other examples of patent applications describing proteolytic compounds include: Patent Document 57, Patent Document 58, Patent Document 59, Patent Document 60, Patent Document 61, Patent Document 62, Patent Document 63, Patent Document 64, Patent Document 65, Patent 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International Publication No. 2023 / 044046 【Patent Document 103】 International Publication No. 2023 / 076161 【Patent Document 104】 International Publication No. 2023 / 049790 【Patent Document 105】 International Publication No. 2023 / 076556 【Non-Patent Document】 【0010】 【Non-Patent Document 1】 Kim SA et. al., "A novel cereblon modulator for targeted protein degradation", Eur J Med Chem. 2019 Mar 15; 166:65-74; 【Non-Patent Document 2】 R. Verma et. al., "Identification of a Cereblon-Independent Protein Degradation Pathway in Residual Myeloma Cells Treated with Immunomodulatory Drugs", Blood (2015) 126 (23): 913 【Non-Patent Document 3】 Liu Y, et al., "A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function", FASEB J. 2015 Dec;29(12):4829-39; 【Non-Patent Document 4】 Martiniani, R. et al., "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma", Adv Hematol, 2012, 2012:842945 【Non-Patent Document 5】 Terpos, E. et al., "Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma", Oncotargets and Therapy, 2013, 6:531 【Non-Patent Document 6】 Ito, T. et al., "Identification of a primary target of thalidomide teratogenicity", Science, 2010, 327:1345 【Non-Patent Document 7】 Lu, G. et al., "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins", Science, 2014, 343:305-309; 【Non-Patent Document 8】 Kroenke, J. et al., "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells", Science, 2014, 343:301-305 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0011】 An object of the present invention is to provide a new compound, method, composition, and manufacturing method useful for degrading a selected protein in vivo. 【Means for Solving the Problems】 【0012】 Provided are cereblon-binding compounds (degrons) having a specific bicyclic substituent at the C3 position of glutarimide. These specific bicyclic substituents correspond to the bicyclics of the following formulas IA, IIA, IIIA, IVA, VA, VIA, VIIA, VIIIA, IXIA, XA, XIA, XIIA, XIIIA, XIVA, XVA, and XVI A, as well as the embodiments described herein. 【Chemical formula】 【0013】 The degrons described can be used to treat disorders mediated by cereblon, or disorders mediated by proteins that are degraded by cereblon when the degrons described herein bind to cereblon. Alternatively, the degrons described herein can be used as intermediates for synthesizing heterobifunctional compounds (Degraders) for targeted proteolysis. In certain embodiments, the degron comprises a linking moiety (tail) that can react with a suitably prepared targeting ligand or targeting ligand precursor to form a Degrader. Also provided are Degraders comprising degrons described herein that can be attached directly to a targeting ligand or attached to a targeting ligand via a linker. 【Chemical formula】 【0014】 The degron compound serves as a "molecular glue" that can bind to the cereblon E3 ligase, thereby creating a new surface on the E3 ligase and enhancing the interaction and binding with the targeted protein. As a result of this interaction, the targeted protein can be ubiquitinated by the cereblon E3 ligase and degraded by the proteasome. In some embodiments, the cereblon-binding affinity of the degron enables the degradation of proteins associated with, but not limited to, cancer and the diseases described in more detail below. 【0015】 For example, a compound of formula IA is a degron and can thus be used as part of a therapeutic active compound that modifies the surface of cereblon, an intermediate for making a degrader, or a heterobifunctional compound (degrader) that degrades a target protein. 【0016】 In certain embodiments, a compound of formula IA, formula IIA, formula IIIA, formula IVA, formula VA, formula VIA, formula VIIA, formula VIIIA, formula IXA, formula XA, formula XIA, formula XIIA, formula XIIIA, formula XIVA, formula XVA, or formula XVI in a pharmaceutically acceptable carrier optionally for forming a pharmaceutical composition: 【Chemical formula】 A degron compound of TIFF2025523393000005.tif127170, or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof, is provided. Wherein m is 0, 1, 2, 3, or 4; In certain embodiments, m is 0 or 1; n is 0, 1, 2, or 3; In certain embodiments, n is 0, 1, or 2; p is 0 or 1; In certain embodiments, p is 1; Q is O, S, NR 17 , or CR 17 R 18 ; In certain embodiments, Q is O, NR 17 , or CH2; In certain embodiments, Q is O; X 1 , X 2 , and X 3 are independently selected from the group consisting of N, CH, and CR 5 ; In certain embodiments, X 1 , X 2 , and X3 Only one of them is selected to be N, X 3b is N, CH, or CR 5b and In a particular embodiment, X 3b is CH, X 4 is N, CH, or CR 5 and In a particular embodiment, X 4 is CH or CR 5 and Z 1 Z 2 Z 5 and Z 6 are independently selected from the group consisting of CH, CR 5 and N, Z 3 and Z 4 are independently selected from the group consisting of S, O, NH, and NR 17 and 【Chemical formula】 is cycloalkyl, heterocyclic ring, or heteroaryl, In a particular embodiment, 【Chemical formula】 is 【Chemical formula】 and R 1 and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen, or R 1 and R 6 combine to form a CH2 or CH2CH2 bridge, each R 2 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic ring, and -C(O)R 9 and each of them, excluding hydrogen, is R 10Optionally substituted with one, two, three, or four substituents independently selected from each R 5 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O)2R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O)2R 9 , -SC(O)R 9 , -OS(O)2R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O)2R 9 , -P(O)(R 9 )2, -SP(O)(R 9 )2, -NR 7 P(O)(R 9 )2, and -OP(O)(R 9 )2, and each of them, excluding hydrogen, halogen, cyano, and nitro, is optionally substituted with one, two, three, or four substituents independently selected from R 10 R 5b is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)alkyl, -C(S)R 9 , -S(O)R 9 , and -S(O)2R 9 , and each of them, excluding hydrogen, is optionally substituted with one, two, three, or four substituents independently selected from R 10 R 5c ​​is hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -OR 7 , -SR 7 , -C(O)R 9b , -C(S)R 9 , -S(O)R 9 , -S(O)2R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O)2R 9 , -SC(O)R 9 , -OS(O)2R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O)2R 9 , -P(O)(R 9 )2, -SP(O)(R 9 )2, -NR 7 P(O)(R 9 )2, and -OP(O)(R 9 )2, and each of them, excluding hydrogen, halogen, cyano, and nitro, is optionally substituted with one, two, three, or four substituents independently selected from 10 R R 7 and R 8 in each case is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -C(O)R 14 , and each of them, excluding hydrogen, is optionally substituted with one, two, three, or four substituents independently selected from 16 R Each R 9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -NR 7 R 8 , -OR 7 , and -SR 7 , and each of them is10 Optionally substituted with one, two, three, or four substituents independently selected from R 9b is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 , and -SR 7 independently selected from, each of which is optionally substituted with one, two, three, or four substituents independently selected from 10 R each R 10 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O)2R 14 , -OC(O)R 14 , -OC(S)R 14 , -OS(O)R 14 , -OS(O)2R 14 , -NR 11 C(O)R 14 , -NR 11 C(S)R 14 , -NR 11 S(O)R 14 , -NR 11 S(O)2R 14 , -P(O)(R 14 )2, -NR 11 P(O)(R 14 )2, and -OP(O)(R 14 )2 independently selected from, excluding hydrogen, halogen, cyano, and nitro, each of which is optionally substituted with one, two, three, or four substituents independently selected from 15a R R 11 and R 13 in each case is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14, -C(S)R 14 , -S(O)R 14 , -S(O)2R 14 , and -P(O)(R 14 )2, independently selected from, each of which is optionally substituted with one, two, three, or four substituents independently selected from R 15b ; Each R 12 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , and -SR 11 , independently selected from, excluding hydrogen, halogen, cyano, and nitro, each of which is optionally substituted with one, two, three, or four substituents independently selected from R 15c ; Each R 14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2, excluding hydrogen, each of which is optionally substituted with one, two, three, or four substituents independently selected from R 15d ; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g are, in each case, independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2; Each R 16 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R14 、 -C(S)R 14 、 -S(O)R 14 、 -S(O)₂R 14 、 -OC(O)R 14 、 -OC(S)R 14 、 -OS(O)R 14 、 -OS(O)₂R 14 、 -NR 11 C(O)R 14 、 -NR 11 C(S)R 14 、 -NR 11 S(O)R 14 、 -NR 11 S(O)₂R 14 、 -P(O)(R 14 )₂、 -NR 11 P(O)(R 14 )₂、 and -OP(O)(R 14 )₂, and each of them independently selected from, excluding hydrogen, halogen, cyano, and nitro, is optionally substituted with one, two, three, or four substituents independently selected from 15e R R 17 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, -C(O)R 14 、 -C(S)R 14 、 -S(O)R 14 、 -S(O)₂R 14 、 and -P(O)(R 14 ) and each of them, excluding hydrogen, is optionally substituted with one, two, three, or four substituents independently selected from 15f R R 18 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 、 -OR 11 、 -SR 11 、 -OC(O)R 14 、 -OC(S)R 14 、 -OS(O)R 14 、 -OS(O)₂R 14 、 -NR 11 C(O)R14 、 -NR 11 C(S)R 14 、 -NR 11 S(O)R 14 、 -NR 11 S(O)2R 14 、 -P(O)(R 14 )2、 -NR 11 P(O)(R 14 )2、 and -OP(O)(R 14 )2, and each of which is selected from and is optionally substituted with one, two, three, or four substituents independently selected from R, excluding hydrogen, halogen, cyano, and nitro. 15g 【0017】 In certain embodiments, provided is a degron of formula XVIIAa, formula XVIIAb, formula XVIIAc, formula XVIIAd, or formula XVIIAe: 【Chemical formula】 or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein, Z 3b is selected from O, NH, and NR 17 and Z 4b is selected from S, NH, and NR 17 and 【Chemical formula】 is a 5-membered heterocycle, 5-membered heteroaryl, pyrimidinyl, pyridazinyl, or pyrazinyl, and all other variable moieties are as defined herein. 【0018】 The degron described herein can be used alone (i.e., not as part of a degrader) as a cereblon in vivo binder, which can be administered to a host in need thereof, such as a human, in an effective amount, optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition, for any therapeutic indication that can be treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex, including, but not limited to, the uses known for cereblon binders including thalidomide, pomalidomide, and lenalidomide. The binding of the degron described herein to cereblon can induce a change in the protein conformation of cereblon and enable the degradation of the target protein. In certain embodiments, the degron described herein is a "molecular glue" that causes target degradation of a target protein, such as a protein having a C2H2 zinc finger degron motif. 【0019】 Non-limiting examples of proteins that may be degraded or downregulated by degrons include ARID2, CDK1, CDK12-Cyclin K, CDK13, CK1α, CSNK1A1, Cyclin K, E4F1, FAM83F, GSPT1, GSPT2, GZF1, IKZF1, IKZF2, IKZF3, IKZF4, ILF2, Myc, ODC1, p63, PDE6D, AB28, RARα-ZBTB16, RBM23, RBM39, RBM39, RNF166, SALL4, WBP4, ZBTB16, ZBTB16-RARα, ZBTB39, ZFP91, ZFP91, ZFP91, ZMYM2-FGFR1, ZMYM2-FLT3, ZNF198, ZNF276, ZNF276, ZNF517, ZNF582, ZNF653, ZNF654, ZNF692, ZNF787, ZNF827, and ZNF98. In certain embodiments, the target protein degraded by the degron of the present invention is selected from ARID2, aromatase, β-catenin, CDK12, NRF2, PDE6D, CK1α, Cyclin K, GSPT1, FAM83, ILF2, ZBTB16, and ZMYM2. In certain embodiments, the target protein degraded by the degron of the present invention is selected from IKZF1, IKZF2, IKZF3, and IKZF4. 【0020】 Non-limiting examples of disorders that may be treated by the degrons described herein include abnormal cell proliferation, including tumors or cancers, or myeloproliferative or lymphoproliferative disorders such as B-cell lymphoma or T-cell lymphoma, multiple myeloma, Waldenström macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes; heart dysfunction diseases including hypercholesterolemia; infectious diseases including viral or bacterial infections; and inflammatory conditions including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis. 【0021】 In certain embodiments, the degrons described herein are used to degrade proteins that mediate multiple myeloma, colorectal cancer, Hodgkin lymphoma, or non-Hodgkin lymphoma. 【0022】 In certain embodiments, the degrons described herein can activate cereblon, reduce or alter its natural activity. Further non-limiting examples of the use of cereblon binders are for treating hematological disorders such as multiple myeloma, myelodysplastic syndromes, cancer, tumors, abnormal cell proliferation, HIV / AIDS, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet's disease, tuberculosis, and myelofibrosis. 【0023】 In other aspects, the degron has a tail portion. For example, the formula: 【Chemical formula】 A degron of TIFF2025523393000012.tif187170TIFF2025523393000013.tif185170 or a pharmaceutically acceptable salt thereof, wherein, the tail is 【Chemical formula】 selected from X 31 and X 32 are each, in each case, a bond, a heterocycle, an aryl, a heteroaryl, a bicyclic, -NR 27 -, -CR 40 R 41 -, -O-, -C(O)-, -C(NR 27 )-, -C(S)-, -S(O)-, -S(O)2-, and -S-, and each of the heterocycle, aryl, heteroaryl, and bicyclic is substituted with one, two, three, or four substituents independently selected from R 40 , X 22 is selected such that the compound is sufficiently stable or results in the intended use, and X 22 is R5 and R 20 、R 21 、R 22 、R 23 、and R 24 are each, independently in each case, selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 27 -, -NR 27 C(O)-, -O-, -S-, -NR 27 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, a bicyclic ring, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and a carbocyclic ring, each of which is optionally substituted with one, two, three, or four substituents independently selected from R 40 ; R 26 is independently in each case selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic, and heteroaliphatic; R 27 is independently in each case selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocycle, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 40 is independently in each case hydrogen, R 27, selected from alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxyl, azide, amino, cyano, -NH (including aliphatic, alkyl), -N (including aliphatic, alkyl)2, -NHSO2 (including aliphatic, alkyl), -N (including aliphatic, alkyl)SO2 alkyl, -NHSO2 (aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl. 【0024】 In certain embodiments When used in a divalent structure 【Chemical formula】 is 【Chemical formula】 as follows. 【0025】 In certain embodiments, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII: 【Chemical formula】 a degrader compound of TIFF2025523393000018.tif120170, or a pharmaceutically acceptable salt thereof, is provided, wherein the targeting ligand is a moiety that binds to the target protein, the target protein is a selected protein that causes or contributes to a disease, the linker is a divalent linking group, and all other variable parts are as defined herein. 【0026】 In other aspects, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, Formula XVI or Formula XVII: [Chemical formula] a degrader compound of TIFF2025523393000020.tif211170TIFF2025523393000021.tif170170, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof is provided, wherein, the targeting ligand is a chemical moiety that binds to a target protein, the target protein is a selected protein that causes or contributes to a disease, the linker is a bivalent linking group, and all other variable parts are as defined herein. 【0027】 In certain embodiments, the targeting ligand is a means for binding to a target protein, and the targeting ligand is a chemical moiety. In certain embodiments, the term targeting ligand as used in the formulas or claims of the present invention is defined as a mean-plus-function under 35 U.S.C. § 112(f). In certain embodiments, the targeting ligand is a chemical moiety described in this patent application, e.g., a chemical moiety described in the figures. 【0028】 The structure of the degrader is typically selected to be sufficiently stable to maintain a shelf life of at least 2, 3, 4, or 5 months under ambient conditions. To achieve this, each R group described herein must be sufficiently stable to maintain the corresponding desired shelf life of at least 2, 3, 4, or 5 months under ambient conditions. Those skilled in the art are well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions. 【0029】 Also, regardless of the presence or absence of any substituents, all R groups should be interpreted in a non-redundant manner (i.e., as is known in the art, alkyl substituted with alkyl is redundant, but for example, alkoxy substituted with alkoxy is not redundant). 【0030】 The degraders provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by a selected target protein that binds to a targeting ligand. Accordingly, in some embodiments, provided is a method of treating a host having a disorder mediated by a target protein, the method comprising administering to the host, typically a human, an effective amount of a degrader described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. 【0031】 In certain embodiments, the selected target protein is derived from a gene that has undergone an amplification, translocation, rearrangement, copy number polymorphism, change, deletion, mutation, or inversion event that causes or is caused by a medical disorder. In certain aspects, the selected target protein has been post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylgeranylation, ubiquitination, SUMOylation, or sulfation that causes or is caused by a medical disorder. In another embodiment, the target protein can be covalently modified by a targeting ligand functionalized to covalently bind to the target protein, and the covalent bond can be irreversible or reversible. 【0032】 One non-limiting example of a disorder treatable by such a compound is abnormal cell proliferation such as a tumor or cancer, the target protein is an oncogenic protein or a signal transduction mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell proliferation. 【0033】 The compounds and methods are presented for the treatment of patients having a disorder mediated by a protein targeted for selective degradation, which optionally comprises administering to a human patient in need thereof, in a pharmaceutically acceptable carrier (composition), an effective amount of one or a combination of the degrons or degraders of the invention described herein. 【0034】 In certain embodiments, the disorder is selected from neoplasms, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, proteinopathies, or fibrotic disorders. 【0035】 In one embodiment, the invention provides a degron covalently linked to a targeting ligand via a linker that can have different lengths and functionalities. In one embodiment, the resulting degron-linker-targeting ligand compound is used to treat the disorders described herein. In one embodiment, the degron is directly linked to the targeting ligand (i.e., the linker is a bond). 【0036】 In certain embodiments, the linker can be any chemically stable group that attaches the degron to the targeting ligand. Examples of linkers are described in Section IV (Linkers). In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms, with at least one of the carbon atoms replaceable by a heteroatom such as O, N, S, or P, such that the resulting molecule has a storage life stable for at least 2 months, 3 months, 6 months, or 1 year as part of a pharmaceutically acceptable dosage form and is itself pharmaceutically acceptable. 【0037】 In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive atoms within the chain. For example, the chain may include one or more ethylene glycol units, and in some embodiments, the linker may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more consecutive, partially consecutive, or non-consecutive ethylene glycol units. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches, which can independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, and in one embodiment, each branch has 10, 8, 6, 4, 3, 2, or 1 carbon. 【0038】 In one embodiment, the target protein is a protein that is not druggable in the classical sense in that it has no binding pocket or active site that can be inhibited or otherwise bound and cannot be readily allosterically controlled. In another embodiment, the target protein is a protein that is druggable in the classical sense. Examples of target proteins are shown below. 【0039】 In certain embodiments, the invention provides administration of an effective amount of a degron or degrader compound to treat a patient, such as a human, having an infectious disease, and the treatment optionally in combination with another bioactive agent targets a target protein of the infectious pathogen or a target protein of the host (degrader), or acts through binding to cereblon or its E3 ubiquitin ligase (degron), or acts through an independent mechanism. 【0040】 A disease state or pathological condition can be caused by other exogenous pathogens such as microbial pathogens or viruses (non-limiting examples include HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, SARS-CoV2, flavivirus, pestivirus, rotavirus, influenza virus, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepadnavirus), bacteria (including but not limited to gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, meningococcus, gonococcus, Chlamydiaceae, Mycoplasmataceae, etc.), fungi, protozoa, helminths, worms, prions, parasites, or other microorganisms. 【0041】 In certain embodiments, the degron or degrader compound has at least one desired isotope substitution of an atom in an amount that exceeds the natural abundance of the isotope, i.e., is enriched. 【0042】 In one embodiment, the degron or degrader compound contains deuterium atoms or a plurality of deuterium atoms. 【0043】 The compounds of the present invention can provide important clinical benefits to patients for the treatment of disease states and pathological conditions particularly regulated by the protein of interest. 【0044】 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In this specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present application, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference to form a part of this specification. The references cited herein are not admitted to be prior art to the present application. In case of conflict, this specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 【0045】 Other features and advantages of the present application will be apparent from the following detailed description and claims. 【0046】 Accordingly, the present invention includes at least the following features: (a) A degron compound as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof; (b) Use of a degron compound as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, which binds to cereblon as a molecular glue and results in the degradation of a target protein; (c) A degron having a tail, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives), or prodrug thereof, or its therapeutic use; (d) A degrader compound as described herein, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives), or prodrug thereof; (e) A degrader compound for the treatment of a disorder mediated by a target protein, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, wherein the compound comprises a targeting ligand for the target protein and the degron is optionally linked to the targeting ligand through a linker; (f) Use of an effective amount of a degron compound in the treatment of a patient, typically a human, having a disorder responsive to such treatment, including altering cereblon-based ubiquitination of a protein, such as abnormal cell proliferation, such as a tumor or cancer, immune disorder or autoimmune disorder or inflammatory disorder, heart disorder, infectious disease, or other disorder responsive to such treatment; (g) Use of an effective amount of a degrader compound in the treatment of a patient, typically a human, having any of the disorders described herein mediated by a target protein, including abnormal cell proliferation, such as a tumor or cancer, immune disorder or autoimmune disorder or inflammatory disorder, heart disorder, infectious disease, or other disorder responsive to such treatment; (h) Use of a degron or degrader, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for the treatment of a medical disorder, as further described herein; (i) A method of manufacturing a medicament for the therapeutic treatment of a disorder of a host, characterized in that a degron or degrader is used in the manufacture; (j) A degron or degrader, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, useful for the treatment of abnormal cell proliferation, such as cancer, in a host, including any of the cancers described herein; (k) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for the treatment of abnormal cell proliferation, such as cancer, including any of the cancers described herein; (l) A method for manufacturing a medicament intended for therapeutic use for treating abnormal cell proliferation such as cancer, including any cancer in the host described herein, characterized in that a degron or a degrader is used in the manufacture; (m) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, which is useful for treating a tumor in a host, including any of the tumors described herein; (n) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, which is useful for treating a tumor in a host, including any of the tumors described herein; (o) A method for manufacturing a medicament intended for the therapeutic treatment of a tumor in a host, including any of the tumors described herein, characterized in that a degron or degrader compound is used in the manufacture; (p) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for treating an immune disorder, autoimmune disorder or inflammatory disorder in a host; (q) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a medicament for treating an immune disorder, autoimmune disorder or inflammatory disorder in a host; (r) A method for manufacturing a medicament intended for the therapeutic treatment of an immune disorder, autoimmune disorder or inflammatory disorder in a host, characterized in that a degron or degrader compound is used in the manufacture; (s) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, which is useful for treating viral infections in a host, including infections such as HIV, HBV, HCV, SARS-CoV2, and RSV; (t) Use of a degron or degrader compound, or a pharmaceutically possible salt, isotope derivative (including deuterated derivative) or prodrug thereof, in the manufacture of a medicament for the treatment of viral infections in a host, such as infections including HIV, HBV, HCV, SARS-CoV2, and RSV; (u) A method for manufacturing a medicament intended for the therapeutic treatment of viral infections in a host, such as infections including HIV, HBV, HCV, SARS-CoV2, and RSV, characterized in that a degron or degrader compound is used in the manufacture; (v) A pharmaceutical preparation comprising a therapeutically effective amount of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient; (w) A degron or degrader compound as described herein as a mixture of enantiomers or diastereomers (related ones), including racemates; (x) A degron or degrader compound as described herein in an enriched form of enantiomers or diastereomers (related ones), including isolated enantiomers or diastereomers (i.e., having a purity greater than 85%, 90%, 95%, 97%, or 99%); and (y) A process for the preparation of a therapeutic product containing an effective amount of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, optionally together with a pharmaceutically acceptable carrier or excipient. 【Brief Description of the Drawings】 【0047】 【Figure 1A-1C】 A figure showing non-limiting examples of targeted ligands of the retinoid X receptor (RXR), where R represents an exemplary point to which a linker can be attached. 【Figure 1D-1F】 A figure showing non-limiting examples of targeted ligands of a general dihydrofolate reductase (DHFR), where R represents an exemplary point to which a linker can be attached. 【Figure 1G】Figure showing non-limiting examples of targeting ligands for dihydrofolate reductase (BaDHFR) of Bacillus anthracis, where R represents an exemplary point to which a linker can be attached. 【Figure 1H-1J】 Figure showing non-limiting examples of targeting ligands for heat shock protein 90 (HSP90), where R represents an exemplary point to which a linker can be attached. 【Figure 1K-1Q】 Figure showing non-limiting examples of targeting ligands for common kinases and phosphatases, where R represents an exemplary point to which a linker can be attached. 【Figure 1R-1S】 Figure showing non-limiting examples of targeting ligands for tyrosine kinase, where R represents an exemplary point to which a linker can be attached. 【Figure 1T】 Figure showing non-limiting examples of targeting ligands for aurora kinase, where R represents an exemplary point to which a linker can be attached. 【Figure 1U】 Figure showing non-limiting examples of targeting ligands for protein tyrosine phosphatase, where R represents an exemplary point to which a linker can be attached. 【Figure 1V】 Figure showing non-limiting examples of targeting ligands for ALK, where R represents an exemplary point to which a linker can be attached. 【Figure 1W】 Figure showing non-limiting examples of targeting ligands for ABL, where R represents an exemplary point to which a linker can be attached. 【Figure 1X】 Figure showing non-limiting examples of targeting ligands for JAK2, where R represents an exemplary point to which a linker can be attached. 【Figure 1Y-1Z】 Figure showing non-limiting examples of targeting ligands for MET, where R represents an exemplary point to which a linker can be attached. 【Figure 1AA】 Figure showing non-limiting examples of targeting ligands for mTORC1 and / or mTORC2, where R represents an exemplary point to which a linker can be attached. 【Figure 1BB-1CC】 A diagram showing non-limiting examples of targeted ligands for the mast cell / stem cell growth factor receptor (SCFR), also known as the c-KIT receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1DD】 A diagram showing non-limiting examples of targeted ligands for IGF1R and / or IR, where R represents an exemplary point to which a linker can be attached. 【Figure 1EE-1FF】 A diagram showing non-limiting examples of targeted ligands for HDM2 and / or MDM2, where R represents an exemplary point to which a linker can be attached. 【Figure 1GG-1MM】 A diagram showing non-limiting examples of targeted ligands for BET bromodomain-containing proteins, where R represents an exemplary point to which a linker can be attached. 【Figure 1NN】 A diagram showing non-limiting examples of targeted ligands for HDAC, where R represents an exemplary point to which a linker can be attached. 【Figure 1OO】 A diagram showing non-limiting examples of targeted ligands for the RAF receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1PP】 A diagram showing non-limiting examples of targeted ligands for the FKBP receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1QQ-1TT】 A diagram showing non-limiting examples of targeted ligands for the androgen receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1UU】 A diagram showing non-limiting examples of targeted ligands for the estrogen receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1VV-1WW】 A diagram showing non-limiting examples of targeted ligands for the thyroid hormone receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 1XX】 A diagram showing non-limiting examples of targeted ligands for HIV protease, where R represents an exemplary point to which a linker can be attached. 【Figure 1YY】 A diagram showing non-limiting examples of targeting ligands for HIV integrase, where R represents an exemplary point to which a linker can be attached. 【Figure 1ZZ】 A diagram showing non-limiting examples of targeting ligands for HCV protease, where R represents an exemplary point to which a linker can be attached. 【Figure 1AAA】 A diagram showing non-limiting examples of targeting ligands for AP1 and / or AP2, where R represents an exemplary point to which a linker can be attached. 【Figure 1BBB-1CCC】 A diagram showing non-limiting examples of targeting ligands for MCL-1, where R represents an exemplary point to which a linker can be attached. 【Figure 1DDD】 A diagram showing non-limiting examples of targeting ligands for IDH1, where R represents an exemplary point to which a linker can be attached. 【Figure 1EEE-1FFF】 A diagram showing non-limiting examples of targeting ligands for RAS or RASK, where R represents an exemplary point to which a linker can be attached. 【Figure 1GGG】 A diagram showing non-limiting examples of targeting ligands for MERTK or MER, where R represents an exemplary point to which a linker can be attached. 【Figure 1HHH-1III】 A diagram showing non-limiting examples of targeting ligands for EGFR, where R represents an exemplary point to which a linker can be attached. 【Figure 1JJJ-1KKK】 A diagram showing non-limiting examples of targeting ligands for FLT3, where R represents an exemplary point to which a linker can be attached. 【Figure 1LLL】 A diagram showing non-limiting examples of targeting ligands for SMARCA2, where R represents an exemplary point to which a linker can be attached. 【Figure 2A】 A diagram showing non-limiting examples of the targeted ligand U09-CX-5279 (derivatized) of a kinase inhibitor, where R represents an exemplary point to which a linker can be attached. 【Figure 2B-2C】Figure showing non-limiting examples of targeted ligands of kinase inhibitors comprising kinase inhibitor compounds Y1W and Y1X (derivatized), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in "Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease" by Millan et al., J. Med. Chem., 54: 7797 (2011). 【Figure 2D】 Figure showing non-limiting examples of targeted ligands of kinase inhibitors comprising kinase inhibitor compounds 6TP and 0TP (derivatized), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in "Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors" by Schenkel et al., J. Med. Chem., 54 (24): 8440 - 8450 (2011). 【Figure 2E】 Figure showing non-limiting examples of targeted ligands of kinase inhibitors comprising kinase inhibitor compound 07U, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes" by Van Eis et al., Biorg. Med. Chem. Lett., 21(24): 7367 - 72 (2011). 【Figure 2F】 【Figure 2F】 is a diagram showing non-limiting examples of targeted ligands of kinase inhibitors containing the kinase inhibitor compound YCF, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy" by Lountos et al., J. Struct. Biol., 176: 292 (2011). 【Figure 2G-2H】 【Figure 2G-2H】 is a diagram showing non-limiting examples of targeted ligands of kinase inhibitors containing the kinase inhibitors XK9 and NXP (derivatized), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy" by Lountos et al., J. Struct. Biol., 176: 292 (2011). 【Figure 2I-2J】 【Figure 2I-2J】 is a diagram showing non-limiting examples of targeted ligands of kinase inhibitors, where R represents an exemplary point to which a spacer can be attached. 【Figure 2K-2M】Figure showing non-limiting examples of targeted ligands for cyclin-dependent kinase 9 (CDK9), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see "The structure of P-TEFb (CDK9 / cyclin T1) its complex with flavopiridol and regulation by phosphorylation." by Baumli et al., Embo J., 27: 1907-1918 (2008), "CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells." by Bettayeb et al., Genes Cancer, 1: 369-380 (2010), "Halogen bonds form the basis for selective P-TEFb inhibition by DRB." by Baumli et al., Chem.Biol. 17: 931-936 (2010), "Comparative Structural and Functional Studies of 4-(Thiazol- 5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity." by Hole et al., J.Med.Chem. 56: 660 (2013), Luecking et al.See the article "Identification of the potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer-From p.o. to i.v. application via scaffold hops." by Luecking et al., U. AACR Annual Meeting, April 1-5, 2017 (Washington, DC, USA). 【Figure 2N-2P】Figure showing non-limiting examples of targeting ligands for cyclin-dependent kinase 4 / 6 (CDK4 / 6), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lu H., Schulze-Gahmen U., "Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition.", J. Med. Chem., 49: 3826-3831 (2006); "4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4 / 6.", Cho et al. (2010) J.Med.Chem. 53: 7938-7957; Cho Y.S. et al., "Fragment-Based Discovery of 7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4 / 6 Inhibitors.", ACS Med Chem Lett 3: 445-449 (2012); Li Z. et al., "Discovery of AMG 925 a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.", J. Med. Chem. 57: 3430-3449 (2014); Chen P. et al.See, e.g., “Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance.” Mol. Cancer Ther. 15: 2273-2281 (2016). 【Figure 2Q】 FIG. showing non-limiting examples of targeting ligands for cyclin-dependent kinase 12 and / or cyclin-dependent kinase 13, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Zhang T. et al., “Covalent Targeting of Remote Cysteine Residues to Develop Cdk12 and Cdk13 Inhibitors.” Nat. Chem. Biol. 12: 876 (2016). 【Figure 2R-2S】 FIG. showing non-limiting examples of targeting ligands for glucocorticoid receptor, where R represents an exemplary point to which a linker can be attached. 【Figure 2T-2U】 FIG. showing non-limiting examples of targeting ligands for RasG12C, where R represents an exemplary point to which a linker can be attached. 【Figure 2V】 FIG. showing non-limiting examples of targeting ligands for Her3, where R represents an exemplary point to which a linker can be attached and R’’ is 【Chemical formula】 as follows. 【Figure 2W】 FIG. showing non-limiting examples of targeting ligands for Bcl-2 or Bcl-XL, where R represents an exemplary point to which a linker can be attached. 【Figure 2X-2NN】Figure showing non-limiting examples of BCL2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see "The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions." by Toure B. B. et al., ACS Med Chem Lett, 4: 186-190 (2013), "Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as Selective Bcl-2 Inhibitors" by Porter J. e.t al., Bioorg. Med. Chem. Lett. 19: 230 (2009), "ABT-199 a potent and selective BCL-2 inhibitor achieves antitumor activity while sparing platelets." by Souers A.J. et al., Nature Med. 19: 202-208 (2013), "A Potent and Highly Efficacious Bcl-2 / Bcl-xL Inhibitor" by Angelo Aguilar et al., J Med Chem. 56(7): 3048-3067 (2013), Longchuan Bai et al."BM-1197: A Novel and Specific Bcl-2 / Bcl-xL Inhibitor Inducing Complete and Long-Lasting Tumor Regression In Vivo" by Ne'mati et al., PLoS ONE 9(6): e99404; "Targeting Bcl-2 / Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts" by Fariba Ne'mati1 et al., PLoS ONE 9(1): e80836; WO 2015 / 011396 entitled "Novel derivatives of indole and pyrrole method for the production thereof and pharmaceutical compositions containing same"; WO 2008 / 060569 entitled "Compounds and methods for inhibiting the interaction of Bcl proteins with binding partners"; "Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review" by Expert Opin. Ther. Patents 22(1):2008 (2012), and Porter et al.See, e.g., “Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors” Bioorg Med Chem Lett., 19(1):230-3 (2009). 【Figure 2OO-2UU】 FIG. showing non-limiting examples of targeted ligands for BCL-XL, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see “Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity” by Zhi-Fu Tao et al., ACS Med. Chem. Lett., 5: 1088-1093 (2014), “Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy” by Joel D. Leverson et al., Science Translational Medicine, 7:279ra40 (2015), and crystal structure PDB 3ZK6 (“Structure-guided design of a selective BCL-XL inhibitor” by Guillaume Lessene et al., Nature Chemical Biology 9: 390-397 (2013)). 【Figure 2VV】 FIG. showing non-limiting examples of targeted ligands for PPAR-γ, where R represents an exemplary point to which a linker can be attached. 【Figure 2WW-2YY】 A diagram showing non-limiting examples of EGFR targeting ligands that target the L858R mutant of EGFR, including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, where R represents an exemplary point to which a linker can be attached. 【Figure 2ZZ-2FFF】 A diagram showing non-limiting examples of EGFR targeting ligands that target the T790M mutant of EGFR, including osimertinib, rociletinib, ormutinib, naquotinib, nazartinib, PF-06747775, icotinib, neratinib, avitinib, talroxitinib, PF-0645998, tesevatinib, Transtinib, WZ-3146, WZ8040, and CNX-2006, where R represents an exemplary point to which a linker can be attached. 【Figure 2GGG】 A diagram showing non-limiting examples of EGFR targeting ligands that target the C797S mutant of EGFR, including EAI045, where R represents an exemplary point to which a linker can be attached. 【Figure 2HHH】 A diagram showing non-limiting examples of BCR-ABL targeting ligands that target the BCR-ABL T315I mutant, including nilotinib and dasatinib, where R represents an exemplary point to which a linker can be attached. See, for example, crystal structure PDB 3CS9. 【Figure 2III】 A diagram showing non-limiting examples of BCR-ABL targeting ligands that target BCR-ABL, including nilotinib, dasatinib, ponatinib, and bosutinib, where R represents an exemplary point to which a linker can be attached. 【Figure 2JJJ-2KKK】 A diagram showing non-limiting examples of ALK targeting ligands that target the L1196M mutant of ALK, including ceritinib, where R represents an exemplary point to which a linker can be attached. See, for example, crystal structure PDB 4MKC. 【Figure 2LLL】 A diagram showing non-limiting examples of JAK2 targeting ligands that target the V617F mutant of JAK2, including ruxolitinib, where R represents an exemplary point to which a linker can be attached. 【Figure 2MMM】 A diagram showing non-limiting examples of BRAF targeting ligands that target the V600E mutant of BRAF containing vemurafenib, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, refer to the crystal structure PBD 3OG7. 【Figure 2NNN】 A diagram showing non-limiting examples of BRAF targeting ligands that target the V600E mutant of BRAF containing dabrafenib, where R represents an exemplary point to which a linker can be attached. 【Figure 2OOO】 A diagram showing non-limiting examples of LRRK2 targeting ligands that target the R1441C mutant of LRRK2, where R represents an exemplary point to which a linker can be attached. 【Figure 2PPP】 A diagram showing non-limiting examples of LRRK2 targeting ligands that target the G2019S mutant of LRRK2, where R represents an exemplary point to which a linker can be attached. 【Figure 2QQQ】 A diagram showing non-limiting examples of LRRK2 targeting ligands that target the I2020T mutant of LRRK2, where R represents an exemplary point to which a linker can be attached. 【Figure 2RRR-2TTT】 A diagram showing non-limiting examples of PDGFRα targeting ligands that target the T674I mutant of PDGFRα including AG-1478, CHEMBL94431, dovitinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, sorafenib, sunitinib, and WHI-P180, where R represents an exemplary point to which a linker can be attached. 【Figure 2UUU】 A diagram showing non-limiting examples of RET targeting ligands that target the G691S mutant of RET including tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2VVV】 A diagram showing non-limiting examples of RET targeting ligands that target the R749T mutant of RET including tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2WWW】A diagram showing non-limiting examples of RET-targeting ligands that target the E762Q mutant of RET containing tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2XXX】 A diagram showing non-limiting examples of RET-targeting ligands that target the Y791F mutant of RET containing tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2YYY】 A diagram showing non-limiting examples of RET-targeting ligands that target the V804M mutant of RET containing tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2ZZZ】 A diagram showing non-limiting examples of RET-targeting ligands that target the M918T mutant of RET containing tozasertib, where R represents an exemplary point to which a linker can be attached. 【Figure 2AAAA】 A diagram showing non-limiting examples of targeting ligands for fatty acid-binding proteins, where R represents an exemplary point to which a linker can be attached. 【Figure 2BBBB】 A diagram showing non-limiting examples of targeting ligands for 5-lipoxygenase activating protein (FLAP), where R represents an exemplary point to which a linker can be attached. 【Figure 2CCCC】 A diagram showing non-limiting examples of targeting ligands for kringle domain V 4BVV, where R represents an exemplary point to which a linker can be attached. 【Figure 2DDDD】 A diagram showing non-limiting examples of targeting ligands for lactoylglutathione lyase, where R represents an exemplary point to which a linker can be attached. 【Figure 2EEEE-2FFFF】 A diagram showing non-limiting examples of targeting ligands for mPGES-1, where R represents an exemplary point to which a linker can be attached. 【Figure 2GGGG-2JJJJ】Figure showing non-limiting examples of targetable ligands for factor Xa, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Maignan S. et al., "Crystal structures of human factor Xa complexed with potent inhibitors," J. Med. Chem. 43: 3226-3232 (2000); Matsusue T. et al., "Factor Xa Specific Inhibitor that Induces the Novel Binding Model in Complex with Human Fxa" (forthcoming); crystal structures PDB 1iqh, 1iqi, 1iqk, and 1iqm; Adler M. et al., "Crystal Structures of Two Potent Nonamidine Inhibitors Bound to Factor Xa," Biochemistry 41: 15514-15523 (2002); Roehrig S. et al., "Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-Oxo-3- [4-(3-Oxomorpholin-4-Yl)Phenyl]-1,3-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An Oral Direct Factor Xa Inhibitor," J. Med. Chem. 48: 5900 (2005); Anselm L. et al.See "Discovery of a Factor Xa Inhibitor (3R 4R)-1-(2 2-Difluoro-Ethyl)-Pyrrolidine-3 4-Dicarboxylic Acid 3-[(5-Chloro-Pyridin-2-Yl)-Amide] 4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a Clinical Candidate." Bioorg. Med. Chem. 20: 5313 (2010), and "Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 5 6 7-tetrahydro- 1H-pyrazolo[3 4-c]pyridine-3-carboxamide (Apixaban BMS-562247) a Highly Potent Selective Efficacious and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa." J. Med. Chem. 50: 5339-5356 (2007). 【Figure 2KKKK】Figure showing non-limiting examples of targeting ligands for kallikrein 7, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Maibaum J. et al., "Small-molecule factor D inhibitors targeting the alternative complement pathway," Nat. Chem. Biol. 12: 1105-1110 (2016). 【Figure 2LLLL-2MMMM】 Figure showing non-limiting examples of targeting ligands for cathepsin K, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Rankovic Z. et al., "Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors," Bioorg. Med. Chem. Lett. 20: 1524-1527 (2010), and Cai J. et al., "Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors," Bioorg. Med. Chem. Lett. 20: 6890-6894 (2010). 【Figure 2NNNN】Figure showing non-limiting examples of targeting ligands for cathepsin L, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see "Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors." by Kuhn B. et al., J. Med. Chem. 60: 2485-2497 (2017). 【Figure 2OOOO】 Figure showing non-limiting examples of targeting ligands for cathepsin S, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see "Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm" by Jadhav P.K. et al., ACS Med. Chem. Lett. 5: 1138-1142. (2014). 【Figure 2PPPP-2SSSS】Figure showing non-limiting examples of MTH1-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Kettle J.G. et al., "Potent and Selective Inhibitors of Mth1 Probe its Role in Cancer Cell Survival.", J. Med. Chem. 59: 2346 (2016); Huber K.V.M. et al., "Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.", Nature 508: 222 (2014); Gad H. et al., "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.", Nature 508: 215-221 (2014); Nissink J.W.M. et al., "Mth1 Substrate Recognition--an Example of Specific Promiscuity.", Plos One 11: 51154 (2016); and Manuel Ellermann et al., "Novel class of potent and selective inhibitors efface MTH1 as broad-spectrum cancer target.", AACR National Meeting Abstract 5226, 2017. 【Figure 2TTTT-2ZZZZ】Figure showing non-limiting examples of targeting ligands for MDM2 and / or MDM4, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Popowicz G.M. et al., "Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX / MDM2 antagonist drug discovery," Cell Cycle, 9 (2010); Miyazaki M. et al., "Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors," Bioorg. Med. Chem. 21: 4319-4331 (2013); Miyazaki M. et al., "Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor," Bioorg Med Chem. 23: 2360-7 (2015); Holzer P. et al., "Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors," J. Med. Chem.58: 6348-6358 (2015), "Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors." by Gonzalez-Lopez de Turiso F. et al., J. Med. Chem. 56: 4053-4070 (2013), "Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode." by Gessier F. et al., Bioorg. Med. Chem. Lett. 25: 3621-3625 (2015), "Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor." by Fry D.C. et al., ACS Med Chem Lett 4: 660-665 (2013), "Discovery of RG7388 a Potent and Selective p53-MDM2 Inhibitor in Clinical Development." by Ding Q. et al., J. Med. Chem. 56: 5979-5983 (2013), "SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression." by Wang S. et al.) See Cancer Res. 74: 5855-5865 (2014), Rew Y. et al., "Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction"; J. Med. Chem. 57: 10499-10511 (2014), Bogen S.L. et al., "Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable Potent and Efficacious HDM2-p53 Inhibitors"; ACS Med. Chem. Lett. 7: 324-329 (2016), and J. Med. Chem. 57: 1454-1472 (2014), Sun D. et al., "Discovery of AMG 232, a Potent, Selective and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development". 【Figure 2AAAAA-2EEEEE】Figure showing non-limiting examples of targeting ligands for PARP1, PARP2, and / or PARP3, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Iwashita A. et al., "Discovery of quinazolinone and quinoxaline derivatives as potent and selective poly(ADP-ribose) polymerase-1 / 2 inhibitors," Febs Lett. 579: 1389-1393 (2005), crystal structure PDB 2RCW (PARP complexed with A861695, Park C.H.), crystal structure PDB 2RD6 (PARP complexed with A861696, Park C.H.), crystal structure PDB 3GN7, Miyashiro J. et al., "Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)," Bioorg. Med. Chem. Lett. 19: 4050-4054 (2009), Gandhi V.B. et al., "Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer," Bioorg. Med. Chem. Lett. 20: 1023-1026 (2010), Penning T.D. et al."Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492) a highly potent and efficacious inhibitor." J. Med. Chem. 53: 3142-3153 (2010), Ye N. et al., "Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors." J. Med. Chem. 56: 2885-2903 (2013), Patel M.R. et al."Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors." J. Med. Chem. 57: 5579-5601 (2014), "Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors." J. Med. Chem. 60:1262-1271 (2012), crystal structure PDB 4RV6 ("Human ARTD1 (PARP1) catalytic domain in complex with inhibitor Rucaparib", Karlberg T. et al.), Papeo G.M.E. et al.See "Discovery of 2-[1-(4,4-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-2,3-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent Orally Available and Highly Selective Parp-1 Inhibitor for Cancer Therapy." J. Med. Chem. 58: 6875 (2015), "Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase." Febs Lett. 556: 43-46 (2004) by Kinoshita T. et al., and "Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors." Bioorg. Med. Chem. Lett. 23: 4501-4505 (2013) by Gangloff A.R. et al.. 【Figure 2FFFFF-2GGGGG】 FIG. showing non-limiting examples of targeting ligands for PARP14, where R represents an exemplary point to which a linker can be attached. 【Figure 2HHHHH】 FIG. showing non-limiting examples of targeting ligands for PARP15, where R represents an exemplary point to which a linker can be attached. 【Figure 2IIIII】It is a diagram showing non-limiting examples of targeting ligands for PDZ domains, where R represents an exemplary point to which a spacer (which may be plural) is attached. 【Figure 2JJJJJ】 It is a diagram showing non-limiting examples of targeting ligands for phospholipase A2 domains, where R represents an exemplary point to which a linker may be attached. 【Figure 2KKKKK】 It is a diagram showing non-limiting examples of targeting ligands for protein S100-A7 2WOS, where R represents an exemplary point to which a linker may be attached. 【Figure 2LLLLL-2MMMMM】 It is a diagram showing non-limiting examples of targeting ligands for saposin-B, where R represents an exemplary point to which a linker may be attached. 【Figure 2NNNNN-2OOOOO】 It is a diagram showing non-limiting examples of targeting ligands for Sec7, where R represents an exemplary point to which a linker may be attached. 【Figure 2PPPPP-2QQQQQ】 It is a diagram showing non-limiting examples of targeting ligands for the SH2 domain of pp60 Src, where R represents an exemplary point to which a linker may be attached. 【Figure 2RRRRR】 It is a diagram showing non-limiting examples of targeting ligands for Tank1, where R represents an exemplary point to which a linker may be attached. 【Figure 2SSSSS】 It is a diagram showing non-limiting examples of targeting ligands for Ubc9 SUMO E2 ligase SF6D, where R represents an exemplary point to which a linker may be attached. 【Figure 2TTTTT】 It is a diagram showing non-limiting examples of targeting ligands for Src including AP23464, where R represents an exemplary point to which a linker may be attached. 【Figure 2UUUUU-2XXXXX】 It is a diagram showing non-limiting examples of targeting ligands for Src-AS1 and / or Src AS2, where R represents an exemplary point to which a linker may be attached. 【Figure 2YYYYY】 It is a diagram showing non-limiting examples of targeting ligands for JAK3 including tofacitinib, where R represents an exemplary point to which a linker may be attached. 【Figure 2ZZZZZ】A diagram showing non-limiting examples of ABL-targeting ligands including tofacitinib and ponatinib, where R represents an exemplary point to which a linker can be attached. 【Figure 3A-3B】 A diagram showing non-limiting examples of MEK1-targeting ligands including PD318088, trametinib, and G-573, where R represents an exemplary point to which a linker can be attached. 【Figure 3C】 A diagram showing non-limiting examples of KIT-targeting ligands including regorafenib, where R represents an exemplary point to which a linker can be attached. 【Figure 3D-3E】 A diagram showing non-limiting examples of HIV reverse transcriptase-targeting ligands including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir, where R represents an exemplary point to which a linker can be attached. 【Figure 3F-3G】 A diagram showing non-limiting examples of HIV protease-targeting ligands including ritonavir, raltegravir, and atazanavir, where R represents an exemplary point to which a linker can be attached. 【Figure 3H-3I】 A diagram showing non-limiting examples of KSR1-targeting ligands, where R represents an exemplary point to which a linker can be attached. 【Figure 3J-3L】FIG. showing non-limiting examples of CTNNB1 targeting ligands, where R represents exemplary points to which a linker can be attached. (See "Direct Targeting of b-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt / b-Catenin Signaling", Cell Rep 2016, 16(1), 28; "Rational Design of Small-Molecule Inhibitors for β-Catenin / T-Cell Factor Protein-Protein Interactions by Bioisostere Replacement", ACS Chem Biol 2013, 8, 524; and "Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer", Sci Rep 2020, 10, 8096). 【Figure 3M】 FIG. showing non-limiting examples of BCL6 targeting ligands, where R represents exemplary points to which a linker can be attached. 【Figure 3N-3O】 FIG. showing non-limiting examples of PAK1 targeting ligands, where R represents exemplary points to which a linker can be attached. 【Figure 3P-3R】 FIG. showing non-limiting examples of PAK4 targeting ligands, where R represents exemplary points to which a linker can be attached. 【Figure 3S-3T】 FIG. showing non-limiting examples of TNIK targeting ligands, where R represents exemplary points to which a linker can be attached. 【Figure 3U】 It is a diagram showing non-limiting examples of a targeting ligand for MEN1, where R represents an exemplary point to which a linker can be attached. 【Figure 3V-3W】 It is a diagram showing non-limiting examples of a targeting ligand for ERK1, where R represents an exemplary point to which a linker can be attached. 【Figure 3X】 It is a diagram showing non-limiting examples of a targeting ligand for IDO1, where R represents an exemplary point to which a linker can be attached. 【Figure 3Y】 It is a diagram showing non-limiting examples of a targeting ligand for CBP, where R represents an exemplary point to which a linker can be attached. 【Figure 3Z-3SS】Figure showing non-limiting examples of MCL1-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see "Discovery of potent Mcl-1 / Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins." by Tanaka Y. et al., J. Med. Chem. 56: 9635-9645 (2013); "Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design." by Friberg A. et al., J. Med. Chem. 56: 15-30 (2013); "Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein." by Petros A. M. et al., Bioorg. Med. Chem. Lett. 24: 1484-1488 (2014); "Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design." by Burke J.P. et al., J. Med. Chem. 58: 3794-3805 (2015); Pelz N.F. et al."Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods." J. Med. Chem. 59: 2054-2066 (2016), "A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1." by Clifton M.C. et al., Plos One 10: e0125010-e0125010 (2015), "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models." by Kotschy A et al., Nature 538:477-482 (2016), European Patent Application Publication No. 2886545 entitled "New thienopyrimidine derivatives, a process for their preparation and pharmaceutical compositions containing them", "Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors" by Jeffrey W. Johannes et al., ACS Med. Chem. Lett. (2017); DOI: 10.1021 / acsmedchemlett.6b00464, Bruncko M. et al."Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity," J. Med. Chem. 58: 2180-2194 (2015); "Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors," FEBS Letters 591: 240-251 (2017); "Structure-Based Design of 3-Carboxy-Substituted 1,2,3,4-Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukemia-1 (Mcl-1)," Org. Biomol. Chem. 14:5505-5510 (2016); U.S. Patent Application Publication No. 2016 / 0068545, entitled "Tetrahydronaphthalene derivatives that inhibit mcl-1 protein"; International Publication No. 2016 / 207217, entitled "Preparation of new bicyclic derivatives as pro-apoptotic agents"; Gizem Akcay et al.See the article "Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain" Nature Chemical Biology 12: 931-936 (2016). 【Figure 3TT】 A diagram showing non-limiting examples of targeting ligands for ASH1L, where R represents an exemplary point to which a linker can be attached. See, for example, the crystal structure PDB 4YNM ("Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)" Rogawski D.S. et al.). 【Figure 3UU-3WW】FIG. showing non-limiting examples of ATAD2-targeting ligands, where R represents an exemplary point to which a linker can be attached.For additional examples and related ligands, see Chaikuad A. et al., "Structure-based approaches towards identification of fragments for the low-drugability ATAD2 bromodomain", Med Chem Comm 5: 1843-1848 (2014); Poncet-Montange G. et al., "Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.", Biochem. J. 466: 337-346 (2015); Harner M.J. et al., "Fragment-Based Screening of the Bromodomain of ATAD2.", J. Med. Chem. 57: 9687-9692 (2014); Demont E.H. et al., "Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors.", J. Med. Chem. 58: 5649 (2015); and Bamborough P. et al., "Structure-Based Optimization of Naphthyridones into Potent Atad2 Bromodomain Inhibitors.", J. Med. Chem. 58: 6151 (2015). 【Figure 3XX-3AAA】Figure showing non-limiting examples of targeting ligands for BAZ2A and BAZ2B, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 4CUU ("Human Baz2B in Complex with Fragment-6 N09645" Bradley A. et al.), crystal structure PDB 5CUA ("Second Bromodomain of Bromodomain Adjacent to Zinc Finger Domain Protein 2B (BAZ2B) in complex with 1-Acetyl-4-(4-hydroxyphenyl)piperazine." Bradley A. et al.), "Targeting low-drugability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain." by Ferguson F.M. et al., J. Med. Chem. 56: 10183-10187 (2013), "Derivatives of 3-Amino-2-methylpyridine as BAZ2B Bromodomain Ligands: In Silico Discovery and in Crystallo Validation." by Marchand J.R. et al., J. Med. Chem. 59: 9919-9927 (2016), Drouin L. et al.See the following: "Structure Enabled Design of BAZ2-ICR A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B." J. Med. Chem. 58: 2553-2559 (2015); and "Discovery and characterization of GSK2801 a selective chemical probe for the bromodomains BAZ2A and BAZ2B." J. Med. Chem. 59:1410-1424 (2016), by Chen P. et al. 【Figure 3BBB】FIG. showing non-limiting examples of BRD1-targeting ligands, where R represents exemplary points to which a linker can be attached.For additional examples and related ligands, see the crystal structure PDB 5AME ("the Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment 4-Acetyl-Piperazin-2-One", Pearce, N.M. et al.), the crystal structure PDB 5AMF ("Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment Ethyl 4 5 6 7-Tetrahydro-1H-Indazole-5-Carboxylate", Pearce N.M. et al.), the crystal structure PDB 5FG6 ("the Crystal structure of the bromodomain of human BRD1 (BRPF2) in complex with OF-1 chemical probe.", Tallant C. et al.), and Filippakopoulos P. et al., "Histone recognition and large-scale structural analysis of the human bromodomain family.", Cell, 149: 214-231 (2012). 【Figure 3CCC-3EEE】Figure showing non-limiting examples of targeting ligands for the BRD2 bromodomain 1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 2ydw, crystal structure PDB 2yek, crystal structure PDB 4a9h, crystal structure PDB 4a9f, crystal structure PDB 4a9i, crystal structure PDB 4a9m, crystal structure PDB 4akn, crystal structure PDB 4alg, and crystal structure PDB 4uyf. 【Figure 3FFF-3HHH】Figure showing non-limiting examples of targeting ligands for BRD2 bromodomain 2, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 3oni, "Selective Inhibition of BET Bromodomains" by Filippakopoulos P. et al., Nature 468: 1067-1073 (2010); crystal structure PDB 4j1p, "RVX-208: an Inducer of ApoA-I in Humans is a BET Bromodomain Antagonist" by McLure K.G. et al., Plos One 8: e83190-e83190 (2013); "Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes" by Baud M.G. et al., Science 346: 638-641 (2014); "New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition" by Baud M.G. et al., J. Med. Chem. 59: 1492-1500 (2016); Gosmini R. et al.See “The Discovery of I-Bet726 (Gsk1324726A) a Potent Tetrahydroquinoline Apoa1 Up-Regulator and Selective Bet Bromodomain Inhibitor,” J. Med. Chem. 57: 8111 (2014); Crystal Structure PDB 5EK9, “Crystal structure of the second bromodomain of human BRD2 in complex with a hydroquinolinone inhibitor,” Tallant C. et al; Crystal Structure PDB 5BT5; Crystal Structure PDB 5dfd; and “New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition,” Baud M.G. et al., J. Med. Chem. 59: 1492-1500 (2016). 【Figure 3 III-3 JJJ】 FIG. showing non-limiting examples of targeting ligands for BRD4 bromodomain 1, where R represents an exemplary point to which a linker can be attached. See Crystal Structure PDB 5WUU and Crystal Structure PDB 5F5Z for additional examples and related ligands. 【Figure 3 KKK-3 LLL】Figure showing non-limiting examples of targeting ligands for BRD4 bromodomain 2, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see "Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains" by Chung C.W. et al., J. Med. Chem. 54: 3827 (2011), and "Structure-Based Design of gamma-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors" by Ran X. et al., J. Med. Chem. 58: 4927-4939 (2015). 【Figure 3 MMM】 Figure showing non-limiting examples of targeting ligands for BRDT, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 4flp and crystal structure PDB 4kcx. 【Figure 3 NNN-3 QQQ】 Figure showing non-limiting examples of targeting ligands for BRD9, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 4nqn, PDB 4uit, PDB 4uiu, PDB 4uiv, PDB 4z6h, PDB 4z6i, PDB 5e9v, PDB 5eu1, PDB 5f1h, PDB 5fp2 ("Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor", J Med Chem., 2016, 59(10), 4462, and International Publication No. WO 2016 / 139361). 【Figure 3 RRR】 FIG. showing non-limiting examples of targeting ligands for SMARCA4 PB1 and / or SMARCA2, where R represents an exemplary point to which a linker can be attached, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. 【Figure 3 SSS-3 XXX】 FIG. showing non-limiting examples of targeting ligands for additional bromodomains, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see “3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands.” by Hewings et al., J. Med. Chem. 54, 6761-6770 (2011), “Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia.” by Dawson et al., Nature, 478, 529-533 (2011), U.S. Patent Application Publication No. 2015 / 0256700, U.S. Patent Application Publication No. 2015 / 0148342, International Publication No. 2015 / 074064, International Publication No. 2015 / 067770, International Publication No. 2015 / 022332, International Publication No. 2015 / 015318, and International Publication No. 2015 / 011084. 【Figure 3 YYY】 FIG. showing non-limiting examples of targeting ligands for PB1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 3mb4, crystal structure PDB 4q0n, and crystal structure PDB 5fh6. 【Figure 3 ZZZ】A diagram showing non-limiting examples of SMARCA4-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure 3uvd and crystal structure 5dkd. 【Figure 3 AAAA】 A diagram showing non-limiting examples of SMARCA2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure 5dkc and crystal structure 5dkh, as well as International Publication No. WO 2020 / 023657, U.S. Patent Application Publication No. 2020 / 0038378, International Publication No. WO 2020 / 010227, International Publication No. WO 2020 / 078933, International Publication No. WO 2019 / 207538, International Publication No. WO 2016 / 138114, International Publication No. WO 2020 / 035779, and "Discovery of Orally Active Inhibitors of Brahma Homolog (BRM) / SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1) / SMARCA4-Mutant Cancers", J Med Chem 2018, 61, 10155. 【Figure 3 BBBB】 A diagram showing non-limiting examples of TRIM24 (TIF1a)- and / or BRPF1-targeting ligands, where R represents an exemplary point to which a linker can be attached and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. 【Figure 3 CCCC】Figure showing non-limiting examples of targeting ligands for TRIM24 (TIF1a), where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see Palmer W.S. et al., "Structure-Guided Design of IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor," J. Med. Chem. 59: 1440-1454 (2016). 【Figure 3 DDDD-3 FFFF】 Figure showing non-limiting examples of targeting ligands for BRPF1, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see crystal structures PDB 4uye, PDB 5c7n, PDB 5c87, PDB 5c89, PDB 5d7x, PDB 5dya, PDB 5epr, PDB 5eq1, PDB 5etb, PDB 5ev9, PDB 5eva, PDB 5ewv, PDB 5eww, PDB 5ffy, PDB 5fg5, and PDB 5g4r. 【Figure 3 GGGG】 Figure showing non-limiting examples of targeting ligands for CECR2, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see Moustakim M. et al., Med. Chem. Comm. 7:2246-2264 (2016), and Crawford T. et al., Journal of Med. Chem. 59; 5391-5402 (2016). 【Figure 3 HHHH-3 OOOO】A diagram showing non-limiting examples of CREBBP-targeting ligands, where R represents an exemplary point to which a linker can be attached, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For additional examples and related ligands, see crystal structures PDB 3p1d, crystal structure PDB 3svh, crystal structure PDB 4nr4, crystal structure PDB 4nr5, crystal structure PDB 4ts8, crystal structure PDB 4nr6, crystal structure PDB 4nr7, crystal structure PDB 4nyw, crystal structure PDB 4nyx, crystal structure PDB 4tqn, crystal structure PDB 5cgp, crystal structure PDB 5dbm, crystal structure PDB 5ep7, crystal structure PDB 5i83, crystal structure PDB 5i86, crystal structure PDB 5i89, crystal structure PDB 5i8g, crystal structure PDB 5j0d, crystal structure PDB 5ktu, crystal structure PDB 5ktw, crystal structure PDB 5ktx, crystal structure PDB 5tb6. 【Figure 3 PPPP】 A diagram showing non-limiting examples of EP300-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 5BT3. 【Figure 3 QQQQ】 A diagram showing non-limiting examples of PCAF-targeting ligands, where R represents an exemplary point to which a linker can be attached. See, for example, M. Ghizzoni et al. Bioorg. Med. Chem. 18: 5826-5834 (2010). 【Figure 3 RRRR】 A diagram showing non-limiting examples of PHIP-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Mol Cancer Ther. 7(9): 2621-2632 (2008). 【Figure 3 SSSS】 A diagram showing non-limiting examples of TAF1- and TAF1L-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Picaud S. et al. Sci Adv 2: e1600760-e1600760 (2016). 【Figure 3 TTTT】 Figure showing non-limiting examples of targeted ligands for histone deacetylase 2 (HDAC2), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lauffer B. E. J. Biol. Chem. 288: 26926-26943 (2013), Wagner F. F. Bioorg. Med. Chem. 24: 4008-4015 (2016), Bressi J. C. Bioorg. Med. Chem. Lett. 20: 3142-3145 (2010), and Lauffer B. E. J. Biol. Chem. 288: 26926-26943 (2013). 【Figure 3 UUUU-3 VVVV】 Figure showing non-limiting examples of targeted ligands for histone deacetylase 4 (HDAC4), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Burli R. W. J. Med. Chem. 56: 9934 (2013), Luckhurst C. A. ACS Med. Chem. Lett. 7: 34 (2016), Bottomley M. J. J. Biol. Chem. 283: 26694-26704 (2008). 【Figure 3 WWWW】 Figure showing non-limiting examples of targeted ligands for histone deacetylase 6, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Harding R. J. (forthcoming), Hai Y. Nat. Chem. Biol. 12: 741-747, (2016), and Miyake Y. Nat. Chem. Biol. 12: 748 (2016). 【Figure 3 XXXX-3 YYYY】Figure showing non-limiting examples of targeting ligands for histone deacetylase 7, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lobera M. Nat. Chem. Biol. 9: 319 (2013), and Schuetz A. J. Biol. Chem. 283: 11355-11363 (2008). 【Figure 3 ZZZZ-3 DDDDD】 Figure showing non-limiting examples of targeting ligands for histone deacetylase 8, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Whitehead L. Biol. Med. Chem. 19: 4626-4634 (2011), Tabackman A. A. J. Struct. Biol. 195: 373-378 (2016), Dowling D. P. Biochemistry 47, 13554-13563 (2008), Somoza J. R. Biochemistry 12, 1325-1334 (2004), Decroos C. Biochemistry 54: 2126-2135 (2015), Vannini A. Proc. Natl Acad. Sci. 101: 15064 (2004), Vannini A. EMBO Rep. 8: 879 (2007), crystal structure PDB 5BWZ, Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014), Somoza J. R. Biochemistry 12: 1325-1334 (2004), Decroos C. Biochemistry 54: 6501-6513 (2015), Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014), and Dowling D. P. Biochemistry 47: 13554-13563 (2008). 【Figure 3 EEEEE】Figure showing non-limiting examples of targeting ligands for histone acetyltransferase (KAT2B), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Chaikuad A. J. Med. Chem. 59: 1648-1653 (2016), crystal structure PDB 1ZS5, and Zeng L. J. Am. Chem. Soc. 127: 2376-2377 (2005). 【Figure 3 FFFFF-3 GGGGG】 Figure showing non-limiting examples of targeting ligands for histone acetyltransferase (KAT2A), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Ringel A. E. Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016). 【Figure 3 HHHHH】 Figure showing non-limiting examples of targeting ligands for the B-type histone acetyltransferase catalytic unit (HAT1), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 2P0W. 【Figure 3 IIIII】 Figure showing non-limiting examples of targeting ligands for the cyclic AMP-dependent transcription factor (ATF2), where R represents an exemplary point to which a linker can be attached. 【Figure 3 JJJJJ】 Figure showing non-limiting examples of targeting ligands for histone acetyltransferase (KAT5), where R represents an exemplary point to which a linker can be attached. 【Figure 3 KKKKK-3 MMMMM】Figure showing non-limiting examples of targeting ligands for lysine-specific histone demethylase 1A (KDM1A), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Mimasu S. Biochemistry 49: 6494-6503 (2010), Sartori L. J. Med. Chem. 60: 1673-1693 (2017), and Vianello P. J. Med. Chem. 60: 1693-1715 (2017). 【Figure 3 NNNNN】 Figure showing non-limiting examples of targeting ligands for the HDAC6 Zn finger domain, where R represents an exemplary point to which a linker can be attached. 【Figure 3 OOOOO-3 PPPPP】 Figure showing non-limiting examples of targeting ligands for general lysine methyltransferases, where R represents an exemplary point to which a linker can be attached. 【Figure 3 QQQQQ-3 TTTTT】Figure showing non-limiting examples of DOT1L-targeting ligands, where R represents an exemplary point to which a linker can be attached, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For additional examples and related ligands, see crystal structure PDB 5MVS (“Dot1L in complex with adenosine and inhibitor CPD1” Mobitz, H. et al., ACS Med Chem Lett., 2017, 8: 338-343), crystal structures PDB 5MW3, 5MW4 (“Dot1L in complex inhibitor CPD7” Be C. et al.), crystal structure PDB 5DRT (“Dot1L in complex inhibitor CPD2” Chen, C., et al., ACS Med Chem Lett., 2016, 7: 735-740), crystal structure PDB 5DRY (“Dot1L in complex with CPD3”, Chen, C., et al., ACS Med Chem Lett., 2016, 7: 735-740), crystal structure of PDB 5DSX (“Dot1L in complex with CPD10”, Chen, C., et al., ACS Med Chem Lett., 2016, 7: 735-740), crystal structure PDB 5DT2 (“Dot1L in complex with CPD11”, Chen, C., et al., ACS Med Chem Lett., 2016, 7: 735-740), crystal structure PDB 5JUW (“Dot1L in complex with SS148” Yu W. et al.See the Structural Genomics Consortium and the crystal structure PDB 6TE6 ("Dot1L in complex with an inhibitor, compound 3", Stauffer, F., et al., ACS Med Chem Lett., 2019, 10: 1655-1660). 【Figure 3 UUUUU】 Figure showing non-limiting examples of targeting ligands for EHMT1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 5TUZ ("EHMT1 in complex with inhibitor MS0124", Babault N. et al.). 【Figure 3 VVVVV】 Figure showing non-limiting examples of targeting ligands for EHMT2, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 5TUY ("EHMT2 in complex with inhibitor MS0124", Babault N. et al.), PDB crystal structure 5TTF ("EHMT2 in complex with inhibitor MS012", Dong A. et al.), PDB crystal structure 3RJW (Dong A. et al., Structural Genomics Consortium), PDB crystal structure 3K5K (Liu F. et al. J. Med. Chem. 52: 7950-7953 (2009)), and PDB crystal structure 4NVQ ("EHMT2 in complex with inhibitor A-366", Sweis R.F. et al.). 【Figure 3 WWWWW】A diagram showing non-limiting examples of SETD2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 5LSY ("SETD2 in complex with cyproheptadine", Tisi D. et al.), Tisi D. et al. ACS Chem. Biol. 11: 3093-3105 (2016), crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6, 5LT7, and 5LT8, PDB crystal structure 4FMU, and Zheng W. et al. J. Am. Chem. Soc. 134: 18004-18014 (2012). 【Figure 3 XXXXX-3 YYYYY】 A diagram showing non-limiting examples of SETD7-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 5AYF ("SETD7 in complex with cyproheptadine.", Niwa H. et al.), PDB crystal structure 4JLG ("SETD7 in complex with (R)-PFI-2", Dong A. et al.), PDB crystal structure 4JDS (Dong A. et. al Structural Genomics Consortium), PDB crystal structure 4E47 (Walker J.R. et al. Structural Genomics Consortium), PDB crystal structure 3VUZ ("SETD7 in complex with AAM-1.", Niwa H. et al.), PDB crystal structure 3VVO, and Niwa H et al. Acta Crystallogr. Sect.D 69: 595-602 (2013). 【Figure 3 ZZZZZ】Figure showing non-limiting examples of SETD8 targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5TH7 ("SETD8 in complex with MS453", Yu W. et al.), and PDB crystal structure 5T5G (Yu W et. al., scheduled for publication). 【Figure 4 A-4 B】 Figure showing non-limiting examples of SETDB1 targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5KE2 ("SETDB1 in complex with inhibitor XST06472A", Iqbal A. et al.), PDB crystal structure 5KE3 ("SETDB1 in complex with fragment MRT0181a", Iqbal A. et al.), PDB crystal structure 5KH6 ("SETDB1 in complex with fragment methyl 3-(methylsulfonylamino)benzoate", Walker J.R. et al. Structural Genomics Consortium), and PDB crystal structure 5KCO ("SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide", Walker J.R. et al.). 【Figure 4 C-4 P】Figure showing non-limiting examples of SMYD2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5KJK ("SMYD2 in complex with inhibitor AZ13450370", Cowen S.D. et al.), PDB crystal structure 5KJM ("SMYD2 in complex with AZ931", Cowen S.D. et al.), PDB crystal structure 5KJN ("SMYD2 in complex with AZ506", Cowen S.D. et al.), PDB crystal structure 5ARF ("SMYD2 in complex with N-[3-(4-chlorophenyl)-1-{N'-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-4,5-dihydro-1H-pyrazol-4-YL]-N-ethyl-2-hydroxyacetamide", Eggert E. et al.), PDB crystal structure 5ARG ("SMYD2 in complex with BAY598", Eggert E. et al.), PDB crystal structure 4YND ("SMYD2 in complex with A-893", Sweis R.F. et al.), PDB crystal structure 4WUY ("SMYD2 in complex with LLY-507", Nguyen H. et al.) and the PDB crystal structure 3S7B (N-cyclohexyl-N~3~-[2-(3,4-dichlorophenyl)ethyl]-N-(2-{[2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide, Ferguson A.D. et al.). See also. 【Figure 4 Q-4 R】 Figure showing non-limiting examples of SMYD3-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure 5H17 (SMYD3 in complex with 5'-{[(3S)-3-amino-3-carboxypropyl][3-(dimethylamino)propyl]amino}-5'-deoxyadenosine, Van Aller G.S. et al.), crystal structure 5CCL (SMYD3 in complex with oxindole compound, Mitchell L.H. et al.), and crystal structure 5CCM (Crystal structure of SMYD3 with SAM and EPZ030456). 【Figure 4 S】Figure showing non-limiting examples of targeting ligands for SUV4-20H1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5CPR ("SUV4-20H1 in complex with inhibitor A-196", Bromberg K.D. et al.). 【Figure 4 T-4 AA】Figure showing non-limiting examples of targeted ligands for wild-type androgen receptor, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 5T8E and 5T8J ("Androgen Receptor in complex with 4-(pyrrolidin-1-yl)benzonitrile derivatives", Asano M. et al.), Asano M. et al. Bioorg. Med. Chem. Lett. 27: 1897-1901 (2017), PDB crystal structure 5JJM ("Androgen Receptor", Nadal M. et al.), PDB crystal structure 5CJ6 ("Androgen Receptor in complex with 2-Chloro-4-[[(1R 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile derivatives", Saeed A. et al.), PDB crystal structure 4QL8 ("Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolines derivatives", Ullrich T. et al.), PDB crystal structure 4HLW ("Androgen Receptor Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening", Munuganti R.S. et al.) PDB crystal structure 3V49 ("Androgen Receptor lbd with activator peptide and sarm inhibitor 1", Nique F. et al.), Nique F. et al. J. Med. Chem. 55: 8225 - 8235 (2012), PDB crystal structure 2YHD ("Androgen Receptor in complex with AF2 small molecule inhibitor", Axerio-Cilies P. et al.), PDB crystal structure 3RLJ ("Androgen Receptor ligand binding domain in complex with SARM S-22", Bohl C.E. et al.), Bohl C.E. et al. J. Med. Chem. 54: 3973 - 3976 (2011), PDB crystal structure 3B5R ("Androgen Receptor ligand binding domain in complex with SARM C-31", Bohl C.E. et al.), Bohl C.E. et al. Bioorg. Med. Chem. Lett.18: 5567 - 5570 (2008), PDB crystal structure 2PIP ("Androgen Receptor ligand binding domain in complex with small molecule", Estebanez-Perpina E. et al.), Estebanez-Perpina. E. Proc. Natl. Acad. Sci.See 104:16074-16079 (2007), PDB crystal structure 2PNU ("Androgen Receptor ligand binding domain in complex with EM5744", Cantin L. et al.), and PDB crystal structure 2HVC ("Androgen Receptor ligand binding domain in complex with LGD2226", Wang F. et al.). For additional related ligands, see "Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor (Ar(Ccr)) Derived from an Androgen-Independent Prostate Cancer." by Matias P.M. et al., J. Med. Chem. 45: 1439 (2002), "Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone." by Sack J.S. et al., Proc. Natl. Acad. Sci. 98: 4904-4909 (2001), He B. et al."Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance." Mol. Cell 16: 425-438 (2004), by Pereira de Jesus-Tran K.; "Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity." Protein Sci. 15: 987-999 (2006), by Bohl C.E. et al.; "Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor." Mol Pharmacol. 63(1):211-23 (2003), by Bohl C.E. et al.; "Discovery of potent orally-active and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold." J. Med. Chem., by Sun C. et al.49: 7596-7599 (2006), "N-aryl-oxazolidin-2-imine muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation." by Nirschl A.A. et al., J. Med. Chem. 52: 2794-2798 (2009); "Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators." by Bohl C.E. et al., Bioorg. Med. Chem. Lett. 18: 5567-5570 (2008); "3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration." by Ullrich T. et al., J. Med. Chem. 57: 7396-7411 (2014), Saeed A. et al.See the book "2-Chloro-4-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy." J. Med. Chem. 59: 750-755 (2016), "Discovery of diarylhydantoins as new selective androgen receptor modulators." J. Med. Chem. 55: 8225-8235 (2012) by Nique et al., and "Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC)." J. Med. Chem. 53: 2779-2796 (2010) by Michael E. Jung et al.. 【Figure 4 BB】Figure showing non-limiting examples of targeted ligands for the mutant T877A androgen receptor, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4OGH ("Androgen Receptor T877A-AR-LBD", Hsu C.L. et al.), and PDB crystal structure 2OZ7 ("Androgen Receptor T877A-AR-LBD", Bohl C.E. et al.). 【Figure 4 CC】 Figure showing non-limiting examples of targeted ligands for the mutant W741L androgen receptor, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4OJB ("Androgen Receptor T877A-AR-LBD", Hsu C.L. et al.). 【Figure 4 DD-4 EE】 Figure showing non-limiting examples of targeted ligands for estrogen and / or androgen, where R represents an exemplary point to which a linker can be attached. 【Figure 5 A】 Figure showing a non-limiting example of afatinib, a targeted ligand for the EGFR and ErbB2 / 4 receptors. R represents an exemplary point to which a linker can be attached. 【Figure 5 B】 Figure showing a non-limiting example of axitinib, a targeted ligand for the VEGFR1 / 2 / 3 receptors, the PDGFRβ receptor, and the Kit receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 C-5 D】 Figure showing a non-limiting example of bosutinib, a targeted ligand for the BCR-Abl receptor, the Src receptor, the Lyn receptor, and the Hck receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 E】Figure showing non-limiting examples of cabozantinib, a targeting ligand for the RET receptor, c-Met receptor, VEGFR1 / 2 / 3 receptors, Kit receptor, TrkB receptor, Flt3 receptor, Axl receptor, and Tie2 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 F】 Figure showing non-limiting examples of ceritinib, a targeting ligand for the ALK receptor, IGF-1R receptor, InsR receptor, and ROS1 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 G】 Figure showing non-limiting examples of crizotinib, a targeting ligand for the ALK receptor, c-Met receptor, HGFR receptor, ROS1 receptor, and MST1R receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 H】 Figure showing non-limiting examples of dabrafenib, a targeting ligand for the B-Raf receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 I】 Figure showing non-limiting examples of dasatinib, a targeting ligand for the BCR-Abl receptor, Src receptor, Lck receptor, Lyn receptor, Yes receptor, Fyn receptor, Kit receptor, EphA2 receptor, and PDGFRβ receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 J】 Figure showing non-limiting examples of erlotinib, a targeting ligand for the EGFR receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 K-5 M】 Figure showing non-limiting examples of everolimus, a targeting ligand for the HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 N】 Figure showing non-limiting examples of gefitinib, a targeting ligand for the EGFR receptor and PDGFR receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 O】Figure showing a non-limiting example of ibrutinib, a targeted ligand for the BTK receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 P-5 Q】 Figure showing a non-limiting example of imatinib, a targeted ligand for the BCR-Abl receptor, Kit receptor, and PDGFR receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 R-5 S】 Figure showing a non-limiting example of lapatinib, a targeted ligand for the EGFR receptor and ErbB2 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 T】 Figure showing a non-limiting example of lenvatinib, a targeted ligand for the VEGFR1 / 2 / 3 receptors, FGFR1 / 2 / 3 / 4 receptors, PDGFRα receptor, Kit receptor, and RET receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 U-5 V】 Figure showing a non-limiting example of nilotinib, a targeted ligand for the BCR-Abl receptor, PDGRF receptor, and DDR1 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 W-5 X】 Figure showing a non-limiting example of nintedanib, a targeted ligand for the FGFR1 / 2 / 3 receptors, Flt3 receptor, Lck receptor, PDGFRα / β receptors, and VEGFR1 / 2 / 3 receptors. R represents an exemplary point to which a linker can be attached. 【Figure 5 Y-5 Z】 Figure showing a non-limiting example of palbociclib, a targeted ligand for the CDK4 / 6 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 AA】 Figure showing a non-limiting example of pazopanib, a targeted ligand for the VEGFR1 / 2 / 3 receptors, PDGFRα / β receptors, FGFR1 / 3 receptors, Kit receptor, Lck receptor, Fms receptor, and Itk receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 BB-5 CC】Figure showing non-limiting examples of ponatinib, a targeted ligand for the BCR-Abl receptor, the T315I VEGFR receptor, the PDGFR receptor, the FGFR receptor, the EphR receptor, the Src family kinase receptor, the Kit receptor, the RET receptor, the Tie2 receptor, and the Flt3 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 DD】 Figure showing non-limiting examples of regorafenib, a targeted ligand for VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα / β, RET, FGFR1 / 2, Tie2, and Eph2A. R represents an exemplary point to which a linker can be attached. 【Figure 5 EE】 Figure showing non-limiting examples of ruxolitinib, a targeted ligand for the JAK1 / 2 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 FF-5 GG】 Figure showing non-limiting examples of sirolimus, a targeted ligand for the FKBP12 / mTOR receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 HH】 Figure showing non-limiting examples of sorafenib, a targeted ligand for the B-Raf receptor, the CDK8 receptor, the Kit receptor, the Flt3 receptor, the RET receptor, the VEGFR1 / 2 / 3 receptor, and the PDGFR receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 II-5 JJ】 Figure showing non-limiting examples of sunitinib, a targeted ligand for PDGFRα / β, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, RET. R represents an exemplary point to which a linker can be attached. 【Figure 5 KK-5 LL】 Figure showing non-limiting examples of temsirolimus, a targeted ligand for FKBP12 / mTOR. R represents an exemplary point to which a linker can be attached. 【Figure 5 MM】 Figure showing non-limiting examples of tofacitinib, a targeted ligand for the JAK3 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 NN】 Figure showing a non-limiting example of trametinib, a targeted ligand for the MEK1 / 2 receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 OO-5 PP】 Figure showing a non-limiting example of vandetanib, a targeted ligand for EGFR, VEGFR, RET, Tie2, Brk, and EphR. R represents an exemplary point to which a linker can be attached. 【Figure 5 QQ】 Figure showing a non-limiting example of vemurafenib, a targeted ligand for the A / B / C-Raf receptor, KSR1 receptor, and B-Raf(V600E) receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 RR】 Figure showing a non-limiting example of Idelasib, a targeted ligand for the PI3Ka receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 SS】 Figure showing a non-limiting example of buparlisib, a targeted ligand for the PI3Ka receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 TT】 Figure showing a non-limiting example of taselisib, a targeted ligand for the PI3Ka receptor. R represents an exemplary point to which a linker can be attached. 【Figure 5 UU】 Figure showing a non-limiting example of copanlisib, a targeted ligand for PI3Ka. R represents an exemplary point to which a linker can be attached. 【Figure 5 VV】 Figure showing a non-limiting example of alpelisib, a targeted ligand for PI3Ka. R represents an exemplary point to which a linker can be attached. 【Figure 5 WW】 Figure showing a non-limiting example of niclosamide, a targeted ligand for CNNTB1. R represents an exemplary point to which a linker can be attached. 【Figure 6 A-6 B】Figure showing non-limiting examples of targeted ligands of the BRD4 bromodomains of PCAF and GCN5 receptors 1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5tpx ("Discovery of a PCAF Bromodomain Chemical Probe"), Moustakim, M., et al. Angew. Chem. Int. Ed. Engl. 56: 827 (2017), PDB crystal structure 5mlj ("Discovery of a Potent, Cell Penetrant, and Selective p300 / CBP-Associated Factor (PCAF) / General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe"), and Humphreys, P. G. et al. J. Med. Chem. 60: 695 (2017). 【Figure 6 C-6 D】FIG. showing non-limiting examples of targeting ligands for G9a (EHMT2), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 3k5k, (Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a), Liu, F. et al. J. Med. Chem. 52: 7950 (2009), PDB crystal structure 3rjw (A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells), Vedadi, M. et al. Nat. Chem. Biol. 7: 566 (2011), PDB crystal structure 4nvq (Discovery and development of potent and selective inhibitors of histone methyltransferase g9a), and Sweis, R.F. et al. ACS Med Chem Lett 5: 205 (2014). 【Figure 6 E-6 G】Figure showing non-limiting examples of EZH2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 5ij8 (“Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance”, Brooun, A. et al. Nat Commun 7: 11384 (2016)), PDB crystal structure 5ls6 (“Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas)”, Vaswani, R.G. et al. J. Med. Chem. 59: 9928 (2016)), and refer to PDB crystal structures 5ij8 and 5ls6. 【Figure 6 H-6 I】Figure showing non-limiting examples of EED-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 5h15 and 5h19 (“Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED”), Li, L. et al. PLoS ONE 12: e0169855 (2017), and PDB crystal structure 5h19. 【Figure 6 J】 Figure showing non-limiting examples of KMT5A (SETD8)-targeting ligands, where R represents exemplary points to which a linker can be attached. See, for example, PDB crystal structure 5t5g. 【Figure 6 K-6 L】Figure showing non-limiting examples of DOT1L-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 4eki ("Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L", Basavapathruni, A. et al. Chem. Biol. Drug Des. 80: 971 (2012)), PDB crystal structure 4hra ("Potent inhibition of DOT1L as treatment of MLL-fusion leukemia", Daigle, S.R. et al. Blood 122: 1017 (2013)), PDB crystal structure 5dry ("Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach", Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016)), PDB crystal structure 5dt2 ("Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach", Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016)), and Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016). 【Figure 6 M-6 N】Figure showing non-limiting examples of targeting ligands for PRMT3, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 3smq ("An allosteric inhibitor of protein arginine methyltransferase 3"), Siarheyeva, A. et al. Structure 20: 1425 (2012), PDB crystal structure 4ryl ("A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)"), and Kaniskan, H.U. et al. Angew. Chem. Int. Ed. Engl. 54: 5166 (2015). 【Figure 6 O】 Figure showing non-limiting examples of targeting ligands for CARM1 (PRMT4), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 2y1x and 2y1w and related ligands described in "Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors.", Sack, J.S. et al. Biochem. J. 436: 331 (2011). 【Figure 6 P】Figure showing non-limiting examples of PRMT5 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4x61 and related ligands described in "A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models." Chan-Penebre, E. Nat. Chem. Biol. 11: 432 (2015). 【Figure 6 Q】 Figure showing non-limiting examples of PRMT6 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4y30 and related ligands described in "Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound." Mitchell, L.H. et al. ACS Med. Chem. Lett. 6: 655 (2015). 【Figure 6 R】Figure showing non-limiting examples of LSD1 (KDM1A)-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5lgu and related ligands described in "Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A / LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship." Vianello, P. et al. J. Med. Chem. 60: 1693 (2017). 【Figure 6 S-6 T】Figure showing non-limiting examples of KDM4-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 3rvh, "Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors," Korczynska, M., et al. J. Med. Chem. 59: 1580 (2016), PDB crystal structure 5a7p and related ligands described therein, and PDB crystal structure 3f3c and related ligands described in "8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors," Bavetsias, V. et al. J. Med. Chem. 59: 1388 (2016). 【Figure 6 U】Figure showing non-limiting examples of targeted ligands for KDM5, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 3fun and related ligands described in "Structural Analysis of Human Kdm5B Guides Histone Demethylase Inhibitor Development." Johansson, C. et al. Nat. Chem. Biol. 12: 539 (2016), and PDB crystal structure 5ceh and related ligands described in "An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells." Vinogradova, M. et al. Nat. Chem. Biol. 12: 531 (2016). 【Figure 6 V-6 W】 Figure showing non-limiting examples of targeted ligands for KDM6, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4ask and related ligands described in "A Selective Jumonji H3K27 Demethylase Inhibitor Modulates the Proinflammatory Macrophage Response." Kruidenier, L. et al. Nature 488: 404 (2012). 【Figure 6 X】 Figure showing non-limiting examples of targeted ligands for L3MBTL3, where R represents exemplary points to which a linker can be attached. See, for example, PDB crystal structure 4fl6. 【Figure 6 Y】Figure showing non-limiting examples of menin-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see PDB crystal structures 4x5y and related ligands described in "Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo" Borkin, D. et al. Cancer Cell 27: 589 (2015), and PDB crystal structure 4og8 and related ligands described in "High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction" He, S. et al. J. Med. Chem. 57: 1543 (2014). 【Figure 6 Z-6 AA】 Figure showing non-limiting examples of HDAC6-targeting ligands, where R represents exemplary points to which a linker can be attached. See, for example, PDB crystal structures 5kh3 and 5eei. 【Figure 6 BB】Figure showing non-limiting examples of HDAC7-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the PDB crystal structure 3c10 and related ligands described in "Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity." Schuetz, A. et al. J. Biol. Chem. 283: 11355 (2008), and the PDB crystal structure PDB 3zns and related ligands described in "Selective Class Iia Histone Deacetylase Inhibition Via a Non-Chelating Zinc Binding Group." Lobera, M. et al. Nat. Chem. Biol. 9: 319 (2013). 【Figure 7 A-7 C】Figure showing non-limiting examples of targeting ligands for the non-receptor type 1 protein tyrosine phosphatase PTP1B, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the PDB crystal structure 1bzj described in "Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics", Groves, M.R. et al. Biochemistry 37: 17773-17783 (1998), the PDB crystal structure 3cwe described in "Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor.", Han Y, Bioorg Med Chem Lett. 18:3200-5 (2008), the PDB crystal structures 2azr and 2b07 described in "Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors.", Moretto, A.F. et al. Bioorg. Med. Chem. 14: 2162-2177 (2006), and "Structure-Based Design of Protein Tyrosine Phosphatase-1B Inhibitors.", Black, E. et al. Bioorg. Med. Chem. Lett.PDB crystal structures PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cmb, 2cmc described in "15: 2503 (2005) and 'Structural Basis for Inhibition of Protein-Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics.' Ala, P.J. et al. J. Biol. Chem. 281: 32784 (2006)", PDB crystal structures 2f6t and 2f6w described in "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors." Klopfenstein, S.R. et al. Bioorg. Med. Chem. Lett. 16: 1574-1578 (2006), PDB crystal structures 2h4g, 2h4k, 2hb1 described in "Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48." Wan, Z.K. et al. Bioorg. Med. Chem. Lett. 16: 4941-4945 (2006), "Structure-based optimization of protein tyrosine phosphatase-1 B inhibitors: capturing interactions with arginine 24." Wan, Z. K. et al. Chem Med Chem.Refer to the PDB crystal structure 2zn7 described in 3:1525-9 (2008), the PDB crystal structures 2nt7, 2nta described in "Probing acid replacements of thiophene PTP1B inhibitors." Wan, Z.K. et al. Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007), and International Publication No. WO 2008 / 148744 assigned to Novartis AG entitled "Thiadiazole derivatives as antidiabetic agents." Also refer to "2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases." Andersen, H.S. et al. J. Biol. Chem. 275: 7101-7108 (2000), "Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B." Iversen, L.F. et al. J. Biol. Chem. 275: 10300-10307 (2000), and "Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases." Iversen, L.F. et al.See also the PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 1l8g described in Biochemistry 40: 14812-14820 (2001). 【Figure 7 D】Figure showing non-limiting examples of targeting ligands for non-receptor type 11 tyrosine protein phosphatase SHP2, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 4pvg and 305x described in "Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)." Zhang, X. et al. J. Med. Chem. 53: 2482-2493 (2010), and the crystal structures PDB 5ehr and related ligands described in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." Garcia Fortanet, J. et al. J. Med. Chem. 59: 7773-7782 (2016).See also the crystal structure PDB 5ehr described in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." Garcia Fortanet, J. et al. J. Med. Chem. 59: 7773-7782 (2016), and "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases." Chen, Y.P. et al. Nature 535: 148-152 (2016). 【Figure 7 E】 Figure showing non-limiting examples of targeting ligands for non-receptor type 22 tyrosine protein phosphatase, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 4j51 described in "A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases." He, Y. et al. J. Med. Chem. 56: 4990-5008 (2013). 【Figure 7 F】Figure showing non-limiting examples of targeting ligands for the scavenger mRNA decapping enzyme DcpS, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb, and related ligands described in "DcpS as a therapeutic target for spinal muscular atrophy." Singh, J. et al. ACS Chem.Biol. 3: 711-722 (2008). 【Figure 8 A-8 S】Figure showing non-limiting examples of targeting ligands for BRD4 bromodomain 1, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 3u5k and 3u51 and related ligands in Filippakopoulos, P. et al., "Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family", Bioorg. Med. Chem. 20: 1878-1886 (2012); crystal structure PDB 3u5l; crystal structures PDB 3zyu and related ligands described in Dawson, M.A. et al., "Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for Mll-Fusion Leukaemia.", Nature 478: 529 (2011); crystal structures PDB 4bw1 and related ligands described in Mirguet, O. et al., "Naphthyridines as Novel Bet Family Bromodomain Inhibitors.", Chemmedchem 9: 589 (2014); crystal structures PDB 4cfl and related ligands described in Dittmann, A. et al., "The Commonly Used Pi3-Kinase Probe Ly294002 is an Inhibitor of Bet Bromodomains", ACS Chem. Biol. 9: 495 (2014); Fish, P.V. et al.The crystal structure PDB 4e96 and related ligands described in the article "Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit." J. Med. Chem. 55: 9831-9837 (2012), the crystal structure PDB 4clb and related ligands described in the article "The Structure Based Design of Dual Hdac / Bet Inhibitors as Novel Epigenetic Probes." Medchemcomm 5: 342 (2014) by Atkinson, S.J. et al., the crystal structure PDB 4f3i and related ligands described in the article "Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition." J. Biol. Chem. 287: 28840-28851 (2012) by Zhang, G. et al., the crystal structure PDB 4hxl and related ligands described in the article "Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain." J. Med. Chem. 56: 3833-3851 (2013) by Zhao, L., Zhao, L. et al.The crystal structure PDB 4hxs and related ligands described in the article "Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain." J. Med. Chem. 56: 3833-3851 (2013), the crystal structure PDB 4lrg and related ligands described in "Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors." ACS Med Chem Lett 4: 835-840 (2013) by Gehling, V.S. et al., the crystal structure PDB 4mep and related ligands described in "Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening." J. Med. Chem. 56: 8073-8088 (2013) by Vidler, L.R. et al., the crystal structures PDB 4nr8 and PDB 4c77 and related ligands described in "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors." ACS Chem.Biol. 9: 1160-1171 (2014) by Ember, S.W. et al., Ember, S.W. et al.The crystal structure PDB 4o7a and related ligands described in "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.", Ember, S.W. et al. (2014) ACS Chem. Biol. 9: 1160-1171, the crystal structure PDB 407b and related ligands described in "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.", Ember, S.W. et al. (2014) ACS Chem. Biol. 9: 1160-1171, the crystal structure PDB 4o7c and related ligands described in "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.", Ember, S.W. et al. (2014) ACS Chem. Biol. 9: 1160-1171, the crystal structure PDB 4gpj, "The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.", Theodoulou, N.H. et al. J. Med. Chem.The crystal structure PDB 4uix and related ligands described in Theodoulou, N.H., et al., "The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.", J. Med. Chem. 59: 1425 (2016); the crystal structure PDB 4uiz and related ligands described in McKeown, M.R. et al., "Biased multicomponent reactions to develop novel bromodomain inhibitors.", J. Med. Chem. 57: 9019-9027 (2014); the crystal structure PDB 4wiv and related ligands described in Taylor, A.M. et al., "Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.", ACS Med. Chem. Lett. 7: 145-150 (2016); the crystal structure PDB 4x2i and related ligands described in Duffy, B.C., "Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.", Bioorg. Med. Chem. Lett.The crystal structure PDB 4yh3 and related ligands described in 25: 2818-2823 (2015), "Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design" by Duffy, B.C., Bioorg. Med. Chem. Lett. 25: 2818-2823 (2015); the crystal structure PDB 4yh4 and related ligands described in "Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains" by Taylor, A.M., ACS Med. Chem. Lett. 7: 145-150 (2016); the crystal structure PDB 4z1q and related ligands; the crystal structure PDB 4zw1; the crystal structure PDB 5a5s and related ligands described in "Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors" by Demont, E.H., J. Med. Chem. 58: 5649 (2015); the crystal structure PDB 5a85 and related ligands described in "Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain Inhibitors" by Bamborough, P., J. Med. Chem. 58: 6151 (2015); Sullivan, J.M.The crystal structure PDB 5acy and related ligands described in the article "Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice." J. Exp. Med. 212: 1771 (2015), the crystal structure PDB 5ad2 and related ligands described in the article "Potent and Selective Bivalent Inhibitors of Bet Bromodomains." Nat. Chem. Biol. 12: 1097 (2016) by Waring, M.J. et al., the crystal structure PDB 5cfw and related ligands described in the article "Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities." Chem. Biol. 22: 1588-1596 (2015) by Chekler, E.L. et al., the crystal structure PDB 5cqt and related ligands described in the article "Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation." J. Med. Chem. 59: 1565-1579 (2016) by Xue, X. et al., Hugle, M. et al.The crystal structure PDB 5d3r and related ligands described in the article "4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1).", J. Med. Chem. 59: 1518-1530 (2016), the crystal structure PDB 5dlx and related ligands described in "Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.", Milhas, S. et al. (2016) ACS Chem.Biol. 11: 2140-2148, the crystal structure PDB 5dlz and related ligands described in "Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.", Milhas, S. et al. ACS Chem. Biol. 11: 2140-2148 (2016), the crystal structure PDB 5dw2 and related ligands described in "RVX-297 - a novel BD2 selective inhibitor of BET bromodomains.", Kharenko, O.A. et al. Biochem. Biophys. Res. Commun. 477: 62-67 (2016), the crystal structure PDB 5dlx, Albrecht, B.K. et al.The crystal structure PDB 5his and related ligands described in "Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials." J. Med. Chem. 59: 1330-1339 (2016), the crystal structure PDB 5ku3 and related ligands described in "Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP / EP300." J. Med. Chem. 59: 10549-10563 (2016), the crystal structure PDB 5lj2 and related ligands described in "A Chemical Probe for the ATAD2 Bromodomain." Angew. Chem. Int. Ed. Engl. 55: 11382-11386 (2016), and the fragment-based, structure-enabled discovery of novel pyridones and pyridone macrocycles as potent bromodomain and extra-terminal domain (BET) family bromodomain inhibitors described in "Fragment-based, structure-enabled discovery of novel pyridones and pyridone macrocycles as potent bromodomain and extra-terminal domain (BET) family bromodomain inhibitors." J. by Wang, L.See the crystal structure PDB 5dlx and related ligands described in Med. Chem. 10.1021 / acs.jmedchem.7b00017 (2017), International Publication No. WO 2015 / 169962, assigned to Boehringer Ingelheim International GmbH (Germany) and entitled "Benzimidazole derivatives as BRD4 inhibitors and their preparation and use for the treatment of cancer", and International Publication No. WO 2011 / 143669, assigned to Dana-Farber Cancer Institute, Inc (USA) and entitled "Azolodiazepine derivatives and their preparation, compositions and methods for treating neoplasia, inflammatory disease and other disorders". 【Figure 8 T-8 V】Figure showing non-limiting examples of ALK-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 2xb7 and 2xba and related ligands described in Bossi, R.T. et al., "Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors," Biochemistry 49: 6813-6825 (2010), the crystal structures PDB 2yfx, 4ccb, 4ccu, and 4cd0 and related ligands described in Huang, Q. et al., "Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib," J. Med. Chem. 57: 1170 (2014), Johnson, T.W. et al.The crystal structures PDB 4cli, 4cmo, and 4cnh and related ligands described in the article "Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic Inhibitor of Alk / Ros1 with Pre-Clinical Brain Exposure and Broad Spectrum Potency Against Alk-Resistant Mutations." J. Med. Chem. 57: 4720 (2014), and the crystal structure PDB 4fny and related ligands described in the article "The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase." J. Biol. Chem. 287: 37447-37457 (2012), Epstein, L.F. et al., Bryan, M.C.See the crystal structures PDB 4dce and associated ligands described in "Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors." J. Med. Chem. 55: 1698-1705 (2012) by et al., the crystal structures PDB 4joa and associated ligands described in "Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode." (2013) Bioorg. Med. Chem. Lett. 23: 4911-4918 by Gummadi, V.R. et al., and the crystal structures PDB 5iui and associated ligands described in "Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)." J. Med. Chem. 59: 3906-3919 (2016) by Tu, C.H. et al.. 【Figure 8 W-8 X】Figure showing non-limiting examples of BTK-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 3gen, 3piz and related ligands described in Marcotte, D.J. et al., "Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases.", Protein Sci. 19: 429-439 (2010) and Kuglstatter, A. et al., "Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures", Protein Sci. 20: 428-436 (2011), the crystal structures PDB 3ocs, 4ot6 and related ligands described in Lou, Y. et al., "Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis", J. Med. Chem. 58: 512-516 (2015), Liu, J. et al.See the crystal structures PDB 5fbn and 5fbo and the associated ligands described in the article "Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis." ACS Med. Chem. Lett. 7: 198-203 (2016), the crystal structures PDB 3pix and the associated ligands described in the article "Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures." Protein Sci. 20: 428-436 (2011), and the crystal structures PDB 3pij and the associated ligands described in the article "Crystal structures of the apo form of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose." Febs J. 278: 1728-1744 (2011). 【Figure 8 Y】Figure showing non-limiting examples of FLT3-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 4xuf and 4rt7 and related ligands described in Zorn, J.A. et al., "Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220).", Plos One 10: e0121177-e0121177 (2015). 【Figure 8 Z-8 AA】 Figure showing non-limiting examples of TNIK-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 2x7f, PDB 5ax9 and 5d7a and related ligands described in Masuda, M. et al., "TNIK inhibition abrogates colorectal cancer stemness.", Nat Commun 7: 12586-12586 (2016). 【Figure 8 BB-8 CC】Figure showing non-limiting examples of NTRK1, NTRK2, and NTRK3 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 4aoj and related ligands described in Wang, T. et al., "Discovery of Disubstituted Imidazo[4,5-b]Pyridines and Purines as Potent Trka Inhibitors," ACS Med. Chem. Lett. 3: 705 (2012), the crystal structures PDB 4pmm, 4pmp, 4pms, and 4pmt and related ligands described in Stachel, S.J. et al., "Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain," J. Med. Chem. 57: 5800-5816 (2014), the crystal structures PDB 4yps and 4yne and related ligands described in Choi, H.S. et al., "(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors," ACS Med. Chem. Lett. 6: 562-567 (2015), the crystal structures of Trka and Trkb described in Bertrand, T. et al., "The Crystal Structures of Trka and Trkb Suggest Key Regions for Achieving Selective Inhibition," J.See the crystal structures PDB 4at5 and 4at3 and related ligands described in Mol. Biol. 423: 439 (2012), and the crystal structures PDB 3v5q and 4ymj and related ligands described in Albaugh, P. et al., "Discovery of GNF-5837, a selective TRK Inhibitor with efficacy in rodent cancer tumor models.", ACS Med. Chem. Lett. 3:140-145 (2012) and Choi, H.S. et al., "(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors.", ACS Med Chem Lett 6: 562-567 (2015). 【Figure 8 DD-8 EE】Figure showing non-limiting examples of FGFR1-targeted ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 3tto and 2fgi and related ligands described in Brison, Y. et al., "Functional and structural characterization of alpha-(1-2) branching sucrase derived from DSR-E glucansucrase," J. Biol. Chem. 287: 7915-7924 (2012) and Mohammadi, M. et al., "Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain," EMBO J. 17: 5896-5904 (1998), the crystal structure PDB 4fb3, the crystal structure PDB 4rwk and related ligands described in Harrison, C. et al., "Polyomavirus large T antigen binds symmetrical repeats at the viral origin in an asymmetrical manner," J. Virol. 87: 13751-13759 (2013), and Sohl, C.D. et al., "Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.)」 See the crystal structures PDB 4rwl and related ligands described in ACS Chem. Biol. 10: 1319-1329 (2015), the crystal structure PDB 4uwc, "Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4." by Tucker, J.A. et al. in Structure 22: 1764 (2014), the crystal structure PDB 4v01 and related ligands described in "Structural and Dynamic Insights Into the Energetics of Activation Loop Rearrangement in Fgfr1 Kinase." by Klein, T. et al. in Nat. Commun. 6: 7877 (2015), the crystal structure PDB 5a46 and related ligands described in "Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use." by Patani, H. et al. in Oncotarget 7: 24252-24268 (2016), and the crystal structure PDB 5ew8 and related ligands. 【Figure 8 FF】Figure showing non-limiting examples of targeting ligands for FGFR2 and FGFR3, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 2pvf and related ligands described in Chen, H. et al., "A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases," Mol. Cell 27: 717-730 (2007), and "Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2," Bioorg Med Chem 2020, 28, 115453. 【Figure 8 GG】 Figure showing non-limiting examples of targeting ligands for FGFR4, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 4tyi and related ligands described in Lesca, E. et al., "Structural analysis of the human fibroblast growth factor receptor 4 kinase," J. Mol. Biol. 426: 3744-3756 (2014). 【Figure 8 HH-8 II】Figure showing non-limiting examples of MET targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 3qti and 3zcl, Peterson, E.A. et al., "Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors," J. Med. Chem. 58: 2417-2430 (2015) and Cui, J.J. et al., "Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2, 4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with High Protein Kinase Selectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats," J. Med. Chem. 56: 6651 (2013), the crystal structures PDB 4xmo, 4xyf, and 3zcl and related ligands described therein, Boezio, A.A. et al.Described in the crystal structure PDB 5eyd and related ligands in the article "Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity." J. Med. Chem. 59: 2328-2342 (2016), the crystal structure PDB 3ce3 and related ligands in the article "Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities." J. Med. Chem. 51: 5330-5341 (2008), and the article "c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations." J. by Bellon, S.F. et alSee the crystal structure PDB 2rfn and related ligands described in Biol. Chem. 283: 2675-2683 (2008), and the crystal structure PDB 5dg5 and related ligands described in Smith, B.D. et al, "Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.", Mol. Cancer Ther. 14: 2023-2034 (2015). 【Figure 8 JJ】Figure showing non-limiting examples of JAK1-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 4ivd and related ligands described in Zak, M. et al., "Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.", J. Med. Chem. 56: 4764-4785 (2013); the crystal structure PDB 5e1e and related ligands described in Vasbinder, M.M. et al., "Identification of azabenzimidazoles as potent JAK1 selective inhibitors.", Bioorg. Med. Chem. Lett. 26: 60-67 (2016); the crystal structure PDB 5hx8 and related ligands described in Simov, V., et al., "Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.", Bioorg. Med. Chem. Lett. 26: 1803-1808 (2016); Caspers, N.L. et al.See the crystal structure PDB 5hx8 and related ligands described in the work “Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system.” Acta Crystallogr. Sect. F 72: 840-845 (2016), and the work “Discovery of the JAK1 selective kinase inhibitor AZD4205” by Kettle, J. G., AACR National Meeting, April 2017. 【Figure 8 KK-8 LL】Figure showing non-limiting examples of JAK2-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 3ugc and related ligands described in Andraos, R. et al., "Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.", Cancer Discov 2: 512-523 (2012), the crystal structures PDB 5cf4, 5cf5, 5cf6, and 5cf8 and related ligands described in Hart, A.C. et al., "Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.", ACS Med. Chem. Lett. 6: 845-849 (2015), the crystal structure PDB 5aep and related ligands described in Brasca, M.G. et al., "Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders", Bioorg. Med. Chem. 23: 2387 (2015), and Farmer, L.J. et al., "Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.", J. Med. Chem.See the crystal structures PDB 4ytf, 4yth, and 4yti and related ligands described in 58: 7195-7216 (2015), Menet, C.J. et al., "Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634," J. Med. Chem. 57: 9323-9342 (2014), the crystal structures PDB 4ytf, 4yth, 4yti, and related ligands described in Siu, M. et al., "2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors," Bioorg. Med. Chem. Lett. 23: 5014-5021 (2013), the crystal structure PDB 4ji9 and related ligands described in Schenkel, L.B. et al., "Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors," J. Med. Chem. 54: 8440-8450 (2011), and the crystal structures PDB 3io7 and 3iok and related ligands described therein. 【Figure 8 MM】Figure showing non-limiting examples of JAK3-targeted ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 3zc6 and related ligands described in Lynch, S.M. et al., "Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the Jak Family and the Kinome.", Bioorg. Med. Chem. Lett. 23: 2793 (2013), and the crystal structures PDB 4hvd, 4i6q, and 3zep and related ligands described in Soth, M. et al., "3-Amido Pyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1 Selective Inhibitor and Evaluation in Cellular and in Vivo Models.", J. Med. Chem. 56: 345-356 (2013), and Jaime-Figueroa, S. et al., "Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.", Bioorg. Med. Chem. Lett. 23: 2522-2526 (2013). 【Figure 8 NN-8 OO】Figure showing non-limiting examples of the targeting ligands of the KIT, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 1t46 and related ligands described in Mol, C.D. et al., "Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase," J. Biol. Chem. 279: 31655-31663 (2004), and the crystal structure PDB 4u0i and related ligands described in Garner, A.P. et al., "Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients," Clin. Cancer Res. 20: 5745-5755 (2014). 【Figure 88 PP-8 VV】Figure showing non-limiting examples of EGFR-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 5hcy, 4rj4, and 5cav, Heald, R., "Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study", J. Med. Chem. 58, 8877-8895 (2015), Hanano, E. J., "Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.", J. Med. Chem., 57, 10176-10191 (2014), Chan, B. K. et al., "Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor", J. Med. Chem. 59, 9080 (2016), Jia, Y. et al., "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors", Nature 534, 129 (2016), the crystal structures PDB 5d41 and related ligands described therein, Ward, R. A.The crystal structures PDB 4zau and related ligands described in the article "Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)" J. Med. Chem. 56, 7025-7048 (2013), the crystal structures PDB 5em7 and related ligands described in the article "Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor" J. Med. Chem., 57 (20), 8249-8267 (2014), the crystal structures PDB 3IKA and related ligands described in the article "Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR" ACS Med. Chem. Lett., 7 (1), 100-104 (2016) by Bryan, M. C. et al., the crystal structures PDB 3IKA and related ligands described in the article "Novel mutant-selective EGFR kinase inhibitors against EGFR T790M" Nature 462(7276), 1070-1074 (2009) by Zhou, W. et al., Lelais, G., J.Described in the crystal structure PDB 5feq and related ligands in "Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers", Med. Chem., 59 (14), 6671-6689 (2016); the crystal structure PDB 5j7h and related ligands in "Noncovalent Wild-type-Sparing Inhibitors of EGFR T790M", Cancer Discov. 3(2): 168-181 (2013) by Lee, H.-J.; "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.", J. Med. Chem. 59: 4948-4964 (2016) by Huang, W-S. et al.; Hennessy, E. J. et al.The crystal structure PDB 4v0g and related ligands described in the work "Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation." ACS. Med. Chem. Lett. 7: 514-519 (2016), the crystal structure PDB 5hg7 and related ligands described in "Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants." J. Med. Chem. 59: 2005-2024 (2016), Hao, Y."Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R / T790M Resistance Mutation." J. Med. Chem. 59: 7111-7124 (2016), "Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR." J. Med. Chem. 60: 3002-3019 (2017), the crystal structures PDB 5ug8, 5ug9, and 5ugc and related ligands described therein, Wang, A.See the crystal structures PDB 5gnk and the related ligands described in "Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode." J. Med. Chem. 60: 2944-2962 (2017) and "Trisubstituted imidazoles with a rigidized hinge binding motif act as single digit nM inhibitors of clinically relevant EGFR L858R / T790M and L858R / T790M / C797S mutants: An example of target hopping." J. Med. Chem. DOI: 10.1021 / acs.jmedchem.7b00178 (2017) by Juchum, M.. 【Figure 8 WW-8 XX】Figure showing non-limiting examples of PAK1-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see Rudolph, J. et al., "Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window," J. Med. Chem. 59, 5520-5541 (2016), and Karpov AS, et al., ACS Med Chem Lett. 22;6(7):776-81 (2015). 【Figure 8 YY】 Figure showing non-limiting examples of PAK4-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see Staben ST, et al., J Med Chem. 13;57(3):1033-45 (2014), and Guo, C. et al., "Discovery of pyrroloaminopyrazoles as novel PAK inhibitors," J. Med. Chem. 55, 4728-4739 (2012). 【Figure 8 ZZ-8 AAA】Figure showing non-limiting examples of IDO targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Yue, E. W.; et al., "Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model," J. Med. Chem. 52, 7364-7367 (2009); Tojo, S.; et al., "Crystal structures and structure, and activity relationships of imidazothiazole derivatives as IDO1 inhibitors," ACS Med. Chem. Lett. 5, 1119-1123 (2014); Mautino, M.R. et al., "NLG919, a novel indoleamine-2,3- dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy," Abstract 491, AACR 104th Annual Meeting 2013; Apr 6-10, 2013 (Washington, DC); and International Publication No. WO 2012 / 142237 entitled "Fused imidazole derivatives useful as IDO inhibitors." 【Figure 8 BBB-8 EEE】Figure showing non-limiting examples of targeted ligands for ERK1 and ERK2, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 5K4I and 5K4J and related ligands described in Blake, J.F. et al., "Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1 / 2 (ERK1 / 2) Inhibitor in Early Clinical Development," J. Med. Chem. 59: 5650-5660 (2016), the crystal structures PDB 5BVF and related ligands described in Bagdanoff, J.T. et al., "Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase," Bioorg. Med. Chem. Lett. 25, 3788-3792 (2015), and Deng, Y. et al., "Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase," J. Med. Chem.The crystal structure PDB 4QYY described in 57: 8817-8826 (2014) and related ligands, the crystal structures PDB 5HD4 and 5HD7 described in Jha, S. et al., "Dissecting Therapeutic Resistance to ERK Inhibition," Mol. Cancer Ther. 15: 548-559 (2016) and related ligands, the crystal structure PDB 4XJ0 described in Ren, L. et al., "Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1 / 2.", J. Med. Chem. 58: 1976-1991 (2015) and related ligands, the crystal structure PDB 4XJ0 described in Ward, R.A. et al., "Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1 / 2.", J. Med. Chem. 58: 4790 (2015), KO-947 (KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors) described in Burrows, F. et al., "KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors," Poster No. 5168, AACR National Conference 2017, Bhagwat, S. V. et al."Discovery of LY3214996, a selective and novel ERK1 / 2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations." The crystal structures PDB 4ZZM, 4ZZN, 4ZZO, and related ligands described in the 2017 AACR National Conference, the crystal structures PDB 3FHR and 3FXH and related ligands described in "High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand" by Cheng, R. et al., Protein Sci. 19: 168-173 (2010), the crystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and 5NHV and related ligands described in "Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1 / 2 from a Modestly Active and Promiscuous Chemical Start Point." by Ward, R.A. et al., J. Med. Chem. 60, 3438-3450 (2017), and the crystal structures and related ligands described in "Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series." by Oubrie, A. et al., Bioorg. Med. Chem. Lett.22: 613-618 (2012), "Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control," J Med Chem 2009, 52(20), 6362, International Publication No. WO 2015 / 051341, "Discovery of a Potent and Selective Oral Inhibitor of ERK1 / 2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Non-small Cell Lung Cancer (NSCLC)," J Med Chem 2019, 62(24), 11004, and "ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine," Mol Cancer Ther 2020, 19, 325. See the crystal structures PDB 3SHE and 3R1N and related ligands described therein. 【Figure 8FFF-8III】Figure showing non-limiting examples of ABL1 targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 1fpu and 2e2b and related ligands described in Schindler, T., et al., "Structural mechanism for STI-571 inhibition of abelson tyrosine kinase," Science 289: 1938-1942 (2000), and Horio, T. et al., "Structural factors contributing to the Abl / Lyn dual inhibitory activity of 3-substituted benzamide derivatives," Bioorg. Med. Chem. Lett. 17: 2712-2717 (2007); the crystal structures PDB 2hzn and 2hiw and related ligands described in Cowan-Jacob, S.W. et al., "Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukemia," Acta Crystallog. Sect. D 63: 80-93 (2007) and Okram, B. et al., "A general strategy for creating," Chem. Biol. 13: 779-786 (2006); Weisberg, E. et al.The crystal structure PDB 3cs9 and related ligands described in the article "Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl" by O'Hare, T. et al., Cancer Cell 7: 129-14 (2005), the crystal structure PDB 3ik3 and related ligands described in the article "AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance" by O'Hare, T. et al., Cancer Cell 16: 401-412 (2009), the crystal structure PDB 3mss and related ligands described in the article "Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay" by Jahnke, W. et al., J. Am. Chem. Soc. 132: 7043-7048 (2010), and the crystal structure PDB 3mss and related ligands described in the article "Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance" by Zhou, T. et al., Chem. Biol. Drug Des.The crystal structures PDB 3oy3 and related ligands described in 77: 1-11 (2011), the crystal structures PDB 3qri and 3qrk and related ligands described in Chan, W.W. et al., "Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036", Cancer Cell 19: 556-568 (2011), the crystal structures PDB 5hu9 and 2f4j and related ligands described in Liu, F. et al., "Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)", Oncotarget 7: 45562-45574 (2016) and the crystal structure PDB 5hu9 and 2f4j and related ligands described in Young, M.A. et al., "Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680", Cancer Res. 66: 1007-1014 (2006), Tokarski, J.S. et al.The crystal structures PDB 2gqg and 2qoh and related ligands described in "The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants," Cancer Res. 66: 5790-5797 (2006) and "Crystal Structure of the T315I Mutant of Abl Kinase," Chem. Biol. Drug Des. 70: 171-181 (2007) by Zhou, T. et al., and Tokarski, J.S. et al. in "The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants," Cancer Res. 66: 5790-5797 (2006) and "Crystal Structure of the T315I Mutant of Abl Kinase," Chem. Biol. Drug Des. 70: 171-181 (2007), the crystal structures PDB 2gqg and 2qoh and related ligandsThe crystal structures PDB 2gqg and 2qoh and the related ligands described in the article "The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants" by Nagar, B. et al., Cancer Res. 66: 5790-5797 (2006) and the crystal structures PDB 3dk3 and 3dk8 and the related ligands described in the article "Crystal Structure of the T315I Mutant of Abl Kinase" by Zhou, T. et al., Chem. Biol. Drug Des. 70: 171-181(2007), the crystal structures PDB 3dk3 and 3dk8 and the related ligands described in the article "Catalytic cycle of human glutathione reductase near 1 A resolution" by Berkholz, D.S. et al., J. Mol. Biol. 382: 371-384 (2008), the crystal structure PDB 3ue4 and the related ligand described in the article "Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain" by Levinson, N.M. et al., Plos One 7: e29828-e29828 (2012), Jensen, C.N. et al.The crystal structure PDB 4cy8 and related ligands described in the article "Structures of the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase (Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution", Chembiochem 16: 968 (2015), the crystal structure PDB 2hz0 and related ligands described in the article "Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia", Acta Crystallogr D Biol Crystallogr. 63(Pt 1):80-93 (2007), the crystal structure PDB 3pyy and related ligands described in the article "Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site", Chem. Biol. 18: 177-186 (2011), and the article "Structural basis for dual specificity of yeast N-terminal amidase in the N-end rule pathway" by Kim, M.K., et al., Proc. Natl. Acad. Sci. U.S.A.See the crystal structure PDB 5k5v and related ligands described in 113: 12438-12443 (2016). 【Figure 8JJJ】 A diagram showing non-limiting examples of ABL2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 2xyn and related ligands described in Salah, E. et al., "Crystal Structures of Abl-Related Gene (Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type I Inhibitor of the Triazole Carbothioamide Class," J. Med. Chem. 54: 2359 (2011); the crystal structure PDB 4xli and related ligands described in Ha, B.H. et al., "Structure of the ABL2 / ARG kinase in complex with dasatinib," Acta Crystallogr. Sect. F 71: 443-448 (2015); and the crystal structure PDB 3gvu and related ligands described in Salah, E. et al., "The crystal structure of human ABL2 in complex with Gleevec" (forthcoming). 【Figure 8KKK-8MMM】Figure showing non-limiting examples of AKT1-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lippa, B. et al., "Synthesis and structure based optimization of novel Akt inhibitors", Bioorg. Med. Chem. Lett. 18: 3359-3363 (2008), Freeman-Cook, K.D. et al., "Design of selective, ATP-competitive inhibitors of Akt", J. Med. Chem. 53: 4615-4622 (2010), Blake, J.F. et al., "Discovery of pyrrolopyrimidine inhibitors of Akt", Bioorg. Med. Chem. Lett. 20: 5607-5612 (2010), Kallan, N.C. et al., "Discovery and SAR of spirochromane Akt inhibitors", Bioorg. Med. Chem. Lett. 21: 2410-2414 (2011), Lin, K., "An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt", Sci.Signal. 5: ra37-ra37 (2012), Addie, M. et al."Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases," J. Med. Chem. 56: 2059-2073 (2013), by Wu, W.I., et al.; "Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition," Plos One 5: 12913-12913 (2010), by Ashwell, M.A. et al.; "Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors," J. Med. Chem. 55: 5291-5310 (2012), by Lapierre, J.M. et al.See the article "Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor)", J. Med. Chem. 59: 6455-6469 (2016). 【Figure 8NNN-8OOO】Figure showing non-limiting examples of AKT2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 2jdo and 2jdr and related ligands described in Davies, T.G. et al., "A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera," J. Mol. Biol. 367: 882 (2007), the crystal structure PDB 2uw9 and related ligands described in Saxty, G. et al., "Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery," J. Med. Chem. 50: 2293-2296 (2007), the crystal structures PDB 2x39 and 2xh5 and related ligands described in McHardy, T. et al., "Discovery of 4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides as Selective, Orally Active Inhibitors of Protein Kinase B (Akt)," J. Med. Chem. 53: 2239d (2010), Hadler, K.S. et al.Please refer to the crystal structure PDB 3d03 and related ligands described in the publication "Substrate-promoted formation of a catalytically competent binuclear center and regulation of reactivity in a glycerophosphodiesterase from Enterobacter aerogenes", J. Am. Chem. Soc. 130: 14129-14138 (2008), as well as the crystal structures PDB 3e87, 3e8d, and 3e88 and related ligands described in the publication "Aminofurazans as potent inhibitors of AKT kinase" by Rouse, M.B. et al., Bioorg. Med. Chem. Lett. 19: 1508-1511 (2009). 【Figure 8PPP】 FIG. showing non-limiting examples of BMX-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, please refer to the crystal structures PDB 3sxr and 3sxr and related ligands described in the publication "X-ray crystal structure of bone marrow kinase in the x chromosome: a Tec family kinase" by Muckelbauer, J. et al., Chem. Biol. Drug Des. 78: 739-748 (2011). 【Figure 8QQQ-8SSS】Figure showing non-limiting examples of CSF1R-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 2i0v and 2i1m and related ligands described in Schubert, C. et al., "Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors," J. Biol. Chem. 282: 4094-4101 (2007), the crystal structures PDB 3bea and related ligands described in Huang, H. et al., "Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors," Bioorg. Med. Chem. Lett. 18: 2355-2361 (2008), the crystal structure PDB 3dpk and related ligands described in M.T., McKay, D.B. Overgaard, "Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon" (forthcoming), Illig, C.R. et al.Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141), described in J. Med. Chem. 54: 7860-7883 (2011), the crystal structures PDB 3krj and 3krl and the related ligands, Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor: described in Tap, W.D. et al., N Engl J Med 373: 428-437 (2015), the crystal structures PDB 4r7h and the related ligands, Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mod described in Meyers, M.J. et al., Bioorg. Med. Chem. Lett. 20: 1543-1547 (2010), the crystal structures PDB 3lcd and 3lcoa and the related ligands, Zhang, C. et al.See the crystal structure PDB 4hw7 and related ligands described in the article "Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor" by Liao, X. et al., Proc. Natl. Acad. Sci. USA 110: 5689-5694 (2013), and the crystal structure PDB 4r7i and related ligands described in the article "Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor" by Tap, W.D. et al., N Engl J Med 373: 428-437 (2015). 【Figure 8TTT】 FIG. shows non-limiting examples of CSK-targeted ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Levinson, N.M. et al., "Structural basis for the recognition of c-Src by its inactivator Csk", Cell 134: 124-134 (2008). 【Figure 8UUU-8YYY】Figure showing non-limiting examples of DDR1-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 3zos and 4bkj and related ligands described in Canning, P. et al., "Structural Mechanisms Determining Inhibition of the Collagen Receptor Ddr1 by Selective and Multi-Targeted Type II Kinase Inhibitors," J. Mol. Biol. 426: 2457 (2014), the crystal structures PDB 4ckr and related ligands described in Kim, H. et al., "Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor," ACS Chem. Biol. 8: 2145 (2013), the crystal structures PDB 5bvk, 5bvn, and 5bvw and related ligands described in Murray, C.W et al., "Fragment-Based Discovery of Potent and Selective DDR1 / 2 Inhibitors," ACS Med. Chem. Lett. 6: 798 - 803 (2015), and the crystal structures and related ligands described in Wang, Z. et al., "Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors," J. Med. Chem.See the crystal structure PDB 5fdp and related ligands described in 59: 5911-5916 (2016), and the crystal structure PDB 5fdx and related ligands described in "Structure of DDR1 receptor tyrosine kinase in complex with D2164 inhibitor at 2.65 Angstroms resolution" by Bartual, S.G. et al. (scheduled for publication). 【Figure 8ZZZ-8CCCC】Figure showing non-limiting examples of EPHA2-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 5i9x, 5i9y, 5ia0, and 5ia1 and related ligands described in Heinzlmeir, S. et al., "Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug," ACS Chem. Biol. 11: 3400-3411 (2016), the crystal structure PDB 5i9z and related ligands described in Heinzlmeir, S. et al., "Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with danusertib (PHA739358)," ACS Chem Biol 11 3400-3411 (2016), and the crystal structures PDB 5ia2, 5ia3, 5ia4, and 5ia5 and related ligands described in Heinzlmeir, S. et al., "Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug," ACS Chem. Biol. 11: 3400-3411 (2016). 【Figure 8DDDD-8FFFF】Figure showing non-limiting examples of targeting ligands for EPHA3, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 4g2f and related ligands described in Zhao, H. et al., "Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics," ACS Med. Chem. Lett. 3: 834-838 (2012), the crystal structures PDB 4gk2 and 4gk3 and related ligands described in Lafleur, K. et al., "Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography," J. Med. Chem. 56: 84-96 (2013), the crystal structure PDB 4gk3 and related ligands described in Lafleur, K. et al., "Optimization of Inhibitors of the Tyrosine Kinase EphB4. 2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography," J. Med. Chem. 56: 84-96 (2013), Unzue, A. et al.The crystal structures PDB 4p4c and 4p5q and the related ligands described in Unzue, A. et al., "Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation," J. Med. Chem. 57: 6834-6844 (2014), the crystal structure PDB 4p5z and the related ligands described in Unzue, A. et al., "Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation," J. Med. Chem. 57: 6834-6844 (2014), the crystal structure PDB 4twn and the related ligands described in Dong, J. et al., "Structural Analysis of the Binding of Type I, I1 / 2, and II Inhibitors to Eph Tyrosine Kinases," ACS Med.Chem.Lett. 6: 79-83 (2015), Walker, J.R.Refer to the crystal structure PDB 3dzq and related ligands described in the publication-in-preparation "Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex with ALW-II-38-3". 【Figure 8GGGG】 Figure showing non-limiting examples of targeting ligands for EPHA4, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, refer to the crystal structure PDB 2y60 and related ligands described in Clifton, I.J. et al., "The Crystal Structure of Isopenicillin N Synthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals Thioether Coordination to Iron", Arch. Biochem. Biophys. 516: 103 (2011), and the crystal structure PDB 2xyu and related ligands described in Van Linden, O.P et al., "Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase", Eur. J. Med. Chem. 47: 493 (2012). 【Figure 8HHHH】A diagram showing non-limiting examples of targeting ligands for EPHA7, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 3dko and related ligands described in "Kinase domain of human ephrin type-a receptor 7 (epha7) in complex with ALW-II-49-7" (scheduled for publication) by Walker, J.R. et al. 【Figure 8IIII-8LLLL】Figure showing non-limiting examples of EPHB4-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 2vx1 and related ligands described in Bardelle, C. et al., "Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-Based Discovery and Optimization of 3,5-Bis Substituted Anilinopyrimidines," Bioorg. Med. Chem. Lett. 18: 5717 (2008), the crystal structure PDB 2x9f and related ligands described in Bardelle, C. et al., "Inhibitors of the Tyrosine Kinase Ephb4. Part 3: Identification of Non-Benzodioxole-Based Kinase Inhibitors," Bioorg. Med. Chem. Lett. 20: 6242-6245 (2010), and Barlaam, B.et al., "Inhibitors of the Tyrosine Kinase Ephb4."Part 4: Discovery and Optimization of a Benzylic Alcohol Series", the crystal structure PDB 2xvd and related ligands described in Bioorg. Med. Chem. Lett. 21: 2207 (2011), "Completing the Structural Family Portrait of the Human Ephb Tyrosine Kinase Domains" by Overman, R.C. et al., the crystal structure PDB 3zew and related ligands described in Protein Sci. 23: 627 (2014), "The Design, Synthesis, and Biological Evaluation of Potent Receptor Tyrosine Kinase Inhibitors." by Kim, M.H. et al., the crystal structure PDB 4aw5 and related ligands described in Bioorg. Med. Chem. Lett. 22: 4979 (2012), "Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors" by Vasbinder, M.M. et al., the crystal structure PDB 4bb4 and related ligands described in J. Med. Chem. 56: 1996.", (2013), inhibitors of the tyrosine kinase Ephb4."Part 1: Structure-Based Design and Optimization of a Series of 2,4-Bis-Anilinopyrimidines (Inhibitors of the Tyrosine Kinase Ephb4)", crystal structures PDB 2vwu, 2vwv, and 2vww and related ligands described in Bioorg. Med. Chem. Lett. 18: 2776-2780 (2008), "Part 2: Structure-Based Discovery and Optimization of 3,5-Bis Substituted Anilinopyrimidines (Inhibitors of the Tyrosine Kinase Ephb4)", crystal structures PDB 2vwx, 2vwy, and 2vwz and related ligands described in Bioorg. Med. Chem. Lett. 18: 5717 (2008), and "Substrate Specificity and Oligomerization of Human Gmp Synthetas", crystal structure PDB 2vxo and related ligands described in J. Mol. Biol. 425: 4323 (2013). See also. 【Figure 8MMMM】Figure showing non-limiting examples of targeted ligands for ERBB2, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see the crystal structures and related ligands described in Aertgeerts, K. et al., "Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein," J. Biol. Chem. 286: 18756-18765 (2011), and Ishikawa, T. et al., "Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2) / Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold," J. Med. Chem. 54: 8030-8050 (2011). 【Figure 8NNNN】 Figure showing non-limiting examples of targeted ligands for ERBB3, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see Littlefield, P. et al., "An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase," Chem. Biol. 21: 453-458 (2014). 【Figure 8OOOO】Figure showing non-limiting examples of targeted ligands for ERBB4, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see Qiu, C. et al., "Mechanism of Activation and Inhibition of the HER4 / ErbB4 Kinase", Structure 16: 460-467 (2008) and Wood, E.R. et al., "6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases", Proc. Natl. Acad. Sci. Usa 105: 2773-2778 (2008). 【Figure 8PPPP-8QQQQ】 Figure showing non-limiting examples of targeted ligands for FES, where R represents exemplary points to which linkers can be attached. For additional examples and related ligands, see Filippakopoulos, P. et al, "Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation.", Cell 134: 793-803 (2008) and Hellwig, S. et al., "Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase", Chem. Biol. 19: 529-540 (2012). 【Figure 8RRRR】Figure showing non-limiting examples of targeting ligands for FYN, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see "Structure of human Fyn kinase domain complexed with staurosporine" by Kinoshita, T. et. al., Biochem. Biophys. Res. Commun. 346: 840-844 (2006). 【Figure 8SSSS-8VVVV】 Figure showing non-limiting examples of targeting ligands for GSG2 (Haspin), where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 3e7v, PDB 3f2n, 3fmd and related ligands described in "Crystal Structure of Human Haspin with a pyrazolo-pyrimidine ligand" (to be published) by Filippakopoulos, P. et al., crystal structure PDB 3iq7 and related ligands described in "Structure and functional characterization of the atypical human kinase haspin" by Eswaran, J. et al., Proc. Natl. Acad. Sci. USA 106: 20198-20203 (2009), and crystal structure PDB 4qtc and related ligands described in "A unique inhibitor binding site in ERK1 / 2 is associated with slow binding kinetics" by Chaikuad, A. et al., Nat. Chem. Biol. 10: 853-860 (2014). 【Figure 8WWWW-8AAAAA】Figure showing non-limiting examples of HCK-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 1qcf and related ligands described in Schindler, T. et al., "Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor," Mol. Cell 3: 639-648 (1999); the crystal structures PDB 2c0i and 2c0t and related ligands described in Burchat, A. et al., "Discovery of A-770041, a Src-Family Selective Orally Active Lck Inhibitor that Prevents Organ Allograft Rejection," Bioorg. Med. Chem. Lett. 16: 118 (2006); the crystal structure PDB 2hk5 and related ligands described in Sabat, M.et al., "The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck)," Bioorg. Med. Chem. Lett. 16: 5973-5977 (2006); Saito, Y. et al.The crystal structures PDB 3vry, 3vs3, 3vs6, and 3vs7 and related ligands described in the article "A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo", Sci Transl Med 5: 181ra52-181ra52 (2013), and the crystal structure PDB 4lud and related ligands described in "Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002", Acta Crystallogr., Sect. D 70: 392-404 (2014) by Parker, L.J. et al. are referred to. 【Figure 8BBBBB-8FFFFF】Figure showing non-limiting examples of IGF1R-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 2oj9 and related ligands described in Velaparthi, U. et al., "Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R)", Bioorg. Med. Chem. Lett. 17: 2317-2321 (2007), the crystal structure PDB 3i81 and related ligands described in Wittman, M.D. et al., "Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.", J. Med. Chem. 52: 7360-7363 (2009), and Sampognaro, A.J. et al., "Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase", Bioorg. Med. Chem. Lett.The crystal structure PDB 3nw5 and related ligands described in 20: 5027-5030 (2010), the crystal structure PDB 3qqu and related ligands described in Buchanan, J.L. et al., "Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors", Bioorg. Med. Chem. Lett. 21: 2394-2399 (2011), the crystal structure PDB 4d2r and related ligands described in Kettle, J.G. et al., "Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a Mek Resistance Hypothesis.", J. Med. Chem. 58: 2834 (2015), the crystal structure PDB 3fxq and related ligands described in Monferrer, D. et al., "Structural studies on the full-length LysR-type regulator TsaR from Comamonas testosteroni T-2 reveal a novel open conformation of the tetrameric LTTR fold", Mol. Microbiol. 75: 1199-1214 (2010), Degorce, S. et al.The crystal structure PDB 5fxs and related ligands described in the forthcoming publication "Discovery of Azd9362, a Potent Selective Orally Bioavailable and Efficacious Novel Inhibitor of Igf-R1", the crystal structure PDB 2zm3 and related ligands described in Mayer, S.C.et al., "Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment", Bioorg. Med. Chem. Lett. 18: 3641-3645 (2008), the crystal structure PDB 3f5p and related ligands described in "Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment", Bioorg. Med. Chem. Lett. 19: 62-66 (2009), the crystal structure PDB 3lvp and related ligands described in Nemecek, C. et al., "Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles", Chem. Biol. Drug Des. 76: 100-106 (2010), Lesuisse, D. et al.Refer to the crystal structure PDB 3o23 and related ligands described in the article "Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: Advantages in comparison with competitive inhibitors", Bioorg. Med. Chem. Lett. 21: 2224-2228 (2011), the crystal structure PDB 3d94 and related ligands described in the article "Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor", Embo J. 27: 1985-1994 (2008) by Wu, J. et al., and the crystal structure PDB 5hzn and related ligands described in the article "Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors", Bioorg. Med. Chem. Lett. 26: 2065-2067 (2016) by Stauffer, F. et al.. 【Figure 8GGGGG-8JJJJJ】Figure showing non-limiting examples of INSR-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 2z8c and related ligands described in Katayama, N. et al., "Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors," Proteins 73: 795-801 (2008), the crystal structure PDB 3ekk and related ligands described in Chamberlain, S.D.et al., "Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase," (2009) Bioorg. Med. Chem. Lett. 19: 469-473, the crystal structure PDB 3ekn and related ligands described in Chamberlain, S.D. et al., "Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity," Bioorg. Med. Chem. Lett. 19: 360-364 (2009), and Sanderson, M.P. et al.The crystal structure PDB 5e1s and related ligands described in "BI 885578, a Novel IGF1R / INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis", Mol. Cancer Ther. 14: 2762-2772", (2015), the crystal structure PDB 3eta and related ligands described in "Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase", Bioorg. Med. Chem. Lett. 19: 3136-3140 (2009), the crystal structure PDB 5hhw and related ligands described in "Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors", Bioorg. Med. Chem. Lett. 26: 2065-2067 (2016), and Anastassiadis, T. et al.See the crystal structure PDB 4ibm and related ligands described in the article "A highly selective dual insulin receptor (IR) / insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor", J. Biol. Chem. 288: 28068-28077 (2013). 【Figure 8KKKKK-8PPPPP】A figure showing non-limiting examples of HBV-targeting ligands, where R represents an exemplary point to which a linker can be attached, Y is methyl or isopropyl, and X is N or C. For additional examples and related ligands, see Weber, O.; et al., "Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model," Antiviral Res. 54, 69-78 (2002), Deres, K.; et al., "Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids," Science, 299, 893-896 (2003), Stray, S. J., Zlotnick, A., "BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly," J. Mol. Recognit. 19, 542-548 (2006), Stray, S. J.; et al., "heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly," Proc. Natl. Acad. Sci. U. S. A., 102, 8138-8143 (2005), Guan, H.; et al."The novel compound Z060228 inhibits assembly of the HBV capsid." Life Sci. 133, 1-7 (2015), Wang, X. Y.; et al., "In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations." Antiviral Ther. 17, 793-803 (2012), Klumpp, K.; et al., "High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein." 112, 15196-15201 (2015), Qiu, Z.; et al., "Design and synthesis of orally bioavailable 4-methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors." J. Med. Chem. 59, 7651-7666 (2016), Zhu, X.; et al."2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly." by Campagna, M. R.; et al., Bioorg. Med. Chem. Lett. 20, 299-301 (2010); "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids." by Campagna, M. R.; et al., J. Virol. 87, 6931-6942 (2013); "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids." by Campagna, M. R.; et al., J. Virol. 87, 6931-6942 (2013); International Publication No. WO 2013 / 096744 entitled "Hepatitis B antiviral agents"; International Publication No. WO 2015 / 138895 entitled "Hepatitis B core protein allosteric modulators"; "A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation." by Wang, Y. J.; et al., Antimicrob. Agents Chemother.See International Publication No. 2014 / 033167, entitled "Fused bicyclic sulfamoyl derivatives for the treatment of hepatitis", 59, 7061-7072 (2015), U.S. Patent Application Publication No. 2015 / 0132258, entitled "Azepane derivatives and methods of treating hepatitis B infections", and International Publication No. 2015 / 057945, "Hepatitis B viral assembly effector". 【Figure 9】 FIG. showing a dendrogram of the human bromodomain family of proteins organized into eight subfamilies involved in epigenetic signaling and chromatin biology. Any of the proteins of the bromodomain family in FIG. 9 can be selected as the target protein according to the present invention. 【Figure 10A-10B】 FIG. showing non-limiting examples of targeting ligands for CBP and / or P300, where R represents an exemplary point to which a linker can be attached. For additional examples of targeting ligands, see, for example, "GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)", J Med Chem 2017, 60(22), 9162, CCS-1477, International Publication No. 2018 / 073586, FT-7051, and International Publication No. 2019 / 055869. 【Figure 11A-11B】Figure showing non-limiting examples of BRD9-targeting ligands, where R is the point at which the linker is attached. For additional examples, see "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor," J Med Chem 2016, 59(10), 4462, International Publication No. WO 2016 / 139361. 【Figure 12A-12C】 Figure showing non-limiting examples of CBL-B-targeting ligands, where R represents exemplary points at which a linker can be attached. For additional examples, see International Publication No. WO 2019 / 14800. 【Figure 13】It is a diagram showing non-limiting examples of targeted ligands for ERK, where R is the point to which the linker is attached. For additional examples, see "Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control", J Med Chem 2009, 52(20), 6362; International Publication No. WO 2015 / 051341; "Discovery of a Potent and Selective Oral Inhibitor of ERK1 / 2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)", J Med Chem 2019, 62(24), 11004; "ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine", Mol Cancer Ther 2020, 19, 325. 【Figure 14A-14C】Figure showing non-limiting examples of WDR5-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see "Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)", J Med Chem 2016, 59(6), 2478; International Publication No. WO 2017 / 147700; "Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity", Cell Rep 2019, 26(11), 2916; and "Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5-MYC Protein-Protein Interaction", J Med Chem 2019, 62(24), 11232. 【Figure 15】Figure showing non-limiting examples of NSP3 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see "Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation", J Med Chem 2010, 53, 4968 and "X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases", J Med Chem 2014, 57, 2393. 【Figure 16】A diagram showing non-limiting examples of RET-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see Pralsetinib, "Precision Targeted Therapy with BLU-667 for RET-Driven Cancers," Cancer Discovery, 2018, 8(7), 836; Selpercatinib; International Publication No. WO 2018 / 071447; "A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants," J Med Chem, 2016, 59, 358. 【Figure 17A-17C】Figure showing non-limiting examples of CTNNB1-targeting ligands, where R is the point to which the linker is attached. For additional examples, see "Direct Targeting of b-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt / b-Catenin Signaling", Cell Rep 2016, 16(1), 28; "Rational Design of Small-Molecule Inhibitors for β-Catenin / T-Cell Factor Protein-Protein Interactions by Bioisostere Replacement", ACS Chem Biol 2013, 8, 524; and "Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer", Sci Rep 2020, 10, 8096. 【Figure 18A-18C】Figure showing non-limiting examples of IRAK4-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see each of the references (Rajapaksa N.S. et al., "Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity," ACS Med. Chem. Lett. 11: 327-333 (2020); McElroy W.T. et al., "Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation," ACS Med. Chem. Lett. 6: 677-682 (2015); Nunes J. et al., "Targeting IRAK4 for Degradation with PROTACs," ACS Med. Chem. Lett. 10: 1081-1085 (2019); 4); Degorce S. L. et al., "Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4," Bioorg. Med. Chem. 26: 913-924 (2018); Patent Document 90 and International Publication No. 2019 / 133531) and refer to the crystal structures PDB 6UYA, 4YP8, 5UIU, and 6F3I. 【Figure 19A-19D】A diagram showing non-limiting examples of targeting ligands for FGFR2 and FGFR3, where R is the point to which the linker is attached. For additional examples, see "Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2", Bioorg Med Chem 2020, 28, 115453. 【Figure 20A-20D】 A diagram showing non-limiting examples of targeting ligands for SMARCA2, where R is the point to which the linker is attached. For additional examples, see International Publication No. WO 2020 / 023657, US Patent Application Publication No. US 2020 / 0038378, International Publication No. WO 2020 / 010227, International Publication No. WO 2020 / 078933, International Publication No. WO 2019 / 207538, International Publication No. WO 2016 / 138114, "Discovery of Orally Active Inhibitors of Brahma Homolog (BRM) / SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1) / SMARCA4-Mutant Cancers", J Med Chem 2018, 61, 10155, and 2) International Publication No. WO 2020 / 035779. 【Figure 21A-21J】FIG. showing non-limiting examples of NRAS-targeting ligands, where R represents an exemplary point to which a linker can be attached.For additional examples, see "Small-molecule Ligands Bing to a Distinct Pocket in Ras and Inhibit SOS-Mediated Nucleotide Exchange Activity" PNAS 2012 109 (14) 5299-5304, crystal structure PDB 4EPY ("Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation" Angew. Chem. Int. Ed 2012, 51, 6140-6143), crystal structures PDB 6GQY, 6GQT ("Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds" 2019 PNAS 116 (7), 2545-2550), crystal structures PDB 6FA4, 1HE8 ("Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment" 2018 Nature Communications 9(1), 3169), and "Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding" ACS Omega 2019, 4, 2921-2930. 【Figure 22】 A diagram showing non-limiting examples of ADAR targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structure PDB 6VFF (Thuy-Boun, A.S., et al, Nucleic Acids Res, 2020, 48, 7958-7972), and the crystal structures PDB 5HP2, 5HP3, 5ED1, 5ED2 (Mathews, M.M, et al., Nat Struct Mol Biol., 2016, 23, 426-433). 【Figure 23】 A diagram showing non-limiting examples of NSD2 or WHSC1 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structure PDB 6XCG ("Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934" by Zhou, M.Q, et al. (scheduled for publication)), the crystal structure PDB 6UE6 ("PWWP1 domain of NSD2 in complex with MR837" by Liu, Y et al. (scheduled for publication)), the crystal structures PDB 5LSS, 5LSU, 5LSX, 5LSY, 5LSZ, 5LT6, 5LT7, 5LT8 (Tisi, D., et al, "Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.", ACS Chem Biol., 2016, 11: 3093-3105). 【Figure 24】Figure showing non-limiting examples of targeted ligands for PI3KCA, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structures PDB 3HHM, 3HIZ (Mandelker, D., et al., "A frequent kinase domain mutation that changes the interaction between PI3K{alpha} and the membrane.", Proc Natl Acad Sci U S A., 2009, 106: 16996-17001). 【Figure 25】 Figure showing non-limiting examples of targeted ligands for RIT1, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structure PDB 4KLZ (Shah, D.M., et al., "Inhibition of Small GTPases by Stabilization of the GDP Complex, a Novel Approach applied to Rit1, a Target for Rheumatoid Arthritis" (to be published)). 【Figure 26】A diagram showing non-limiting examples of targeting ligands for WRN, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structure PDB 2FC0 ("WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing.", Perry, J.J., et al., Nat Struct Mol Biol., 2006, 13: 414-422), and the crystal structure PDB 6YHR ("Crystal structure of Werner syndrome helicase", Newman, J.A., et al., (forthcoming)). 【Figure 27】Figure showing non-limiting examples of targeting ligands for ALK fusions, such as EML4-ALK or NMP-ALK, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 4CGB, 4CGC ("Microtubule Association of Eml Proteins and the Eml4-Alk Variant 3 Oncoprotein Require an N-Terminal Trimerization Domain" by Richards, M.W., et al., Biochem J., 2015, 467: 529), crystal structure PDB 3AOX ("CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant" by Sakamoto, H., et al., Cancer Cell, 2011, 19: 679-690), crystal structure PDB 6MX8 ("Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase" by Huang, W.S., et al., J Med Chem., 2016, 59: 4948-4964), 4Z55 ("Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors." by Michellys, P.Y., et al., Bioorg Med Chem Lett., 2016, 26: 1090-1096), and the crystal structures PDB 4FOB, 4FOC, 4FOD (see "The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer." by Lewis, R.T., et al., J Med Chem., 2012, 55: 6523-6540). 【Figure 28】 FIG. showing non-limiting examples of BAP1 targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 2W12, 2W13, 2W14, 2W15 (see "High-Resolution Crystal Structure of the Snake Venom Metalloproteinase Bap1 Complexed with a Peptidomimetic: Insight into Inhibitor Binding" by Lingott, T.J. et al., Biochemistry, 2009, 48: 6166). 【Figure 29】FIG. showing non-limiting examples of targeting ligands for EPAS1 or HIF2α, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 5UFP ("On-target efficacy of a HIF-2 alpha antagonist in preclinical kidney cancer models.", by Cho, H., et al., Nature, 2016, 539: 107-111), crystal structure PDB 6D09 ("Crystal structure of PT1940 bound to HIF2a-B*:ARNT-B* complex", by Du, X (to be published)), crystal structure PDB 5TBM ("A Small-Molecule Antagonist of HIF2 alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.", by Wallace, E.M., et al., Cancer Res., 2016, 76: 5491-5500), and crystal structures PDB 6E3S, 6E3T, 6E3U ("Bidirectional modulation of HIF-2 activity through chemical ligands.", by Wu, D., et al., Nat Chem Biol., 2019, 15: 367-376). 【Figure 30A-30B】Figure showing non-limiting examples of GRB2-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 1CJ1 ("Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic" by Furet, P., et al., J Med Chem., 1999, 42: 2358-2363), crystal structures PDB 2AOA, 2AOB ("Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain" by Phan, J., et al., J Mol Biol., 2005, 353: 104-115), crystal structures PDB 3KFJ, 3IN7, 3IMJ, 3IMD, 3IN8 ("Thermodynamic and structural effects of conformational constraints in protein-ligand interactions."(Thermodynamic and Structural Effects of Conformational Constraints in Protein-Ligand Interactions. Entropic Paradoxy Associated with Ligand Preorganization.)", J Am Chem Soc., 2009, 131: 16758-16770), crystal structure PDB 2HUW, 3C71 (Benfield, A.P., et al., "Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein-Ligand Interactions.", Angew Chem Int Ed Engl., 2006, 45: 6830-6835), and crystal structure PDB 1X0N (Ogura, K et al., "NMR structure of growth factor receptor binding protein SH2 domain complexed with the inhibitor" (scheduled for publication)). See also.", 【Figure 31】FIG. showing non-limiting examples of targeting ligands for KMT2D or MLL2 / MLL4, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 7BRE ("Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases" by Li, Y., et al., Structure, 2020), crystal structure PDB 4ZAP ("Evolving Catalytic Properties of the MLL Family SET Domain." by Zhang, Y., et al., Structure, 2015, 23: 1921-1933), crystal structure PDB 6KIZ ("Structural basis of nucleosome recognition and modification by MLL methyltransferases." by Xue, H., et al., Nature, 2019, 573: 445-449), and crystal structure PDB 3UVK ("The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases." by Zhang, P., et al., Nucleic Acids Res., 2012, 40: 4237-4246). 【Figure 32】Figure showing non-limiting examples of targeting ligands for MLLT1 or ENL, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 6HT0, 6HT1 (Discovery of an MLLT1 / 3 YEATS Domain Chemical Probe by Moustakin, M. et al., Angew Chem Int Ed Engl., 2018, 57: 16302-16307), crystal structures PDB 6T1I, 6T1J, 6TIL, 6T1M, 6T1N, 6T1O (Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1 by Ni, X., et al., ACS Med Chem Lett., 2019, 10: 1661-1666), and crystal structures PDB 6HPW, 6HPY, 6HPX, 6HPZ (Structure-Based Approach toward Identification of Inhibitory Fragments for Eleven-Nineteen-Leukemia Protein (ENL) by Heidenreich, D., et al., J Med Chem., 2018, 61: 10929-10934). 【Figure 33】FIG. showing non-limiting examples of targeted ligands for NSD3, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 6G24, 6G25, 6G29, 6G2B, 6G2C, 6G2E, 6G2F, 6G2O, 6G3T (Bottcher, J., et al., "Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3", Nat Chem Biol., 2019, 15: 822-829), crystal structure PDB 5UPD (Tempel, W., et al., "Methyltransferase domain of human Wolf-Hirschhorn Syndrome Candidate 1-Like protein 1 (WHSC1L1)" (to be published)), and crystal structure PDB 6CEN (Morrison, M.J., et al., "Identification of a peptide inhibitor for the histone methyltransferase WHSC1", PLoS One, 2018, 13: e0197082-e0197082). 【Figure 34】A diagram showing non-limiting examples of targeting ligands for PPM1D or WIP1, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structure PDB 3UYH, ADA3, 4DAQ (Micco, M., et al., "Structure-based design and evaluation of naphthalene diimide g-quadruplex ligands as telomere targeting agents in pancreatic cancer cells", J Med Chem., 2013, 56: 2959-2974). 【Figure 35A-35B】Figure showing non-limiting examples of SOS1-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see crystal structures PDB 5OVE, 5OVF, 5OVG, 5OVH, 5OVI (Hillig, R.C., et al., "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction", Proc Natl Acad Sci U S A., 2019, 116: 2551-2560), crystal structure PDB 6F08 (Ballone, A., et al., "Structural characterization of 14-3-3 zeta in complex with the human Son of sevenless homolog 1 (SOS1)", J Struct Biol., 2018, 202: 210-215), crystal structures PDB 6D5E, 6D5G, 6D5H, 6D5J, 6D5L, 6D5M, 6D5V, 6D5W, 6D55, 6D59 (Hodges, T.R. et al., "Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS", J Med Chem., 2018, 61: 8875-8894), crystal structures PDB 6SCM, 6SFR (Kessler, D., et al., "SOS1 in Complex with Inhibitor BI-3406" (to be published)), crystal structures PDB 6V94, 6V9J, 6V9L, 6V9M, 6V9N (Sarkar, D., et al., "Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods," J Med Chem., 2020, 63: 8325-8337). See also. 【Figure 36A】 Figure showing non-limiting examples of targeting ligands for TBXT or Brachyury, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 5QS6, 5QSC, 5QSE, 5QSF, 5QRW (Newman, J. A., et al., "PanDDA analysis group deposition" (to be published)), and crystal structure PBD 6ZU8 (Newman, J. A., et al., "Crystal structure of human Brachyury G177D variant in complex with Afatinib" (to be published)). 【Figure 37A-37C】Figure showing non-limiting examples of USP7-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see crystal structures PDB 5UQV, 5UQX ("USP7 small-molecule inhibitors interfere with ubiquitin binding", by Kategaya, L., et al., Nature, 2017, 550: 534-538), crystal structures PDB 6VN2, 6VN3, 6VN4, 6VN5, 6VN6 ("Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.", by Leger, P.R., et al., J Med Chem., 2020, 63: 5398-5420), and crystal structures PDB 5N9R, 5N9T ("Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.", by Gavory, G., et al., Nat Chem Biol., 2018, 14: 118-125), and crystal structures PDB 5NGE, 5NGF ("Molecular basis of USP7 inhibition by selective small-molecule inhibitors", by Turnbull, A.P., et al., Nature, 2017, 550: 481-486). 【Figure 38】A diagram showing non-limiting examples of targeted ligands for BKV and JCV, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 5J4V, 5J4Y ("Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors" by Bonafoux, D., et al., J Med Chem., 2016, 59: 7138-7151). 【Figure 39】 A diagram showing non-limiting examples of targeted ligands for CK1α (casein kinase 1α), where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 5ML5, 5MQV ("Optimized 4,5-Diarylimidazoles as Potent / Selective Inhibitors of Protein Kinase CK1 delta and Their Structural Relation to p38 alpha MAPK" by Halekotte, J., et al., Molecules, 2017, 22). 【Figure 40】 A diagram showing non-limiting examples of targeted ligands for GSPT1 / ERF3, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 5LZT, 5LZS, 5LZV, 5LZU, 5LZX, 5LZW, 5LZZ, 5LZY ("Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes" by Shao, S., et al., Cell, 2016, 167: 1229-1240.e15). 【Figure 41】Figure showing non-limiting examples of targeting ligands for IFZV, where R represents exemplary points to which a linker can be attached. For additional examples, see crystal structure PDB (Iyer, S., et al., "The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 A resolution.", J Biol Chem., 2001, 276: 12153-12161), and crystal structure PDB IRV6 (Christinger, H.W., et al., "The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1", J Biol Chem., 2004, 279: 10382-10388). 【Figure 42】 Figure showing non-limiting examples of targeting ligands for NSD2, where R represents exemplary points to which a linker can be attached. For additional examples, see crystal structure PDB 6XCG (Zhou, M.Q., "Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934" (scheduled for publication)), and crystal structure PDB 6UE6 (Liu, Y., et al., "PWWP1 domain of NSD2 in complex with MR837" (scheduled for publication)). 【Figure 43】Figure showing non-limiting examples of targeting ligands for TAU, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structures PDB 6VA2, 6VA3 ("Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing." by Chen, J.L. et al., J Am Chem Soc., 2020, 142: 8706-8727). 【Figure 44】 Figure showing non-limiting examples of targeting ligands for CYP17A1, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structures PDB 3RUK, 3SWZ ("Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001" by Devore, N.M. et al., Nature, 2012, 482: 116-119), and the crystal structures PDB 6CHI, 6CIZ ("Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2" by Fehl, C., et al., J Med Chem., 2018, 61: 4946-4960). 【Figure 45】Figure showing non-limiting examples of SALL4-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structures PDB 7BQU, 7BQV ("Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide" by Furihata, H., et al., Nat Commun., 2020, 11: 4578-4578), and the crystal structure PDB 6UML ("Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex" by Matyskiela, M.E., et al., Nat Struct Mol Biol., 2020, 27: 319-322). 【Figure 46】 Figure showing non-limiting examples of FAM38-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structure PDB 6KG7 ("Structure and mechanogating of the mammalian tactile channel PIEZO2." by Wang, L., et al., Nature, 2019, 573: 225-229). 【Figure 47】 Figure showing non-limiting examples of CYP20A1-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see Durairaj et al. Biological Chemistry, 2020, 401(3), 361-365. 【Figure 48】Figure showing non-limiting examples of HTT-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structure PDB 5XI1 ("Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington's Disease (HD) and Spino Cerebellar Ataxia (SCAs).", Khan, E., et al., ACS Chem Biol., 2018, 13: 180-188). 【Figure 49】 Figure showing non-limiting examples of KRAS-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see the crystal structure PDB 6CU6 ("Atypical KRASG12RMutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer.", Hobbs, G.A., et al., Cancer Discov., 2020, 10: 104-123), crystal structures PDB 6GJ5, 6GJ6, 6GJ8, 6JG7 ("Drugging an Undruggable Pocket on KRAS", PNAS 2019 116 (32) 15823-15829), and crystal structure PDB 6BP1 ("KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation.", Lu, J., et al., Biochemistry, 2018, 57: 324-333). 【Figure 50】Figure showing non-limiting examples of NRF2 (NFE2L2)-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 5CGJ ("Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling." by Winkel, A.F., et al., J Biol Chem., 2015, 290: 28446-28455), and 6TYM, 6TYP ("Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators" by Ma, B., et al., Bioorg Med Chem Lett., 2020, 30: 126852-126852). 【Figure 51】Figure showing non-limiting examples of P300-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 4PZR, 4PZS, 4PZT (Maksimoska, J., et al., "Structure of the p300 Histone Acetyltransferase Bound to Acetyl-Coenzyme A and Its Analogues," Biochemistry, 2014, 53: 3415-3422), and the crystal structure PDB 6PGU (Gardberg, A.S., et al., "Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT," Struct Dyn., 2019, 6: 054702-054702). 【Figure 52】Figure showing non-limiting examples of PIK3CA-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see crystal structure PDB 6OAC (Rageot, D., et al., " (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase," J Med Chem., 2019, 62: 6241-6261), and crystal structures PDB 5SX8, 5SWP (Miller, M.S. et al., "Identification of allosteric binding sites for PI3K alpha oncogenic mutant specific inhibitor design.", Bioorg Med Chem., 2017, 25: 1481-1486). 【Figure 53】A diagram showing non-limiting examples of SARM1-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structure PDB 6QWV ("Structural Evidence for an Octameric Ring Arrangement of SARM1" by Sporny, M., et al., J Mol Biol., 2019, 431: 3591-3605), and the crystal structures PDB 6O0Q, 6O0R, 6O0T, 6O0V, 6O0W ("NAD+ cleavage activity by animal and plant TIR domains in cell death pathways" by Horsefield, S., et al., Science, 2019, 365: 793-799). 【Figure 54】 A diagram showing non-limiting examples of SNCA-targeting ligands, where R represents an exemplary point to which a linker can be attached. For additional examples, see the crystal structures PDB 4I5M, 4I5P, 4I6B, 4I6F, 4I6H ("Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain" by Aubele, D.L., et al., Chem Med Chem., 2013, 8: 1295-1313). 【Figure 55】A diagram showing non-limiting examples of targeted ligands for MAPT, where R represents an exemplary point to which a linker can be attached. For example, crystal structures PDB 6VI3, 6VHL (Arakhamia, T., et al., "Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains", Cell, 2020, 180: 633-644.e12), and crystal structures PDB 6FAU, 6FAV, 6FAW, 6FBW, 6FBY, 6FI4, 6FI5 (Andrei, S. A., et al., "Inhibition of 14-3-3 / Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes.", ACS Chem Neurosci., 2018, 9: 2639-2654). 【Figure 56】 A diagram showing non-limiting examples of targeted ligands for PTPN2 or TCPTP, where R represents an exemplary point to which a linker can be attached. For example, crystal structures PDB 2FJN, 2FJM (Asante-Appiah, E., et al., "Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase", J Biol Chem., 2006, 281: 8010-8015). 【Figure 57】A diagram showing non-limiting examples of STAT3-targeting ligands, where R represents an exemplary point to which a linker can be attached. The examples shown here are derived from the compounds in Zheng, W. et al., "MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain", Theranostics 2017, 7(18):4632, and US Patent Application Publication No. 2006 / 0247318. For additional examples, see Yang, L. et al., "Novel Activators and Small-Molecule Inhibitors of STAT3 in Cancer, Cytokine & Growth Factor", Reviews 2019, 49, 10-22. 【Figure 58】It is a diagram showing non-limiting examples of MyD88-targeting ligands, where R represents an exemplary point to which a linker can be attached. The examples shown here are derived from compounds in "Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signaling" by Sucking, C. et al (2018) 8:2123, and "Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound." by Loiarro, M. et al, Journal of Leukocyte Biology, (2007) 82: 801-810. 【Figure 59】Figure showing non-limiting examples of PTP4A3-targeting ligands, where R represents an exemplary point to which a linker can be attached. The examples shown here are derived from the compounds in "Synthesis and Biological Evaluation of Rhodanine D derivatives as PRL-3 Inhibitors" by Ahn, J. et al, Bioorganic & Medicinal Chemistry Letters (2006) 16(11):2996-2999, and "Rhodanine-Based PRL-3 Inhibitors Blocked the Migration and Invasion of Metastatic Cancer Cells" by Min, G. et al, Bioorganic & Medicinal Chemistry Letters (2013) 23(13):3769-3774. For additional examples, see "Tapping the Therapeutic Potential of Protein Tyrosine Phosphatase 4A with Small Molecule Inhibitors" by Tasker, N. et al, Bioorganic & Medicinal Chemistry Letters (2019) 29(16):2008-2015. 【Figure 60】Figure showing non-limiting examples of SF3B1-targeting ligands, where R represents exemplary points to which a linker can be attached. The examples shown herein are derived from the compounds in Kaida, D. et al, "Spliceostatin A Targets SF3b and Inhibits Both Splicing and Nuclear Retention of pre-mRNA," Nature Chemical Biology (2007) 3:576-583, and Kotake, Y. et al, "Splicing Factor SF3b as a Target of the Antitumor Natural Product Pladienolide," Nature Chemical Biology (2007) 3:570-575. For additional examples, see Effenberger, K. et al, "Modulating Splicing with Small Molecular Inhibitors of the Spliceosome," WIREs RNA (2016) 8:e1381. 【Figure 61】 Figure showing non-limiting examples of ARID1B- and ARID2-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see Chory et al. ACS Chemical Biology 2020, 15(6), 1685. 【Figure 62】 Figure showing non-limiting examples of class II BRAF mutant-targeting ligands, where R represents exemplary points to which a linker can be attached. For additional examples, see Cho et al. Biochemical and Biophysical Research Communications 2020, 352(2), 315. 【Figure 63】Figure showing non-limiting examples of targeted ligands for NRAS Q61K, where R represents an exemplary point to which a linker can be attached. For additional examples, see Song et al. Am J Cancer Res 2017, 7(4), 831, and Johnson et al. Curr Treat Options Oncol.2015, 16(4), 15. 【Figure 64A-64E】 Figure showing non-limiting examples of targeted ligands for ataxia telangiectasia mutated (ATM) kinase, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in J Med Chem, 2019, 62: 2988-3008. 【Figure 65A-65B】 Figure showing non-limiting examples of targeted ligands for ATR, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in Journal of Molecular Biology Volume 429, Issue 11, 2 June 2017, Pages 1684-1704. 【Figure 66A-66C】 Figure showing non-limiting examples of targeted ligands for BPTF, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in Organic & Biomolecular Chemistry 2020, 18(27): 5174-5182. 【Figure 67A-67B】 Figure showing non-limiting examples of targeted ligands for DNA-PK, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in J. Med. Chem. 2020, 63, 7, 3461-3471. 【Figure 68A-68B】 Figure showing non-limiting examples of targeted ligands for elf4E, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in J. Am. Chem. Soc. 2020, 142, 4960-4964. 【Figure 69】A diagram showing non-limiting examples of targeting ligands for TEAD, such as TEAD1, TEAD2, TEAD3, and / or TEAD4, where R represents an exemplary point to which a linker can be attached. 【Figure 70】 A diagram showing non-limiting examples of targeting ligands for YAP, where R represents an exemplary point to which a linker can be attached. 【Figure 71】 A diagram showing non-limiting examples of the formula of the degron of the present invention. 【Figure 72】 A diagram showing non-limiting examples of targeting ligands for B-cell lymphoma 6 protein (BCL6), where R represents an exemplary point to which a linker can be attached. Additional examples are shown in J. Bio. Chem. 2021, 297, 2, 100928 and Cancer Lett. 2022, 529, 100 - 111. 【Figure 73A-73B】 A diagram showing non-limiting examples of HDAC corepressors of targeting ligands for repressor element-1 silencing transcription factor (CoREST) or CoREST complex targeting ligands, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in ACS Chem. Neurosci. 2019, 10, 1729 - 1743. 【Figure 74A-74M】 A diagram showing non-limiting examples of targeting ligands for colony-stimulating factor 1 receptor (CSF1R), where R represents an exemplary point to which a linker can be attached. Additional examples are shown in Expert Opin. on Ther. Pat. 2021, 31, 2, 107 - 117 and Nature Communications 2019, 10, 3758. Crystal structures related to these targeting ligands include PDB code 3krj and PDB code 4r7h. 【Figure 75A-75B】FIG. showing non-limiting examples of diacylglycerol kinase (DGK)-targeting ligands, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in Cell Chem. Biol. 2017, 24, 870-880, International Publication No. 2022 / 187406, and International Publication No. 2021 / 127554. 【Figure 76】 FIG. showing non-limiting examples of son of sevenless homolog 1 (SOS1)-targeting ligands, where R represents an exemplary point to which a linker can be attached. Crystal structures related to these targeting ligands include 5ovi, 6scm, and 7ukr. 【Figure 77】 FIG. showing non-limiting examples of tyrosine kinase 2 (TYK2)-targeting ligands, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in J. Med. Chem. 2023, 66, 4378-4416. 【Figure 78】 FIG. showing non-limiting examples of ubiquitin-specific peptidase 1 (USP1)-targeting ligands, where R represents an exemplary point to which a linker can be attached. Additional examples are shown in International Publication No. 2021 / 163530. 【Figure 79A-79J】 FIG. showing non-limiting examples of hematopoietic progenitor kinase (HPK1)-targeting ligands, where R represents an exemplary point to which a linker can be attached. Additional examples are described in Expert Opin. on Ther. Pat. 2021, 31, 10, 893-910. 【DETAILED DESCRIPTION OF THE INVENTION】 【0048】 I. DEFINITIONS Compounds are described using their official names. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. 【0049】 Compounds of any of the formulas described herein can exist in isomeric forms such as racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, or rotamers, as if each were specifically recited, unless specifically excluded by context. 【0050】 The terms "a" and "an" are not intended to denote a limitation of quantity but rather the presence of at least one of the items being referred to. The term "or" means "and / or". The recitation of a range of values is intended to serve simply as a convenient method of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is hereby incorporated by reference as if it were individually recited herein. All endpoints of the ranges are included within the range and can be combined independently. All methods described herein can be performed in a suitable order, unless otherwise specified herein or clearly precluded by context. The use of the word "example" or "exemplary" (e.g., "such as") is intended merely to better illustrate the invention and does not denote a limitation of the scope of the invention, unless otherwise recited in the claims. 【0051】 The present invention includes degron or degrader compounds having isotope substitution of at least one desired atom at an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., having the same number of protons but different numbers of neutrons. 【0052】 Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F,31 P, 32 P, 35 S, 36 Cl and 125 I, respectively. In a non-limiting embodiment, an isotope-labeled compound can be used in metabolic studies (e.g., 14 using 2 C), kinetic studies (e.g., 3 using 18 H or 【0053】 H), detection or imaging techniques including drug or substrate tissue distribution assays or radiotherapy of patients, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). In particular, 【0054】 【0055】 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and prodrugs of the present invention can generally be prepared by replacing readily available non-isotope-labeled reagents with isotope-labeled reagents and performing the schemes or procedures disclosed in the following examples and preparations. 【0053】 Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched at 90%, 95% or 99% or more at any position of the subject. In a non-limiting embodiment, deuterium is enriched at 90%, 95% or 99% at the desired position. 【0054】 In a non-limiting embodiment, substitution of a hydrogen atom by a deuterium atom can be effected in a degron or degrader compound. 【0055】 In a non-limiting embodiment, substitution of a hydrogen atom by a deuterium atom is effected in one or more groups selected from R or a variable part, a linker, and a targeting ligand as described herein. For example, any of the groups may be methyl, ethyl, or methoxy, or an alkyl residue may be deuterated if containing these by substitution (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated. 【0056】 The compounds of the present invention may form solvates with solvents (including water). Accordingly, in one non-limiting embodiment, the present invention includes compounds in solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. Solvates can be in liquid form or solid form. 【0057】 A dash symbol ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached via the carbon of the carbonyl (C=O) group. 【0058】 "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one non-limiting embodiment, alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, alkyl is C1 or C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein indicate alkyl groups having each member of the range described as a separate species. For example, the term C1-C6 alkyl as used herein refers to straight-chain or branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species, and thus each subset is considered to be separately disclosed. For example, the term C1-C4 alkyl as used herein refers to straight-chain or branched-chain alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when a term containing "alk" is used, "cycloalkyl" or "carbocyclic(al)" may be part of its definition, unless clearly excluded by the context. For example, without limitation, terms such as alkyl, alkoxy, haloalkyl, etc. may be considered to include the cyclic forms of alkyl, unless clearly excluded by the context. 【0059】 In one embodiment, "alkyl" is C1-C 10It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl. 【0060】 In one embodiment, "alkyl" contains 1 carbon. 【0061】 In one embodiment, "alkyl" contains 2 carbons. 【0062】 In one embodiment, "alkyl" contains 3 carbons. 【0063】 In one embodiment, "alkyl" contains 4 carbons. 【0064】 In one embodiment, "alkyl" contains 5 carbons. 【0065】 In one embodiment, "alkyl" contains 6 carbons. 【0066】 Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl. 【0067】 Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl. 【0068】 Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl. 【0069】 Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl. 【0070】 Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl. 【0071】 In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl or C6-C8 cycloalkyl. 【0072】 In one embodiment, "cycloalkyl" has 3 carbons. 【0073】 In one embodiment, "cycloalkyl" has 4 carbons. 【0074】 In one embodiment, "cycloalkyl" has 5 carbons. 【0075】 In one embodiment, "cycloalkyl" has 6 carbons. 【0076】 In one embodiment, "cycloalkyl" has 7 carbons. 【0077】 In one embodiment, "cycloalkyl" has 8 carbons. 【0078】 In one embodiment, "cycloalkyl" has 9 carbons. 【0079】 In one embodiment, "cycloalkyl" has 10 carbons. 【0080】 Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl. 【0081】 Additional non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring. 【0082】 For example, [Chemistry] is a "cycloalkyl" group. 【0083】 However, [Chemistry] is an "aryl" group. 【0084】 "Alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at any stable point along the chain. The specified ranges used herein indicate alkenyl groups having each member of the ranges described as independent species as above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation. 【0085】 "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The specified ranges used herein indicate alkynyl groups having each member of the ranges described as independent species as above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. The term "alkynyl" also encompasses cycloalkyl or carbocyclic groups having at least one triple bond. 【0086】 "Alkylene" is a divalent saturated hydrocarbon. Alkylene has, for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 1 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C1 or C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene or C1-C6 alkylene. 【0087】 "Alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylene has, for example, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C2-C4 alkenylene. 【0088】 "Alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylene has, for example, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C2-C4 alkynylene. 【0089】 "Halo" and "halogen" each independently refer to fluorine, chlorine, bromine or iodine. 【0090】 "Haloalkyl" is a branched or straight-chain alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl. 【0091】 In one embodiment, "haloalkyl" is C1-C 10It is haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1 or C2 haloalkyl. 【0092】 In one embodiment, "haloalkyl" has one carbon. 【0093】 In one embodiment, "haloalkyl" has one carbon and one halogen. 【0094】 In one embodiment, "haloalkyl" has one carbon and two halogens. 【0095】 In one embodiment, "haloalkyl" has one carbon and three halogens. 【0096】 In one embodiment, "haloalkyl" has two carbons. 【0097】 In one embodiment, "haloalkyl" has three carbons. 【0098】 In one embodiment, "haloalkyl" has four carbons. 【0099】 In one embodiment, "haloalkyl" has five carbons. 【0100】 In one embodiment, "haloalkyl" has six carbons. 【0101】 Non-limiting examples of "haloalkyl" include 【Chemical formula】 may be mentioned. 【0102】 Additional non-limiting examples of "haloalkyl" include 【Chemical formula】 include. 【0103】 Additional non-limiting examples of "haloalkyl" include [Chemical formula] include. 【0104】 Additional non-limiting examples of "haloalkyl" include [Chemical formula] include. 【0105】 "Chain" refers to a straight chain where all other chains, whether long or short or both, can be considered pendant. When two or more chains can be considered equally as the main chain, "chain" refers to the one that leads to the simplest representation of the molecule. 【0106】 "Haloalkoxy" refers to a haloalkyl group as defined herein attached via an oxygen bridge (the oxygen of the alcohol radical). 【0107】 "Heterocycloalkyl" is an alkyl group as defined herein substituted with a heterocyclo group as defined herein. 【0108】 "Arylalkyl" is an alkyl group as defined herein substituted with an aryl group as defined herein. 【0109】 Non-limiting examples of "arylalkyl" include [Chemical formula] include. 【0110】 In one embodiment, "arylalkyl" is [Chemical formula] It is. 【0111】 In one embodiment, "arylalkyl" refers to a C2 alkyl group substituted with an aryl group. 【0112】 Non-limiting examples of "arylalkyl" include 【Chemical formula】 and the like. 【0113】 In one embodiment, "arylalkyl" refers to a C3 alkyl group substituted with an aryl group. 【0114】 "Heteroarylalkyl" is an alkyl group as defined herein substituted with a heteroaryl group as defined herein. 【0115】 As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., where 6, 10, or 14 π electrons are shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms within an aromatic ring system (a radical of "C 6~14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl", for example anthracyl. "Aryl" also includes a ring system in which one or more of the aryl rings defined above are fused with one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. One or more fused carbocyclic or heterocyclic groups may optionally contain one, two or three heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, and may be a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group, for example forming a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In certain embodiments, the aryl group is unsubstituted C 6~14 is aryl. 【0116】 In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl). 【0117】 In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl). 【0118】 In one embodiment, "aryl" is a 6-carbon aromatic group condensed to a heterocycle with the point of attachment being the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring. 【0119】 For example, 【Chemical formula】 is an "aryl" group. 【0120】 However, 【Chemical formula】 is a "heterocyclic" group. 【0121】 In one embodiment, "aryl" is a six-carbon aromatic group fused to a cycloalkyl, where the point of attachment is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the aromatic ring. 【0122】 For example, 【Chemical formula】 is an "aryl" group. 【0123】 However, 【Chemical formula】 is a "cycloalkyl" group. 【0124】 The terms "heterocyclyl", "heterocyclic" and "heterocycle" include saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms can be selected from nitrogen, sulfur and oxygen. Heterocyclic rings include monocyclic 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered rings, and 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered or 16-membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). Heterocycles do not include rings containing -O-O-, -O-S- or -S-S- moieties. 【0125】 Examples of saturated heterocyclic groups include saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1, 2, 3 or 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms (e.g., morpholinyl), and saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclyl radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. 【0126】 Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, benzo[d]thiazol-2(3H)-onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl and dihydrothiazolyl. 【0127】 The terms "heterocyclyl", "heterocyclic", and "heterocycle" groups include moieties in which a heterocyclic radical is fused / condensed with an aryl or heteroaryl radical, such as unsaturated fused heterocyclic groups containing one, two, three, four, or five nitrogen atoms, such as indoline, isoindoline, unsaturated fused heterocyclic groups containing one or two oxygen atoms and one, two, or three nitrogen atoms, unsaturated fused heterocyclic groups containing one or two sulfur atoms and one, two, or three nitrogen atoms, and saturated, partially unsaturated, and unsaturated fused heterocyclic groups containing one or two oxygen or sulfur atoms. 【0128】 In one embodiment, "heterocyclic" refers to a cyclic ring having one nitrogen and three, four, five, six, seven, or eight carbon atoms. 【0129】 In one embodiment, "heterocyclic" refers to a cyclic ring having one nitrogen, one oxygen, and three, four, five, six, seven, or eight carbon atoms. 【0130】 In one embodiment, "heterocyclic" refers to a cyclic ring having two nitrogens and three, four, five, six, seven, or eight carbon atoms. 【0131】 In one embodiment, "heterocyclic" refers to a cyclic ring having one oxygen and three, four, five, six, seven, or eight carbon atoms. 【0132】 In one embodiment, "heterocyclic" refers to a cyclic ring having one sulfur and three, four, five, six, seven, or eight carbon atoms. 【0133】 Non-limiting examples of "heterocyclic" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane. 【0134】 Additional non-limiting examples of "heterocyclic" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine. 【0135】 Additional non-limiting examples of "heterocyclic ring" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. 【0136】 Additional non-limiting examples of "heterocyclic ring" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. 【0137】 Additional non-limiting examples of "heterocyclic ring" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group is on the heterocyclic ring. 【0138】 For example, 【Chem.】 is a "heterocyclic ring" group. 【0139】 However, 【Chem.】 is an "aryl" group. 【0140】 Non-limiting examples of "heterocyclic ring" include 【Chem.】 are also included. 【0141】 Additional non-limiting examples of "heterocyclic ring" include 【Chem.】 are included. 【0142】 Additional non-limiting examples of "heterocyclic ring" include 【Chem.】 include 【0143】 Non-limiting examples of the "heterocyclic ring" include [Chemical formula] also include 【0144】 Non-limiting examples of the "heterocyclic ring" include [Chemical formula] also include 【0145】 Additional non-limiting examples of the "heterocyclic ring" include [Chemical formula] include 【0146】 Additional non-limiting examples of the "heterocyclic ring" include [Chemical formula] include 【0147】 The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 π electrons are shared in a cyclic arrangement and having 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S), wherein the ring nitrogen and sulfur atoms (if plural) are optionally oxidized and the nitrogen atoms (if plural) are optionally quaternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom such as pyranyl, 2-furyl, 3-furyl; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom such as 2-thienyl, 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), but are not limited thereto. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. 【0148】 In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms. 【0149】 Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. 【0150】 Additional non-limiting examples of 5-membered "heteroaryl" groups include 【Chemical formula】 and the like. 【0151】 In one embodiment, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms. 【0152】 Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include 【Chemical formula】 and the like. 【0153】 In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. 【0154】 Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole. 【0155】 Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc. 【0156】 Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc. 【0157】 Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc. 【0158】 In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur. 【0159】 Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. 【0160】 Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc. 【0161】 In one embodiment, the groups described herein that can be substituted with one, two, three, or four substituents are substituted with one substituent. 【0162】 In one embodiment, the groups described herein that can be substituted with one, two, three, or four substituents are substituted with two substituents. 【0163】 In one embodiment, the groups described herein that may be substituted with one, two, three, or four substituents are substituted with three substituents. 【0164】 In one embodiment, the groups described herein that may be substituted with one, two, three, or four substituents are substituted with four substituents. 【0165】 "Aliphatic" refers to saturated or unsaturated straight-chain, branched, or cyclic hydrocarbons. As used herein, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and encompasses each of these definitions. In one embodiment, "aliphatic" is used to denote an aliphatic group having from 1 to 20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or poly-unsaturated, or alkynyl. The unsaturated aliphatic group can be in the cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. 【0166】 In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1 or C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein denote aliphatic groups having each member of the ranges described as independent species. For example, the term C1-C6 aliphatic as used herein denotes straight-chain or branched alkyl, alkenyl, or alkynyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as an independent species. For example, the term C1-C4 aliphatic as used herein denotes straight-chain or branched alkyl, alkenyl, or alkynyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups such that a stable moiety is formed. 【0167】 The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon or boron atom, instead of a carbon atom in the chain. In one embodiment, the heteroatom is only nitrogen. In one embodiment, the heteroatom is only oxygen. In one embodiment, the heteroatom is only sulfur. 【0168】 As used herein, "heteroaliphatic" is intended to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having from 1 to 20 carbon atoms. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc. 【0169】 "Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" may also include an implant, such as an optical implant. 【0170】 "Effective amount", as used herein, means an amount that produces a therapeutic or prophylactic effect. 【0171】 As used herein, "endogenous" refers to any substance that is from or produced within a living organism, cell, tissue or system. 【0172】 As used herein, the term "exogenous" refers to any substance introduced from outside or produced externally to an organism, cell, tissue or system. 【0173】 As used herein, the term "modulate" means to mediate a detectable increase or decrease in the level of response in a subject as compared to the level of response in the subject in the absence of treatment or compound, and / or as compared to the level of response in an untreated subject that is otherwise identical. This term encompasses disturbing or otherwise affecting an intrinsic signal or response to mediate a beneficial therapeutic response in a subject, preferably a human, by disturbing and / or affecting the same. 【0174】 "Parenteral" administration of a pharmaceutical composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.) or intracardiac injection, or infusion. 【0175】 As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably and refer to a compound composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present in the sequence of a protein or peptide is usually of the same order as that found in nature. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, this term refers to both short chains generally referred to in the art as, for example, peptides, oligopeptides and oligomers, and longer chains generally referred to in the art as proteins, of which there are many types. "Polypeptide" includes, in particular, bioactive fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins. Polypeptides include natural peptides, recombinant peptides, synthetic peptides or combinations thereof. 【0176】 As used herein, "treating" a disease means reducing the frequency or severity of at least one sign or symptom of the disease or disorder experienced by a subject (i.e., palliative treatment), or reducing the cause or effect of the disease or disorder (i.e., disease-modifying treatment). 【0177】 Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as limiting the scope of the invention. The description of a range should be considered to specifically disclose all possible sub-ranges and individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. 【0178】 As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance such as a carrier. "Pharmaceutical combinations" are combinations of at least two active agents that can be combined in a single dosage form or administered together in separate dosage forms, and the active agents are indicated to be used in combination for treating any disorder described herein. 【0179】 As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by making non-toxic inorganic and organic acids or their base addition salts. The salts of the present compounds can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in the free acid form with a stoichiometric amount of an appropriate base (hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or reacting these compounds in the free base form with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical when practicable. The salts of the present compounds further include solvates of the compounds and the salts of the compounds. 【0180】 Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids and quaternary ammonium salts. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nSalts prepared from organic acids such as -COOH (where n is from 0 to 4), or from different acids that generate the same counterion, may be mentioned. A further list of more suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). 【0181】 The term "carrier" as used in the pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient or vehicle administered together with the active compound. 【0182】 "Pharmaceutically acceptable excipients" generally means excipients that are safe, non-toxic and not biologically or otherwise inappropriate for administration to a host (usually a human), and are useful in the preparation of pharmaceutical compositions / combinations. In one embodiment, excipients acceptable for veterinary use are employed. 【0183】 "Patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders specifically described herein, which can be regulated, for example, by a natural (wild-type) or modified (non-wild-type) protein that degrades and can bring about a therapeutic effect according to the present invention. Usually, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. 【0184】 The "therapeutically effective amount" of the pharmaceutical compositions / combinations of the present invention means an amount effective to bring about a therapeutic effect such as improvement of symptoms or reduction or alleviation of the disease itself when administered to a host. 【0185】 II. Compounds of the present invention In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula IAa, formula IAb, or formula IAc: 【Chemical formula】 There is provided a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0186】 In certain embodiments, the degron compound of the present invention is 【Chem.】 selected from TIFF2025523393000053.tif48170 or a pharmaceutically acceptable salt thereof. 【0187】 In certain embodiments, the degron compound of the present invention is 【Chem.】 or a pharmaceutically acceptable salt thereof. 【0188】 In certain embodiments, the degron compound of the present invention is 【Chem.】 or a pharmaceutically acceptable salt thereof. 【0189】 In certain embodiments, the degron compound of the present invention is 【Chem.】 selected from TIFF2025523393000057.tif159170 or a pharmaceutically acceptable salt thereof. 【0190】 In certain embodiments, the degron compound of the present invention is 【Chem.】 selected from TIFF2025523393000059.tif53170 or a pharmaceutically acceptable salt thereof. 【0191】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IIAa, formula IIAb, or formula IIAc: 【Chemical formula】 is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0192】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IIIAa, formula IIIAb, or formula IIIAc: 【Chemical formula】 is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0193】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IVAa, formula IVAb, or formula IVAc: 【Chemical formula】 is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0194】 In certain embodiments, the compounds of the invention are of the formula: 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0195】 In certain embodiments, the compounds of the invention are of the formula: 【Chemical formula】 is a compound of formula (I), or a pharmaceutically acceptable salt thereof. 【0196】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VAa, formula VAb, or formula VAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0197】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIAa, formula VIAb, or formula VIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0198】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIIAa, formula VIIAb, or formula VIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0199】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIIIAa, formula VIIIAb, or formula VIIIAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above. 【0200】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula IXAa, formula IXAb, or formula IXAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above. 【0201】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula XAa, formula XAb, or formula XAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above. 【0202】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula XIAa, formula XIAb, or formula XIAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above. 【0203】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIIAa, formula XIIAb, or formula XIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0204】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIIIAa, formula XIIIAb, or formula XIIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0205】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIVAa, formula XIVAb, or formula XIVAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above. 【0206】 In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XVAa, formula XVAb, or formula XVAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, In the formula, all variable parts are as defined above. 【0207】 In certain embodiments, optionally, a degron compound of formula XVIAa, formula XVIAb, or formula XVIAc: 【Chemical formula】 is provided in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, In the formula, all variable parts are as defined above. 【0208】 In certain embodiments, optionally, a degron compound of formula XVIIAa, formula XVIIAb, formula XVIIAc, formula XVIIAd or formula XVIIAe: 【Chemical formula】 is provided in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, In the formula, all variable parts are as defined above. 【0209】 In certain embodiments, the present invention relates to a compound of formula IA: 【Chemical formula】 TIFF2025523393000079.tif213170TIFF2025523393000080.tif53170, or a pharmaceutically acceptable salt thereof. 【0210】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0211】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 compounds of formula IIA selected from, or a pharmaceutically acceptable salt thereof. 【0212】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 selected from TIFF2025523393000084.tif102170 or a pharmaceutically acceptable salt thereof. 【0213】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 compounds of formula IIIA selected from TIFF2025523393000086.tif221170 TIFF2025523393000087.tif221170 TIFF2025523393000088.tif58170, or a pharmaceutically acceptable salt thereof. 【0214】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 or selected from a pharmaceutically acceptable salt thereof. 【0215】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 or selected from a pharmaceutically acceptable salt thereof. 【0216】 In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII: 【Chemical formula】 a degrader compound of TIFF2025523393000092.tif181170TIFF2025523393000093.tif221170TIFF2025523393000094.tif216170TIFF2025523393000095.tif58170, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof is provided, wherein all variable parts are as defined above. 【0217】 In certain embodiments, 【Chemical formula】 is 【Chemical formula】 selected from 【0218】 In certain embodiments, 【Chemical formula】 is 【Chemical formula】 selected from 【0219】 In certain embodiments, 【Chemical formula】 is 【Chemical formula】 selected from 【0220】 In certain embodiments, 【Chemical formula】 is 【Chemical formula】 selected from 【0221】 In certain embodiments, the compounds of the present invention are 【Chemical formula】 compounds of formula VA selected from TIFF2025523393000105.tif248170, or a pharmaceutically acceptable salt thereof. 【0222】 In certain embodiments, the formula: 【Chemical formula】 of the degrader compound is provided, the degron is the degron described herein, and the attachment point to the linker is on the bicyclic ring, A ring, or B ring. In a preferred embodiment, the degron is attached to the linker on the A ring. 【0223】 Alternative positions of the linker, A ring, and B ring In another aspect, compounds are provided in which the A ring, B ring, or linker is attached to one position to the left or right of its depicted position. If the previous linkage position was a carbon on an aromatic ring, the carbon can be replaced with X 5 and X 5 is N, CH, or CR 5 is. 【0224】 For example, in this aspect, the compound of formula I is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0225】 Additional non-limiting formulas of this embodiment include 【Chemical formula】 TIFF2025523393000109.tif254170 or a pharmaceutically acceptable salt thereof. 【0226】 Additional non-limiting formulas of this embodiment include 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0227】 In certain embodiments, the compound of the present invention has the formula: 【Chemical formula】 the compound of TIFF2025523393000112.tif155170, or a pharmaceutically acceptable salt thereof. 【0228】 In certain embodiments, the compound of the present invention has the formula: 【Chemical formula】 the compound of, or a pharmaceutically acceptable salt thereof. 【0229】 In certain embodiments, the compound of the present invention has the formula: 【Chemical formula】 the compound of, or a pharmaceutically acceptable salt thereof. 【0230】 R 1 embodiment In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is alkyl. In certain embodiments, R 1is alkenyl. In certain embodiments, R 1 is alkynyl. In certain embodiments, R 1 is halogen. 【0231】 R 2 embodiments In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is alkyl. In certain embodiments, R 2 is haloalkyl. In certain embodiments, R 2 is alkenyl. In certain embodiments, R 2 is alkynyl. In certain embodiments, R 2 is aryl. In certain embodiments, R 2 is heteroaryl. In certain embodiments, R 2 is a heterocycle. In certain embodiments, R 2 is -C(O)R 9 wherein. 【0232】 R 5 embodiments In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is alkyl. In certain embodiments, R 5 is haloalkyl. In certain embodiments, R 5 is alkenyl. In certain embodiments, R 5 is alkynyl. In certain embodiments, R5 is a halogen. In certain embodiments, R 5 is aryl. In certain embodiments, R 5 is heteroaryl. In certain embodiments, R 5 is a heterocyclic ring. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is nitro. In certain embodiments, R 5 is -NR 7 R 8 wherein. In certain embodiments, R 5 is -OR 7 wherein. In certain embodiments, R 5 is -SR 7 wherein. In certain embodiments, R 5 is -C(O)R 9 wherein. In certain embodiments, R 5 is -C(S)R 9 wherein. In certain embodiments, R 5 is -S(O)R 9 wherein. In certain embodiments, R 5 is -S(O)2R 9 wherein. In certain embodiments, R 5 is -OC(S)R 9 wherein. In certain embodiments, R 5 is -NR 7 S(O)R 9 wherein. In certain embodiments, R 5 is -NR 7 S(O)2R 9 wherein. In certain embodiments, R 5 is -P(O)(R 9 )2. In certain embodiments, R 5 is SP(O)(R 9 )2. In certain embodiments, R 5 is NR 7 P(O)(R 9 )2. In certain embodiments, R 5 is -OP(O)(R 9 )2. 【0233】 Embodiments of R 5b In certain embodiments, R 5b is hydrogen. In certain embodiments, R 5b is alkyl. In certain embodiments, R 5b is alkenyl. In certain embodiments, R 5b is alkynyl. In certain embodiments, R 5b is aryl. In certain embodiments, R 5b is heteroaryl. In certain embodiments, R 5b is a heterocycle. In certain embodiments, R 5b is -C(O)alkyl. In certain embodiments, R 5b is -C(S)R 9 . In certain embodiments, R 5b is -S(O)R 9 . In certain embodiments, R 5b is -S(O)2R 9 . 【0234】 Embodiments of R 5cEmbodiment In certain embodiments, R 5c is hydrogen. In certain embodiments, R 5c is alkyl. In certain embodiments, R 5c is haloalkyl. In certain embodiments, R 5c is alkenyl. In certain embodiments, R 5c is alkynyl. In certain embodiments, R 5c is halogen. In certain embodiments, R 5c is aryl. In certain embodiments, R 5c is heteroaryl. In certain embodiments, R 5c is a heterocyclic ring. In certain embodiments, R 5c is cyano. In certain embodiments, R 5c is nitro. In certain embodiments, R 5c is -OR 7 wherein. In certain embodiments, R 5c is -SR 7 wherein. In certain embodiments, R 5c is -C(O)R 9 wherein. In certain embodiments, R 5c is -C(S)R 9 wherein. In certain embodiments, R 5c is -S(O)R 9 wherein. In certain embodiments, R 5c is -S(O)2R 9 wherein. In certain embodiments, R 5cis -OC(S)R 9 is. In certain embodiments, R 5c is -NR 7 S(O)R 9 is. In certain embodiments, R 5c is -NR 7 S(O)2R 9 is. In certain embodiments, R 5c is -P(O)(R 9 )2. In certain embodiments, R 5c is SP(O)(R 9 )2. In certain embodiments, R 5c is NR 7 P(O)(R 9 )2. In certain embodiments, R 5c is -OP(O)(R 9 )2. 【0235】 R 6 embodiments In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is alkyl. In certain embodiments, R 6 is alkenyl. In certain embodiments, R 6 is alkynyl. In certain embodiments, R 6 is halogen. 【0236】 R 7 embodiments In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is alkyl. In certain embodiments, R 7is a haloalkyl. In certain embodiments, R 7 is an alkenyl. In certain embodiments, R 7 is an alkynyl. In certain embodiments, R 7 is an aryl. In certain embodiments, R 7 is a heteroaryl. In certain embodiments, R 7 is a heterocycle. In certain embodiments, R 7 is C(O)R 14 is. 【0237】 R 8 embodiments In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is an alkyl. In certain embodiments, R 8 is a haloalkyl. In certain embodiments, R 8 is an alkenyl. In certain embodiments, R 8 is an alkynyl. In certain embodiments, R 8 is an aryl. In certain embodiments, R 8 is a heteroaryl. In certain embodiments, R 8 is a heterocycle. In certain embodiments, R 8 is C(O)R 14 is. 【0238】 R 9 embodiments In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is alkyl. In certain embodiments, R 9 is haloalkyl. In certain embodiments, R 9 is alkenyl. In certain embodiments, R 9 is alkynyl. In certain embodiments, R 9 is aryl. In certain embodiments, R 9 is heteroaryl. In certain embodiments, R 9 is a heterocycle. In certain embodiments, R 9 is -NR 7 R 8 wherein. In certain embodiments, R 9 is -OR 7 wherein. In certain embodiments, R 9 is -SR 7 wherein. 【0239】 R 10 embodiments In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is alkyl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is alkenyl. In certain embodiments, R 10 is alkynyl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is halogen. In certain embodiments, R10 is aryl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is alkyl. In certain embodiments, R 10 is heteroaryl. In certain embodiments, R 10 is heterocyclic. In certain embodiments, R 10 is cyano. In certain embodiments, R 10 is nitro. In certain embodiments, R 10 is -NR 11 R 13 is. In certain embodiments, R 10 is -OR 11 is. In certain embodiments, R 10 is -SR 11 is. In certain embodiments, R 10 is -C(O)R 14 is. In certain embodiments, R 10 is -C(S)R 14 is. In certain embodiments, R 10 is -S(O)R 14 is. In certain embodiments, R 10 is -S(O)2R 14 is. In certain embodiments, R 10 is -NR 11 S(O)2R 14 is. In certain embodiments, R 10 is -P(O)(R 14 )2. In certain embodiments, R 10 is -NR 11 P(O)(R 14 )2. In certain embodiments, R 10 is -OP(O)(R 14 )2. 【0240】 Embodiments of R 11 In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 is alkyl. In certain embodiments, R 11 is haloalkyl. In certain embodiments, R 11 is alkenyl. In certain embodiments, R 11 is alkynyl. In certain embodiments, R 11 is aryl. In certain embodiments, R 11 is heteroaryl. In certain embodiments, R 11 is a heterocycle. In certain embodiments, R 11 is -C(O)R 14 . In certain embodiments, R 11 is -C(S)R 14 . In certain embodiments, R 11 is -S(O)R 14 . In certain embodiments, R 11 is -S(O)2R 14 . In certain embodiments, R 11 is -P(O)(R 14 )2. 【0241】 Embodiments of R​12 Embodiment In a particular embodiment, R 12 is hydrogen. In a particular embodiment, R 12 is alkyl. In a particular embodiment, R 12 is haloalkyl. In a particular embodiment, R 12 is alkenyl. In a particular embodiment, R 12 is alkynyl. In a particular embodiment, R 12 is alkynyl. In a particular embodiment, R 12 is halogen. In a particular embodiment, R 12 is aryl. In a particular embodiment, R 12 is a heterocyclic ring. In a particular embodiment, R 12 is heteroaryl. In a particular embodiment, R 12 is cyano. In a particular embodiment, R 12 is nitro. In a particular embodiment, R 12 is -NR 11 R 13 wherein. In a particular embodiment, R 12 is -OR 11 wherein. In a particular embodiment, R 12 is -SR 11 wherein. 【0242】 R 13 Embodiment In a particular embodiment, R 13 is hydrogen. In a particular embodiment, R 13 is alkyl. In certain embodiments, R 13 is haloalkyl. In certain embodiments, R 13 is alkenyl. In certain embodiments, R 13 is alkynyl. In certain embodiments, R 13 is aryl. In certain embodiments, R 13 is heteroaryl. In certain embodiments, R 13 is a heterocycle. In certain embodiments, R 13 is -C(O)R 14 wherein. In certain embodiments, R 13 is -C(S)R 14 wherein. In certain embodiments, R 13 is -S(O)R 14 wherein. In certain embodiments, R 13 is -S(O)2R 14 wherein. In certain embodiments, R 13 is -P(O)(R 14 )2. 【0243】 R 14 Embodiments In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is alkyl. In certain embodiments, R 14 is haloalkyl. In certain embodiments, R 14 is alkenyl. In certain embodiments, R 14 is alkynyl. In certain embodiments, R 14is aryl. In certain embodiments, R 14 is heteroaryl. In certain embodiments, R 14 is a heterocyclic ring. In certain embodiments, R 14 is amino. In certain embodiments, R 14 is hydroxyl. In certain embodiments, R 14 is alkoxy. In certain embodiments, R 14 is -N(H)(alkyl). In certain embodiments, R 14 is -N(alkyl)2. 【0244】 Embodiments of R 15a In certain embodiments, R 15a is hydrogen. In certain embodiments, R 15a is alkyl. In certain embodiments, R 15a is haloalkyl. In certain embodiments, R 15a is alkenyl. In certain embodiments, R 15a is alkynyl. In certain embodiments, R 15a is halogen. In certain embodiments, R 15a is aryl. In certain embodiments, R 15a is heteroaryl. In certain embodiments, R 15a is a heterocyclic ring. In certain embodiments, R 15a is cyano. In certain embodiments, R 15a ​is nitro. In certain embodiments, R 15a is amino. In certain embodiments, R 15a is hydroxyl. In certain embodiments, R 15a is alkoxy. In certain embodiments, R 15a is -N(H)(alkyl). In certain embodiments, R 15a is -N(alkyl)2. 【0245】 R 15b embodiments In certain embodiments, R 15b is hydrogen. In certain embodiments, R 15b is alkyl. In certain embodiments, R 15b is haloalkyl. In certain embodiments, R 15b is alkenyl. In certain embodiments, R 15b is alkynyl. In certain embodiments, R 15b is halog...

Claims

[Claim 1] formula: 【Chemistry 1】 【change】 During the ceremony, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. p is either 0 or 1, Q is O, S, NR 17, or CR 17 R 18. X1, X2, and X3 are selected independently from N, CH, and CR5. X 4 is N, CH, or CR 5, 【Chemistry 2】 These are cycloalkyl, heterocyclic, or heteroaryl compounds. R1 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen, or R1 and R6 are combined to form CH2 or CH2CH2 crosslinks. Each R2 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -C(O)R9, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R10. Alternatively, R2 is a halogen, Each R 5 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 7 R 8, -OR 7, -SR 7, -C(O)R 9, -C(S)R 9, -S(O)R 9, -S(O)2 R 9, -OC(O)R 9, -OC(S)R 9, -OS(O)R 9, -OS(O)2 R 9, -SC(O)R 9, -NR 7 C(O)R 9, -NR 7 C(S)R 9, -NR 7 S(O)R 9, -NR 7 S(O)2 R 9, -P(O)(R 9)2 -SP(O)(R9)2, -NR7P(O)(R9)2, and -OP(O)(R9)2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R10. R7 and R8 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -C(O)R14, respectively, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R16. Each R9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -NR7, R8, -OR7, and -SR7, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R10. Each R 10 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -C(O)R 14, -C(S)R 14, -S(O)R 14, -S(O)2 R 14, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14) 2, -NR 11 P(O)(R 14) 2, and -OP(O)(R 14) 2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15a. R11 and R13 are, in each case, independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -C(O)R14, -C(S)R14, -S(O)R14, -S(O)2R14, and -P(O)(R14)2, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R15b. Each R 12 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11, R 13, -OR 11, and -SR 11, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15c. Each R14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R15d. R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, and R 15g are, in each case, independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2. Each R 16 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -C(O)R 14, -C(S)R 14, -S(O)R 14, -S(O)2 R 14, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14) 2, -NR 11 P(O)(R 14) 2, and -OP(O)(R 14) 2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15e, Each R 17 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, -C(O)R 14, -C(S)R 14, -S(O)R 14, and -S(O)2R 14, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R 15f. R 18 includes hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14)2, -NR 11 P(O)(R 14)2, and -OP(O)(R 14)2 Selected from, each of the elements except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15g. A targeted ligand is a chemical part that binds to a target protein. A target protein is a selected protein that causes or contributes to a disease. The linker is given by formula LI: 【Transformation 3】 It is the divalent chemical part, During the ceremony, X ３１ and X ３２ These are independently, in each case, bond, heterocycle, aryl, heteroaryl, bicycle, and -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ Selected from - and -S-, each of the heterocycle, aryl, heteroaryl, and bicycle is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. R ２０ 、R ２１ 、R ２２ 、R ２３ 、and R ２４ are each, independently in each case, selected from the group consisting of bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, -C(R ４０ R ４０ ), -P(O)(OR ２６ ), -P(O)(OR ２６ ), bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R ４０ . R ２６ In each case, these are independently selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic elements. R ２７ Independently, in each case, is selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic, or heteroaryl), alkenes, and alkynes. R ４０ Independently, in each case, hydrogen and R ２７ Alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl) ２ , - NHSO ２ (Aliphatic, alkyl-containing), -N(Aliphatic, alkyl-containing)SO ２ Alkyl, -NHSO ２ (aryl, heteroaryl, or heterocyclic), -N(alkyl)SO ２ (aryl, heteroaryl, or heterocyclic), -NHSO ２ Alkenyl, -N(alkyl)SO ２ Alkenil, - NHSO ２ Alkinyl, -N(alkyl)SO ２ Selected from the group consisting of alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl, R ４１ is aliphatic, aryl, heteroaryl, or hydrogen. A compound, or a pharmaceutically acceptable salt thereof. [Claim 2] formula: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 3] formula: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 4] formula: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 5] formula: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [Claim 6] A, 【Transformation 8】 The compound according to any one of claims 1 to 5. [Claim 7] The compound according to any one of claims 1 to 5, wherein m is 0. [Claim 8] The compound according to any one of claims 1 to 5, wherein m is 1. [Claim 9] The compound according to any one of claims 1 to 5, wherein m is 2. [Claim 10] The compound according to any one of claims 1 to 5, wherein m is 3. [Claim 11] R ２ The compound according to any one of claims 1 to 5, wherein the compound is a halogen. [Claim 12] The compound according to any one of claims 1 to 5, wherein p is 1. [Claim 13] R ６ and R １ However, both CH ２ A compound according to any one of claims 1 to 5, which forms a crosslink. [Claim 14] R ６ and R １ The compound according to any one of claims 1 to 5, wherein the compound is hydrogen. [Claim 15] The aforementioned compound, 【Chemistry 9】 The compound according to claim 1, which is selected from or a pharmaceutically acceptable salt thereof. [Claim 16] The linker, formula: 【Chemistry 10】 A compound according to any one of claims 1 to 5, which is a linker. [Claim 17] X ３１ The compound according to claim 16, wherein the bond is a combination. [Claim 18] X ３１ The compound according to claim 16, wherein the compound is a heterocycle, -NR27-, or -C(O)-. [Claim 19] X ３２ The compound according to claim 16, wherein the bond is a combination. [Claim 20] X ３２ The compound according to claim 16, wherein the compound is a heterocycle, -NR27-, or -C(O)-. [Claim 21] R ２０ The compound according to claim 16, wherein the bond is a combination. [Claim 22] R ２０ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic. [Claim 23] R ２１ The compound according to claim 16, wherein the bond is a combination. [Claim 24] R ２１ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic. [Claim 25] R ２２ The compound according to claim 16, wherein the bond is a combination. [Claim 26] R ２２ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic. [Claim 27] R ２３ The compound according to claim 16, wherein the bond is a combination. [Claim 28] R ２３ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic. [Claim 29] R ２４ The compound according to claim 16, wherein the bond is a combination. [Claim 30] R ２４ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic. [Claim 31] The compound is 【Chemistry 11】 The compound according to claim 1, which is selected from or a pharmaceutically acceptable salt thereof. [Claim 32] The compound according to any one of claims 1 to 5, wherein the targeted ligand is the chemical portion shown in the figure. [Claim 33] X １ The compound according to any one of claims 1 to 5, wherein the compound is CH. [Claim 34] X ２ The compound according to any one of claims 1 to 5, wherein the compound is CH. [Claim 35] X ３ The compound according to any one of claims 1 to 5, wherein the compound is CH. [Claim 36] The compound according to any one of claims 1 to 4, wherein Q is O or S. [Claim 37] The compound according to any one of claims 1 to 5, wherein X1, X2, and X3 are CH. [Claim 38] The compound according to claim 37, wherein Q is O. [Claim 39] The compound according to claim 37, wherein R1 and R6 are H. [Claim 40] at least one R ２ The compound according to any one of claims 1 to 5, wherein the compound is fluorine. [Claim 41] A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Claim 42] A pharmaceutical composition for treating a target protein-mediated disorder in humans, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [Claim 43] The pharmaceutical composition according to claim 42, wherein the disorder is abnormal cell proliferation. [Claim 44] The pharmaceutical composition according to claim 42, wherein the disorder is an immune system disorder. [Claim 45] Use of a compound or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of claims 1 to 5, in the manufacture of a pharmaceutical product for treating a target protein-mediated disorder in humans. [Claim 46] The use according to claim 45, wherein the aforementioned disorder is abnormal cell proliferation. [Claim 47] The use according to claim 45, wherein the impairment is an immune system disorder.

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