Bicyclic substituted glutarimide cerebron binders

Abstract

The present invention provides a degradation determinant compound bound to a hydroxycerebroside, which is a component of an E3 ubiquitin ligase. The degradation determinants provided herein can be used to modulate the activity of hydroxycerebrosides alone or covalently linked to the tail. Alternatively, the degradation determinant may be linked to a targeting ligand that binds to a target protein for protein degradation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 349,509, filed on June 6, 2022, the entire contents of which are hereby incorporated by reference for all purposes. Technical Field

[0003] The present invention provides a degron compound that binds to cereblon, which is a component of an E3 ubiquitin ligase. The degron provided herein can be used to regulate the activity of cereblon alone or covalently linked to a tail. Alternatively, the degron can be linked to a targeting ligand that binds to a target protein for protein degradation. Background Art

[0004] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Selective recognition and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of virtually all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis and viral infection.

[0005] Proteins are tagged for proteasomal degradation by covalently attaching multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligases, where proteins are digested into small peptides and ultimately into their constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation has been implicated in a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] The drug thalidomide and its analogs lenalidomide and pomalidomide have attracted attention as immunomodulators and antitumor drugs, especially in multiple myeloma (Kim SA et al., "A novel cereblon modulator for targeted protein degradation", Eur J Med Chem. 2019 Mar 15; 166: 65-74; R. Verma et al., "Identification of acereblon-Independent Protein Degradation Pathway in Residual Myeloma Cells Treated with Immunomodulatory Drugs" Blood (2015) 126(23): 913. 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; Martiniani, R. et al. "Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma” Adv Hematol, 2012, 2012: 842945; and Terpos, E. et al. “Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma” Oncotargets and Therapy, 2013, 6: 531). Although the exact therapeutic mechanism of action of thalidomide, lenalidomide and pomalidomide is unclear, the compounds show activity. Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Ito, T. et al. “Identification of a primary target of thalidomide teratogenicity” Science, 2010, 327: 1345).Cereblon is part of the E3 ubiquitin ligase complex, which interacts with damaged DNA binding protein 1, forms an E3 ubiquitin ligase complex with Cullin 4 and E2 binding protein ROC1 (called RBX1), in which it acts as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon promotes the subsequent binding of cereblon to Ikaros and Aiolos, causing them to be ubiquitinated and degraded by the proteasome (see Lu, G. et al. "The myeloma drug lenalidomide promotes thecereblon-dependent destruction of Ikaros proteins" Science, 2014, 343: 305-309;. J. et al. "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells" Science, 2014, 343: 301-305).

[0007] The disclosure of thalidomide binding to the cereblon E3 ubiquitin ligase has sparked research into incorporating thalidomide and certain derivatives into compounds for targeted protein destruction. Celgene has disclosed imides for similar uses, including in U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,95 those disclosed in 9,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; 9,101,622; 9,587,281; 9,857,359; and 10,092,555.

[0008] Patent applications filed by C4 Therapeutics, Inc. describe compounds that can bind to E3 ubiquitin ligases and target proteins for degradation, including: WO / 2023 / 055952, entitled “Neurotrophic tyrosine receptor kinase (NTRK) degradation compounds”; WO / 2023 / 039208, entitled “Selected compounds for targeted degradation of BRD9”; WO / 2023 / 283610, entitled “Compounds for targeted degradation of IRAK4 protein”; WO / 2023 / 283372, entitled “Compounds for targeted degradation of IRAK4 protein”; WO / 2022 / 251539, entitled “Compounds for the treatment of cancer metastasis”; WO / 2022 / 081928, entitled "Tricyclic heterobifunctional compounds for degrading target proteins"; WO / 2022 / 081927, entitled "Tricyclic compounds for degrading novel substrates for medical treatment"; WO / 2022 / 081925, entitled "Tricyclic ligands for degrading IKZF2 or IKZF4"; WO / 2022 / 032132, entitled "Advantageous treatment for Ikaros or Aiolos-mediated disorders"; WO / 2021 / 255213, entitled "Heterobifunctional compounds as BRAF degraders"; WO / 2021 / 255212, entitled "Tricyclic compounds for degrading novel substrates for medical treatment"; Titled "BRAF degraders"; WO / 2021 / 178920, titled "Compounds for targeted degradation of BRD9"; WO / 2021 / 127561, titled "Isoindolinone and indazole compounds for EGFR degradation"; WO / 2021 / 086785, titled "Bifunctional compounds"; WO / 2021 / 083949, titled "Bifunctional compounds for the treatment of cancer"; WO / 2020 / 210630, titled "Tricyclic degraders of Ikaros and Aiolos"; WO / 2020 / 181232, titled "Heterocyclic compounds for medical treatment"; WO / 2020 / 132561 , entitled “Targeted protein degradation”; WO / 2019 / 236483, entitled “Spirocyclic compounds”; WO2020 / 051235, entitled “Compounds for degrading BRD9 or MTH1”; WO / 2019 / 191112, entitled “Cereblon binders for Ikaros degradation”; WO / 2019 / 204354, entitled “Spirocyclic compounds”; WO / 2019 / 099868, entitled “Degraders and degraders for targeted protein degradation”; WO / 2018 / 237026, entitled “N / O-linked degraders and degraders for protein degradation”; WO 2017 / 197051, entitled “Amine-linked C3-glutarimide degraders for targeted protein degradation”;WO 2017 / 197055, entitled "Heterocyclic Degraders for Targeted Protein Degradation"; WO 2017 / 197036, entitled "Spirocyclic Degraders for Targeted Protein Degradation"; WO 2017 / 197046, entitled "C3-Carbon-Linked Glutarimide Degraders for Targeted Protein Degradation"; and WO 2017 / 197056, entitled "Bromodomain Targeted Degraders for Targeted Protein Degradation". ;

[0009] Other examples of patent applications describing protein degradation compounds include: WO 2015 / 160845; WO 2016 / 105518; WO 2016 / 118666; WO 2016 / 149668; WO 2016 / 197032; WO 2016 / 197114; WO 2017 / 007612; WO 2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 2017 / 046036; WO 2017 / 079267; WO 2017 / 176708; WO 2017 / 176957; WO 2017 / 180417; WO 2018 / 053354; WO 2018 / 071606; WO 2018 / 102067; WO 2018 / 102725; WO 2018 / 118598; WO 2018 / 119357; WO 2018 / 119441; WO 2018 / 119448; WO 2018 / 140809; WO 2018 / 144649; WO 2018 / 119448; WO 2018 / 226542; WO 2019 / 023553; WO 2019 / 060693; WO 2019 / 060742; WO 2019 / 140380; WO 2019 / 140387; WO 2019 / 195201;WO 2019 / 199816;WO 2019 / 099926;WO 2019 / 195609;WO 2020 / 023851;WO 2020 / 041331;WO 2020 / 051564;WO 2021 / 053495;WO 2021 / 053555;WO 2021 / 162493; WO 2022 / 012622; WO 2022 / 174269; WO 2022 / 174269; WO 2022 / 236058; WO 2023 / 278759; WO 2023 / 044046; WO 2023 / 076161; WO 2023 / 049790; and WO 2023 / 076556.

[0010] It is an object of the present invention to provide novel compounds, methods, compositions and manufacturing methods that can be used to degrade selected proteins in vivo. Summary of the invention

[0011] Provided are cereblon binding compounds (degrons) having specific bicyclic substituents at the C3 position of the glutarimide. These specific bicyclic substituents correspond to the bicyclic rings of the following formulas IA, IIA, IIIA, IVA, VA, VIA, VIIA, VIIIA, IXA, XA, XIA, XIIA, XIIIA, XIVA, XVA and XVIA, ​​as well as the embodiments described herein.

[0012]

[0013] When the degron described herein is combined with cereblon, the described degron can be used to treat obstacles mediated by cereblon or obstacles mediated by proteins degraded by cereblon. Alternatively, the degron described herein can be used as an intermediate to synthesize heterobifunctional compounds (degradants) for targeted protein degradation. In some aspects, the degron includes a linking portion (tail) that can react with a suitably prepared targeting ligand or targeting ligand precursor to form a degradation agent. A degradation agent is also provided, which includes the degron described herein, which can be directly connected to a targeting ligand or connected to a targeting ligand with a linking group.

[0014]

[0016] Degradation determinant compounds can be "molecular glues" that can bind to cereblon E3 ligases, thereby creating new surfaces on the E3 ligases, resulting in enhanced interaction and binding with the target protein. Due to this interaction, the target 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 diseases (such as but not limited to cancer), and as described in more detail below.

[0017] For example, compounds of Formula IA are degrons and therefore can be used as therapeutically active compounds that alter the surface of cereblon, intermediates for making degraders, or as part of heterobifunctional compounds to degrade target proteins (degraders).

[0018] In certain aspects, a degron compound of Formula IA, IIA, IIIA, IVA, VA, VIA, VIIA, VIIIA, IXA, XA, XIA, XIIA, XIIIA, XIV, XVA, or XVIA is provided:

[0019]

[0020]

[0021]

[0022] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0023] in:

[0024] m is 0, 1, 2, 3, or 4;

[0025] In certain embodiments, m is 0 or 1;

[0026] n is 0, 1, 2, or 3;

[0027] In certain embodiments, n is 0, 1 or 2;

[0028] p is 0 or 1;

[0029] In certain embodiments, p is 1;

[0030] Q is O, S, NR 17 or CR 17 R 18 ;

[0031] In certain embodiments, Q is O, NR 17 or CH 2 ;

[0032] In certain embodiments, Q is O;

[0033] X 1 , X 2 and X 3 Independently selected from N, CH and CR 5 ;

[0034] In certain embodiments, X 1 , X 2 and X 3 No more than one of them is selected as N;

[0035] X 3b is N, CH or CR 5b ;

[0036] In certain embodiments, X 3b It is CH;

[0037] X 4 is N, CH or CR 5 ;

[0038] In certain embodiments, X 4 Is CH or CR 5 ;

[0039] Z 1 , Z 2 , Z 5 and Z 6 Independently selected from CH, CR 5 and N;

[0040] Z 3 and Z 4 Independently selected from S, O, NH and NR 17 ;

[0041] is cycloalkyl, heterocyclic or heteroaryl;

[0042] In certain embodiments, yes

[0043] R 1 and R 6 independently selected from hydrogen, alkyl, alkenyl, alkynyl and halogen;

[0044] or R 1 With R 6 Combine to form CH 2 or CH 2 CH 2 bridge;

[0045] Each R 2 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0046] Each R 5 are independently selected from 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)R9 、-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 、-OS(O) 2 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)(R 9 ) 2 、-NR 7 P(O)(R 9 ) 2 and-OP(O)(R 9 ) 2 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0047] R 5b is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)alkyl, -C(S)R 9 、-S(O)R 9 and -S(O) 2 R 9 wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0048] R 5c is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -OR 7 、-SR 7 、-C(O)R 9b 、-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 、-OS(O) 2 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)(R 9 ) 2 、-NR 7 P(O)(R 9 ) 2 and-OP(O)(R 9 ) 2 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0049] R 7 and R 8 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle at each occurrence; and C(O)R 14 , wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 16 Substituents are substituted;

[0050] Each R 9 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 、-OR 7 and-SR 7 , each of which is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0051] R 9b are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 and-SR 7 , each of which is optionally replaced by 1, 2, 3 or 4 independently selected from R 10Substituents are substituted;

[0052] Each R 10 are independently selected from 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) 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 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15a Substituents are substituted;

[0053] R 11 and R 13 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 、-C(S)R 14 、-S(O)R 14 、-S(O) 2 R 14 and -P(O)(R 14 ) 2 ; each of which is optionally 1, 2, 3 or 4 independently selected from R 15b Substituents are substituted;

[0054] Each R 12are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 、-OR 11 and-SR 11 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15c Substituents are substituted;

[0055] Each R 14 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxy, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 , wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 15d Substituents are substituted;

[0056] R 15a , R 15b , R 15c , R 15d、 R 15e , R 15f and R 15g is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxy, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 ;

[0057] Each R 16 are independently selected from 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) 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 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15e Substituents are substituted;

[0058] 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) 2 R 14 and -P(O)(R 14 ); wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 15f substituted with a substituent; and

[0059] 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) 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 wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15gsubstituted by a substituent.

[0060] In certain aspects, a degron of Formula XVIIAa, Formula XVIIAb, Formula XVIIAc, Formula XVIIAd, or Formula XVIIAe is provided:

[0061]

[0062] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0063] in:

[0064] Z 3b Selected from O, NH and NR 17 ;

[0065] Z 4b Selected from S, NH and NR 17 ;and

[0066] is a 5-membered heterocyclic ring, a 5-membered heteroaryl group, a pyrimidinyl group, a pyridazinyl group or a pyrazinyl group;

[0067] and all other variables are as defined herein.

[0068] The degradation determinants described herein can be used alone (i.e., not as part of a degradation agent) as an in vivo binder of cereblon, which can be administered to a host (e.g., a human) in need thereof 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 an E3 ubiquitin ligase protein complex containing cereblon, including but not limited to the use of known cereblon binders thalidomide, pomalidomide, and lenalidomide. The binding of the degradation determinants described herein to cereblon can induce a protein conformational change in cereblon that allows degradation of the target protein. In certain embodiments, the degradation determinants described herein are "molecular glues" that result in targeted degradation of a target protein (e.g., a protein having a C2H2 zinc finger degradation determinant motif).

[0069] Non-limiting examples of proteins that can be degraded or downregulated by degron 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, RBM2 3, 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 degradation determinant of the present invention is selected from ARID2, aromatase; b-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 invention is selected from IKZF1, IKZF2, IKZF3, and IKZF4.

[0070] Non-limiting examples of disorders that can be treated with the degrons described herein include abnormal cell proliferation, including tumors or cancer, or myeloproliferative or lymphoproliferative disorders, such as B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom's 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; cardiological dysfunction, including hypercholesterolemia; infectious diseases, including viral or bacterial infections; and inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0071] In certain embodiments, the degrons described herein are used to degrade proteins that mediate multiple myeloma, colorectal cancer, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0072] In certain embodiments, the degron described herein can activate, reduce or alter the native activity of cereblon. Additional non-limiting examples of uses for cereblon binders are for the treatment of multiple myeloma, hematological disorders (e.g., myelodysplastic syndrome), cancer, tumors, abnormal cell proliferation, HIV / AIDS, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet's disease, tuberculosis, and myelofibrosis.

[0073] In other aspects, the degron has a tail portion. For example, a degron of the formula:

[0074]

[0075]

[0076]

[0077]

[0078] or a pharmaceutically acceptable salt thereof;

[0079] in:

[0080] The tail is selected from

[0081] X 31 and X 32 is independently selected at each occurrence from a bond, heterocycle, aryl, heteroaryl, bicyclic, -NR 27 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-、-C(S)-、-S(O)-、-S(O) 2 - and -S-; wherein each of the heterocyclic, aryl, heteroaryl and bicyclic rings is 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted, and X 22 is selected to make the compound sufficiently stable or to achieve the intended use; wherein X 22 YesR 5 ;

[0082] R 20 , R 21 , R 22 , R 23 and R 24 is independently selected at each occurrence from a 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 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted;

[0083] R 26 is independently selected at each occurrence from hydrogen, alkyl, aralkyl, heteroaralkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic;

[0084] R 27 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; and

[0085] R 40 is independently selected at each occurrence from hydrogen, R 27 , alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl) 2 、-NHSO 2 (aliphatic, including alkyl), -N(aliphatic, including alkyl)SO 2 Alkyl, -NHSO 2 (aryl, heteroaryl or heterocyclic), -N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic), -NHSO 2 Alkenyl, -N(alkyl)SO 2 Alkenyl, -NHSO 2 Alkynyl, -N(alkyl)SO 2 Alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl.

[0086] In certain embodiments, when used in a bivalent structure, for

[0087] In certain aspects, a degrader compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII is provided:

[0088]

[0089]

[0090]

[0091] or a pharmaceutically acceptable salt thereof;

[0092] in:

[0093] The targeting ligand is the part that binds to the target protein;

[0094] The target protein is a selected protein that causes or contributes to the disease; and

[0095] The linking group is a divalent linking group;

[0096] and wherein all other variables are as defined herein.

[0097] In other aspects, a degrader compound of Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, Formula XVI, or Formula XVII is provided:

[0098]

[0099]

[0100]

[0101]

[0102] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0103] in:

[0104] Targeting ligands are chemical moieties that bind to target proteins;

[0105] The target protein is a selected protein that causes or contributes to the disease; and

[0106] The linking group is a divalent linking group;

[0107] and wherein all other variables are as defined herein.

[0108] In some aspects, the targeting ligand is a means for binding to a target protein, wherein the targeting ligand is a chemical moiety. In some embodiments, the term targeting ligand used in the formula or claims of the present invention is defined as a mean plus function according to 35 U.S.C. 112 (f). In some embodiments, the targeting ligand is a chemical moiety described in this patent application, for example, a chemical moiety described in the figure.

[0109] The structure of the degradation agent is generally selected so that it is sufficiently stable to maintain a shelf life of at least two, three, four, or five months under ambient conditions. To achieve this, each of the R groups described herein must be sufficiently stable to maintain a corresponding desired shelf life of at least two, three, four, or five months under ambient conditions. Those skilled in the art are well aware of the stability of chemical moieties and can avoid those that are unstable or too reactive under appropriate conditions.

[0110] Furthermore, all R groups with or without optional substituents should be interpreted in a manner that does not include redundancy (ie, alkyl substituted with alkyl is redundant as known in the art; however, for example, alkoxy substituted with alkoxy is not redundant).

[0111] The degradation agents provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by a selected target protein bound to a targeting ligand. Thus, in some embodiments, a method of treating a host suffering from a disorder mediated by a target protein is provided, the method comprising administering to the host (usually a human) an effective amount of a degradation agent described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0112] In certain embodiments, the selected target protein is derived from a gene that has undergone amplification, translocation, rearrangement, copy number variation, change, deletion, mutation or inversion events that cause or are caused by a medical disorder. In certain aspects, the selected target protein has been post-translationally modified by phosphorylation, acetylation, acylation (including propionylation and butenylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation (pyroglutamoylation), myristoylation, farnesylation, geranylation, ubiquitination, SUMOylation or sulfation, one or a combination thereof. In another embodiment, the target protein can be covalently modified by a functionalized targeting ligand to form a covalent bond with the target protein, and the covalent bond can be irreversible or reversible.

[0113] One non-limiting example of a disorder treatable by such compounds is abnormal cell proliferation, such as a tumor or cancer, where the target protein is an oncoprotein or a signaling mediator of an abnormal cell proliferation pathway and its degradation reduces abnormal cell growth.

[0114] Compounds and methods for treating patients suffering from disorders mediated by proteins targeted for selective degradation are provided, comprising administering to a human patient in need thereof an effective amount of one or a combination of the degrons or degraders of the invention described herein, optionally in a pharmaceutically acceptable carrier (composition).

[0115] In certain embodiments, the disorder is selected from a neoplasm, a tumor, a cancer, abnormal cell proliferation, an immune disorder, an inflammatory disorder, graft-versus-host rejection, a viral infection, a bacterial infection, an amyloid-based protein conformational disease, a protein conformational disease, or a fibrotic disorder.

[0116] In one embodiment, the present invention provides a degron covalently linked to a targeting ligand via a linker that can have different lengths and functions. 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).

[0117] In certain embodiments, the linker can be any chemically stable group that connects the degron to the targeting ligand. Examples of linkers are provided 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, one or more of which may be replaced by heteroatoms (e.g., O, N, S or P), as long as the resulting molecule has a stable shelf life of at least two months, three months, six months or one year as part of a pharmaceutically acceptable dosage form, and is itself pharmaceutically acceptable.

[0118] In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive atoms in the chain. For example, the chain can contain 1 or more ethylene glycol units, and in some embodiments, can have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more continuous, partially continuous, or discontinuous ethylene glycol units in the linker. 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.

[0119] In one embodiment, the target protein is a protein that is not druggable in the traditional sense because it has no binding pocket or active site, cannot be inhibited or otherwise bound, and cannot be easily allosterically controlled. In another embodiment, the target protein is a protein that is druggable in the traditional sense. Examples of target proteins are provided below.

[0120] In certain embodiments, the invention provides for the administration of an effective amount of a degron or degrader compound to treat a patient (e.g., a human) suffering from an infectious disease, wherein the therapy targets a target protein of the infectious pathogen or a target protein of the host (degrader), or acts by binding to cereblon or its E3 ubiquitin ligase (degrader), or acts by an independent mechanism, optionally in combination with another biologically active agent.

[0121] The disease state or disorder may be caused by a microbial or other exogenous agent, such as a virus (as a non-limiting example, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, SARS-CoV2, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, Viral Pneumovirus, Drug-Resistant Virus, Avian Flu, RNA Virus, DNA Virus, Adenovirus, Poxvirus, Picornavirus, Togavirus, Orthomyxovirus, Retrovirus, or Hepadnovirus), bacteria (including but not limited to Gram-negative, Gram-positive, atypical, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Meningitis, Gonorrhea, Chlamydiaceae, Mycoplasmaceae, etc.), fungus, protozoa, helminth, worm, prion, parasite, or other microorganism.

[0122] In certain embodiments, a degron or degrader compound has at least one desired atom substituted with an isotope in an amount above the natural abundance of the isotope, ie, enriched.

[0123] In one embodiment, the degron or degrader compound comprises one or more deuterium atoms.

[0124] The compounds of the invention may provide important clinical benefits to patients, particularly for the treatment of disease states and conditions modulated by the protein of interest.

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the application belongs. In the specification, unless the context clearly stipulates otherwise, the singular form also includes the plural. Although methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be the prior art of the claimed application. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and embodiments are illustrative only and are not intended to be limiting.

[0126] Other features and advantages of the present application will be apparent from the following detailed description, and from the claims.

[0127] Therefore, the present invention includes at least the following features:

[0128] (a) a degron compound as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof;

[0129] (b) Use of the degron compound described herein or a pharmaceutically acceptable salt thereof, an isotopic derivative or a prodrug thereof as a molecular glue to bind to cereblon, resulting in degradation of a target protein;

[0130] (c) a degron having a tail, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivative) or prodrug thereof, or a therapeutic use thereof;

[0131] (d) a degrader compound as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof;

[0132] (e) a degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof for treating a disorder mediated by a target protein, wherein the compound comprises a targeting ligand for the target protein, and wherein the degron is optionally linked to the targeting ligand via a linker;

[0133] (f) use of an effective amount of a degron compound for treating a patient, typically a human, suffering from a disorder responsive to such treatment, including by altering cereblon-based protein ubiquitination, such as abnormal cell proliferation (e.g., tumor or cancer), immune or autoimmune or inflammatory disorder, cardiological disorder, infectious disease or other disorder responsive to such treatment;

[0134] (g) use of an effective amount of a degrader compound to treat a patient (typically a human) suffering from any disorder mediated by the target protein described herein, including abnormal cell proliferation (e.g., tumor or cancer), immune or autoimmune or inflammatory disorder, cardiac disorder, infectious disease, or other disorder responsive to such treatment;

[0135] (h) use of a degron or degrader, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, in the preparation of a medicament for treating a medical disorder, as further described herein;

[0136] (i) A method for the manufacture of a medicament intended for therapeutic treatment of a disorder in a host, characterized in that a degron) or a degrader is used in the manufacture;

[0137] (j) a degron or degrader, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, which can be used to treat abnormal cell proliferation, such as cancer, including any cancer described herein, in a host;

[0138] (k) use of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof in the manufacture of a medicament for treating abnormal cell proliferation (e.g., cancer, including any cancer described herein);

[0139] (l) A method for the manufacture of a medicament intended for therapeutic use in the treatment of abnormal cell proliferation (e.g., cancer, including any cancer described herein in a host), characterized in that a degron or degrader is used in the manufacture;

[0140] (m) a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, which can be used to treat a tumor in a host, including any tumor described herein;

[0141] (n) Use of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof for treating a tumor (including any tumor described herein) in a host;

[0142] (o) a method for the manufacture of a medicament intended for therapeutic treatment of a tumor (including any of the tumors described herein) in a host, characterized in that a degron or degrader compound is used in the manufacture;

[0143] (p) a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof for use in the manufacture of a medicament for treating an immune, autoimmune or inflammatory disorder in a host;

[0144] (q) use of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof in the manufacture of a medicament for treating an immune, autoimmune or inflammatory disorder in a host;

[0145] (r) a method of manufacturing a medicament intended for therapeutic treatment of an immune, autoimmune or inflammatory disorder in a host, characterized in that a degron or degrader compound is used in the manufacturing;

[0146] (s) a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof for use in treating an infection, including a viral infection, such as HIV, HBV, HCV, SARS-CoV2 and RSV, in a host;

[0147] (t) Use of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof in the manufacture of a medicament for treating an infection (including a viral infection, such as HIV, HBV, HCV, SARS-CoV2 and RSV) in a host;

[0148] (u) a method for the manufacture of a medicament intended for the therapeutic treatment of an infection (including a viral infection such as HIV, HBV, HCV, SARS-CoV2 and RSV) in a host, characterized in that a degron or degrader compound is used in the manufacture;

[0149] (v) a pharmaceutical preparation comprising an amount of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof effective for treating a host and a pharmaceutically acceptable carrier or diluent;

[0150] (w) the degron or degrader compound as described herein is a mixture of enantiomers or diastereomers (as the case may be), including racemates;

[0151] (x) a degron or degrader compound as described herein in an enantiomerically or diastereomerically enriched form, as the case may be, including an individual enantiomer or diastereomer (i.e., greater than 85%, 90%, 95%, 97% or 99% pure); and

[0152] (y) A method for preparing a therapeutic product comprising an effective amount of a degron or degrader compound or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent. BRIEF DESCRIPTION OF THE DRAWINGS

[0153] Figures 1A-1C Non-limiting examples of retinoid X receptor (RXR) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0154] Figures 1D-1F Non-limiting examples of general dihydrofolate reductase (DHFR) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0155] Figure 1G Non-limiting examples of Bacillus anthracis dihydrofolate reductase (BaDHFR) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0156] Figures 1H-1J Non-limiting examples of heat shock protein 90 (HSP90) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0157] Figure 1K-1Q Non-limiting examples of general kinase and phosphatase targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0158] Figure 1R-1S Non-limiting examples of tyrosine kinase targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0159] Figure 1T Non-limiting examples of Aurora kinase targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0160] Figure 1U Non-limiting examples of protein tyrosine phosphatase targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0161] Figure 1V Non-limiting examples of ALK targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0162] Figure 1W Non-limiting examples of ABL targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0163] Figure 1X Non-limiting examples of JAK2 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0164] Figure 1Y-1Z Non-limiting examples of MET Targeting Ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0165] Figure 1AA Non-limiting examples of mTORC1 and / or mTORC2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0166] Figure 1BB-1CCNon-limiting examples of mast cell / stem cell growth factor receptor (SCFR) (also known as c-KIT receptor) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0167] Fig. 1DD Non-limiting examples of IGF1R and / or IR targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0168] Figures 1EE-1FF Non-limiting examples of HDM2 and / or MDM2 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0169] Figure 1GG-1MM Non-limiting examples of BET bromodomain-containing protein targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0170] Figure 1NN Non-limiting examples of HDAC targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0171] Fig. 100 Non-limiting examples of RAF receptor targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0172] Figure 1PP Non-limiting examples of FKBP receptor targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0173] Figure 1QQ-1TT Non-limiting examples of androgen receptor targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0174] Figure 1UU Non-limiting examples of estrogen receptor targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0175] Figure 1VV-1WW Non-limiting examples of thyroid hormone receptor targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0176] Figure 1XX Non-limiting examples of HIV protease targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0177] Figure 1YY Non-limiting examples of HIV integrase targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0178] Figure 1ZZNon-limiting examples of HCV protease targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0179] Figure 1AAA Non-limiting examples of AP1 and / or AP2 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0180] Figure 1BBB-1CCC Non-limiting examples of MCL-1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0181] Figure 1 DDD Non-limiting examples of IDH1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0182] Figure 1EEE-1FFF Non-limiting examples of RAS or RASK targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0183] Figure 1GGG Non-limiting examples of MERTK or MER targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0184] Figure 1HHH-1III Non-limiting examples of EGFR targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0185] Figure 1JJJ-1KKK Non-limiting examples of FLT3 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0186] Figure 1LLL Non-limiting examples of SMARCA2 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0187] Figure 2A A non-limiting example of a Kinase Inhibitor Targeting Ligand U09-CX-5279 (derivatized) is provided, where R represents an exemplary point to which a linker may be attached.

[0188] Figure 2B-2CNon-limiting examples of kinase inhibitor targeting ligands are provided, including kinase inhibitor compounds Y1W and Y1X (derivatized), wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in Millan et al. "Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease" J. Med. Chem., 54: 7797 (2011).

[0189] Figure 2D Non-limiting examples of kinase inhibitor targeting ligands are provided, including kinase inhibitor compounds 6TP and OTP (derivatized), wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in Schenkel et al. "Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors" J. Med. Chem., 54(24): 8440-8450 (2011).

[0190] Figure 2E Non-limiting examples of kinase inhibitor targeting ligands (including kinase inhibitor compound 07U) are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Van Eis et al. "2 6-Naphthyridines as potent and selective inhibitors of the novel proteinkinase Cisozymes" Biorg. Med. Chem. Lett., 21(24): 7367-72 (2011) for kinase inhibitors identified.

[0191] Figure 2FNon-limiting examples of kinase inhibitor targeting ligands (including kinase inhibitor compound YCF) are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lountos et al. "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase2 (Chk2) a Drug Target for Cancer Therapy" J. Struct. Biol., 176: 292 (2011) identified kinase inhibitors.

[0192] Figure 2G-2H Non-limiting examples of kinase inhibitor targeting ligands (including kinase inhibitors XK9 and NXP (derivatization)) are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the kinase inhibitors identified in Lountos et al. "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy" J. Struct. Biol., 176: 292 (2011).

[0193] Figure 2I-2J Non-limiting examples of kinase inhibitor targeting ligands are provided, wherein R represents an exemplary point of attachment of the spacer r.

[0194] Figure 2K-2M Non-limiting examples of cyclin-dependent kinase 9 (CDK9) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Baumli et al." The structure of P-TEFb(CDK9 / cyclin T1)its complex with flavopiridol andregulation by phosphorylation." Embo J., 27:1907-1918(2008); Bettayeb et al. "CDKInhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and ApoptoticCell Death in Neuroblastoma Cells." Genes Cancer, 1: 369-380 (2010); Baumli et al." Halogen bonds form the basis for selective P-TEFb inhibition by DRB." Chem. Biol. 17:931-936 (2010); Hole et al. "Comparative Structural and Functional Studies of 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9Inhibitors Suggest the Basis for Isotype Selectivity." J. Med. Chem. 56:660 (2013); Lücking et al. "Identification of the potent and highly selective PTEFbinhibitor BAY 1251152 for the treatment of cancer-From poto ivapplication via scaffold hops." Lücking et al. U. AACR Annual Meeting, April 1-5, 2017 Washington, DC USA.

[0195] Figure 2N-2P Non-limiting examples of cyclin-dependent kinase 4 / 6 (CDK4 / 6) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see LuH. ; Schulze-GahmenU.;" Toward understanding the structural basis of cyclin-dependent kinase 6specific 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 / 6Inhibitors." ACS Med Chem Lett 3:445-449(2012); Li Z. et al. "Discovery of AMG925a 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. "Spectrumand Degree of CDK Drug Interactions Predicts Clinical Performance." Mol. Cancer Ther. 15:2273-2281 (2016).

[0196] Figure 2Q Non-limiting examples of cyclin-dependent kinase 12 and / or cyclin-dependent kinase 13 targeting ligands are provided, wherein 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).

[0197] Figure 2R-2S Non-limiting examples of glucocorticoid receptor targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0198] Figure 2T-2U Non-limiting examples of RasG12C targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0199] Figure 2V Non-limiting examples of Her3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached, and R" is

[0200] Figure 2WNon-limiting examples of Bcl-2 or Bcl-XL targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0201] Figure 2X-2NN Non-limiting examples of BCL2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Toure BB et al. "The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions." ACS Med Chem Lett, 4: 186-190 (2013); Porter J. et al. "Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as Selective Bcl-2Inhibitors" Bioorg. Med. Chem. Lett. 19: 230 (2009); Souers A.J.et al. "ABT-199a potentand selective BCL-2inhibitor achieves antitumor activity while sparingplatelets." Nature Med.19:202-208(2013); Angelo Aguilar et al. "APotent and HighlyEfficacious Bcl-2 / Bcl-xL Inhibitor" J Med Chem.56(7):3048–3067(2013); LongchuanBai et al. "BM-1197: A Novel and Specific Bcl-2 / Bcl-xL Inhibitor Inducing Complete and Long-Lasting Tumor Regression In Vivo" PLoS ONE 9(6):e99404; Fariba Ne′mati1 et al. "Targeting Bcl-2 / Bcl-XL Induces Antitumor Activity in Uveal MelanomaPatient-Derived Xenografts”PLoS ONE 9(1):e80836; WO2015011396, entitled “Novel derivatives of indole and pyrrole, methods for producing the same and pharmaceutical compositions containing the same”; WO2008060569A1, 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” Expert Opin. Ther. Patents 22(1):2008(2012); and Porter et al. “Tetrahydroisoquinoline amide substituted phenyl pyrazoles as selective Bcl-2 inhibitors” Bioorg Med Chem Lett., 19(1):230-3(2009).

[0202] Figure 2OO-2UUNon-limiting examples of BCL-XL targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Zhi-Fu Tao et al. "Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity" ACS Med. Chem. Lett., 5: 1088-1093 (2014); Joel D. Leverson et al. "Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy" Science Translational Medicine, 7: 279ra40 (2015); and crystal structure PDB 3ZK6 (Guillaume Lessene et al. "Structure-guided design of a selective BCL-XL inhibitor" Nature Chemical Biology 9: 390-397 (2013)).

[0203] Figure 2VV Non-limiting examples of PPAR-γ targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0204] Figure 2WW-2YY Non-limiting examples of EGFR targeting ligands that target the EGFR L858R mutant are provided, including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, where R represents an exemplary point to which a linker can be attached.

[0205] Figure 2ZZ-2FFF Non-limiting examples of EGFR targeting ligands targeting EGFR T790M mutant are provided, including osimertinib, rociletinib, omotinib, naquotinib, nazartinib, PF-06747775, icotinib, neratinib, tarloxotinib, PF-0645998, tesevatinib, transtinib, WZ-3146, WZ8040 and CNX-2006, wherein R represents an exemplary point to which a linker can be attached.

[0206] Figure 2GGGNon-limiting examples of EGFR targeting ligands that target the EGFR C797S mutant are provided, including EAI045, wherein R represents an exemplary point to which a linker can be attached.

[0207] Figure 2HHH Non-limiting examples of BCR-ABL targeting ligands targeting the BCR-ABL T315I mutant are provided, including nilotinib and dasatinib, wherein R represents an exemplary point to which a linker can be attached. See, e.g., crystal structure PDB3CS9.

[0208] Figure 2III Non-limiting examples of targeting ligands that target BCR-ABL are provided, including nilotinib, dasatinib, ponatinib, and bosutinib, where R represents an exemplary point to which a linker can be attached.

[0209] Figure 2JJJ-2KKK Non-limiting examples of ALK targeting ligands targeting the ALK L1196M mutant are provided, including ceritinib, wherein R represents an exemplary point to which a linker can be attached. See, e.g., crystal structure PDB 4MKC.

[0210] Figure 2LLL Non-limiting examples of JAK2 targeting ligands that target the JAK2V617F mutant, including ruxolitinib, are provided, wherein R represents an exemplary point to which a linker can be attached.

[0211] Figure 2MMM Non-limiting examples of BRAF targeting ligands targeting the BRAF V600E mutant are provided, including vemurafenib, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PBD 3OG7.

[0212] Figure 2NNN Non-limiting examples of BRAF targeting ligands are provided, including dabrafenib, wherein R represents an exemplary point to which a linker can be attached.

[0213] Figure 2000 provides non-limiting examples of LRRK2 Targeting Ligands that target the LRRK2 R1441C mutant, where R represents an exemplary point to which a linker can be attached.

[0214] Figure 2PPP Non-limiting examples of LRRK2 targeting ligands that target the LRRK2 G2019S mutant are provided, wherein R represents an exemplary point to which a linker can be attached.

[0215] Figure 2QQQ Non-limiting examples of LRRK2 targeting ligands that target the LRRK2 I2020T mutant are provided, wherein R represents an exemplary point to which a linker can be attached.

[0216] Figure 2RRR-2TTT Non-limiting examples of PDGFRα targeting ligands that target the PDGFRα T674I mutant are provided, including AG-1478, CHEMBL94431, dovitinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, sorafenib, sunitinib and WHI-P180, wherein R represents an exemplary point to which a linker can be attached.

[0217] Figure 2UUU Non-limiting examples of RET targeting ligands that target the RET G691S mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0218] Figure 2VVV Non-limiting examples of RET targeting ligands that target the RET R749T mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0219] Figure 2WWW Non-limiting examples of RET targeting ligands that target the RET E762Q mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0220] Figure 2XXX Non-limiting examples of RET targeting ligands that target the RET Y791F mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0221] Figure 2YYY Non-limiting examples of RET targeting ligands that target the RET V804M mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0222] Figure 2ZZZ Non-limiting examples of RET targeting ligands that target the RET M918T mutant are provided, including tauzerti, wherein R represents an exemplary point to which a linker can be attached.

[0223] Figure 2AAAA Non-limiting examples of fatty acid binding protein targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0224] Figure 2BBBB Non-limiting examples of 5-lipoxygenase activating protein (FLAP) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0225] Figure 2CCCCNon-limiting examples of Kringle domain V 4BVV targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0226] Figure 2DDDD Non-limiting examples of lactoylglutathione lyase targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0227] Figure 2EEEE-2FFFF Non-limiting examples of mPGES-1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0228] Figure 2GGGG-2JJJJ Non-limiting examples of Factor Xa targeting ligands are provided, wherein 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." (to be published); crystal structures PDB 1iqh, 1iqi, 1iqk, and 1iqm; Adler M. et al. "Crystal Structures of Two Potent NonamidineInhibitors 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]-13-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An Oral Direct Factor Xa Inhibitor." J. Med. Chem. 48:5900 (2005); AnselmL.et al. “Discovery of a Factor Xa Inhibitor(3R 4R)-1-(2 2-Difluoro-Ethyl)-Pyrrolidine-3 4-Dicarboxylic Acid and Pinto DJ et al. “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 PotentSelective Efficacious and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa." J. Med. Chem. 50:5339-5356 (2007).

[0229] Figure 2KKKK Non-limiting examples of kallikrein 7 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Maibaum J. et al. "Small-moleculefactor D inhibitors targeting the alternative complement pathway." Nat. Chem. Biol. 12:1105-1110 (2016).

[0230] Figure 2LLLL-2MMMM Non-limiting examples of cathepsin K targeting ligands are provided, wherein 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 Kinhibitors" 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).

[0231] Figure 2NNNN Non-limiting examples of cathepsin L targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Kuhn B. et al. "Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin LInhibitors." J. Med. Chem. 60: 2485-2497 (2017).

[0232] Figure 2OOOO Non-limiting examples of cathepsin S targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see JadhavP.K. et al. "Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm." ACS Med. Chem. Lett. 5:1138-1142. (2014).

[0233] Figure 2PPPP-2SSSS Non-limiting examples of MTH1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Kettle JG et al. "Potent andSelective Inhibitors of Mth1 Probe its Role in Cancer Cell Survival." J. Med. Chem. 59: 2346 (2016); Huber KVMet al. "Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy." Nature 508:222(2014); GadH. et al. "MTH1inhibition eradicates cancer by preventing sanitation of the dNTP pool." Nature 508:215-221 (2014); Nissink J.WM et al., "Mth1 Substrate Recognition--anExample 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.

[0234] Figure 2TTTT-2ZZZZ Non-limiting examples of MDM2 and / or MDM4 targeting ligands are provided, wherein 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); MiyazakiM . et al. "Discovery of DS-5272 as a promising candidate: A potent and orally activep53-MDM2 interaction inhibitor." BioorgMedChem. 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); Gonzalez-Lopez de Turiso F. et al., “Rational Design and Binding Mode Duality of MDM2 - p53 Inhibitors.” J. Med. Chem. 56:4053 - 4070(2013); Gessier F. et al., “Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53 - MDM2 interaction with a distinct binding mode.” Bioorg. Med. Chem. Lett. 25:3621 - 3625(2015); Fry D.C. et al., “Deconstruction of anutlin: dissecting the binding determinants of a potent protein - protein interaction inhibitor.” ACS Med Chem Lett 4:660 - 665(2013); DingQ. et al., “Discovery of RG7388 a Potent and Selective p53 - MDM2 Inhibitor in Clinical Development.” J. Med. Chem. 56:5979 - 5983(2013); Wang S. et al., “SAR405838: an optimized inhibitor of MDM2 - p53 interaction that induces complete and durable tumor regression.” Cancer Res. 74:5855 - 5865(2014); Rew Y.et al. "Discovery of AM-7209a Potent andSelective4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction." J. Med. Chem. 57: 10499-10511 (2014); Bogen S.L. et al. “Discovery of Novel 33-Disubstituted Piperidines as Orally Bioavailable Potent and Efficacious HDM2-p53 Inhibitors.” ACS Med. Chem. Lett. 7:324-329 (2016); and, SunD. et al. "Discovery ofAMG 232a Potent Selective and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development." J. Med. Chem. 57:1454-1472 (2014).

[0235] Figure 2AAAAA-2EEEEE Non-limiting examples of PARP1, PARP2 and / or PARP3 targeting ligands are provided, wherein 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 in complex 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 ofnovel 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); PenningT.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); YeN. 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); PatelM.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); Thorsell A.G.et al. "Structural Basis for Potency and Promiscuity in Poly(ADP-ribose)Polymerase(PARP) and Tankyrase Inhibitors." J.Med.Chem.60:1262–1271(2012); Crystal structure PDB4RV6 ("Human ARTD1(PARP1)catalytic domain in complex with inhibitorRucaparib", Karlberg T. et al.); Papeo GME et al. “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-1Inhibitor for Cancer Therapy." J. Med. Chem. 58: 6875 (2015); Kinoshita T. et al. "Inhibitor-induced structural change of the active site of human poly(ADP-ribose)polymerase." Febs Lett. 556:43-46 (2004); and Gangloff AR et al. "Discovery of novel benzo[b][1 4]oxazin-3(4H)-ones as poly(ADP-ribose)polymeraseinhibitors." Bioorg. Med. Chem. Lett. 23:4501-4505 (2013).

[0236] Figure 2FFFFF-2GGGGG Non-limiting examples of PARP14 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0237] Figure 2HHHHH Non-limiting examples of PARP15 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0238] Figure 2IIIII 1 provides non-limiting examples of PDZ domain targeting ligands, wherein R represents an exemplary point of spacer attachment.

[0239] Figure 2JJJJJ Non-limiting examples of phospholipase A2 domain targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0240] Figure 2KKKKK Non-limiting examples of protein S100-A7 2WOS targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0241] Figure 2LLLLL-2MMMMM Non-limiting examples of Saposin-B targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0242] Figure 2NNNNN-2OOOOO Non-limiting examples of Sec7 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0243] Figure 2PPPPP-2QQQQ Non-limiting examples of SH2 domain targeting ligands for pp60 Src are provided, wherein R represents an exemplary point to which a linker can be attached.

[0244] Figure 2RRRRR Non-limiting examples of Tank1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0245] Figure 2SSSSS Non-limiting examples of Ubc9 SUMO E2 ligase SF6D targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0246] Figure 2TTTTT Non-limiting examples of Src targeting ligands are provided, including AP23464, where R represents an exemplary point to which a linker can be attached.

[0247] Figure 2UUUUU-2XXXXX Non-limiting examples of Src-AS1 and / or Src AS2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0248] Figure 2YYYYY Non-limiting examples of JAK3 targeting ligands are provided, including tofacitinib, wherein R represents an exemplary point to which a linker can be attached.

[0249] Figure 2ZZZZZ Non-limiting examples of ABL targeting ligands are provided, including tofacitinib and ponatinib, where R represents an exemplary point to which a linker can be attached.

[0250] Figure 3A-3BNon-limiting examples of MEK1 targeting ligands are provided, including PD318088, trametinib, and G-573, where R represents an exemplary point to which a linker can be attached.

[0251] Figure 3C Non-limiting examples of KIT targeting ligands are provided, including regorafenib, wherein R represents an exemplary point to which a linker can be attached.

[0252] Figure 3D-3E Non-limiting examples of HIV reverse transcriptase targeting ligands are provided, including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir, where R represents an exemplary point to which a linker can be attached.

[0253] Figure 3F-3G Non-limiting examples of HIV protease targeting ligands are provided, including ritonavir, raltegravir, and atazanavir, where R represents an exemplary point to which a linker can be attached.

[0254] Figures 3H-3I Non-limiting examples of KSR1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0255] Figure 3J-3L Non-limiting examples of CTNNB1 targeting ligands are provided, wherein R represents an exemplary point 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).

[0256] Figure 3MNon-limiting examples of BCL6 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0257] Figure 3N-3O Non-limiting examples of PAK1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0258] Figure 3P-3R Non-limiting examples of PAK4 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0259] Figure 3S-3T Non-limiting examples of TNIK targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0260] Figure 3U Non-limiting examples of MEN1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0261] Figure 3V-3W Non-limiting examples of ERK1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0262] Figure 3X Non-limiting examples of IDO1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0263] Figure 3Y Non-limiting examples of CBP targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0264] Figure 3Z-3SS Non-limiting examples of MCL1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Tanaka Y. et al. "Discovery of potent Mcl-1 / Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins." J. Med. Chem. 56: 9635-9645 (2013); Friberg A. et al.“Discovery of potent myeloid cell leukemia 1(Mcl-1)inhibitors using fragment-based methods and structure-based design.”J.Med.Chem.56:15-30(2013); Petros A.M. et al. “Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.”Bioorg.Med.Chem.Lett.24:1484-1488(2014); Burke J.P. et al. “Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design.”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); Clifton M.C. et al. “A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1.”Plos One 10:e0125010-e0125010(2015); Kotschy A et al."The MCL1inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538: 477-482 (2016); EP 2886545 A1, entitled "Novel thienopyrimidine derivatives, preparation methods thereof and pharmaceutical compositions containing them"; Jeffrey W. Johannes et al. "Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors" ACSMed. Chem. Lett. (2017); DOI: 10.1021 / acsmedchemlett.6b00464; Bruncko M. et al. "Structure-Guided Design of a Series of MCL-1Inhibitors with High Affinity and Selectivity." J. Med. Chem. 58: 2180-2194 (2015); Taekyu Lee et al. "Discovery and biological characterization of potent myeloid cell leukemia-1inhibitors.” FEBS Letters 591:240–251 (2017); Chen L. et al. “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); US2016 / 0068545, entitled “Tetrahydronaphthalene derivatives inhibiting mcl-1 protein”; WO 2016207217 A1, entitled “Preparation of new bicyclic derivatives as pro-apoptotic agents”; Gizem et al. “Inhibition of Mcl-1through covalent modification of a noncatalytic lysine side chain” Nature Chemical Biology 12:931–936 (2016).

[0265] Figure 3TTNon-limiting examples of ASH1L targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See, e.g., crystal structure PDB 4YNM ("Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)" Rogawski DS et al.)

[0266] Figure 3UU-3WW Non-limiting examples of ATAD2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Chaikuad A. et al. "Structure-basedapproaches towards identification of fragments for the low-drugability ATAD2 bromodomain" Med Chem Comm 5:1843-1848 (2014); Poncet-Montange G. et al. "Observedbromodomain 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); DemontE.H. et al. "Fragment-Based Discovery of Low-Micromolar Atad2Bromodomain Inhibitors." J. Med. Chem. 58:5649 (2015); and, Bamborough P. et al. "Structure-Based Optimization of Naphthyridones into Potent Atad2BromodomainInhibitors." J. Med. Chem. 58:6151 (2015).

[0267] Figure 3XX-3AAANon-limiting examples of BAZ2A and BAZ2B targeting ligands are provided, 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 Baz2Bin Complex with Fragment-6N09645" Bradley A. et al.); Crystal structure PDB 5CUA (“Second Bromodomain of Bromodomain Adjacent to Zinc Finger Domain Protein2B(BAZ2B)incomplex with 1-Acetyl-4-(4-hydroxyphenyl)piperazine”. Bradley A. et al.); Ferguson F.M. et al. "Targeting low-drugability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain." J. Med. Chem. 56: 10183-10187 (2013); Marchand J.R. et al. "Derivatives of 3-Amino-2-methylpyridine asBAZ2BBromodomain Ligands: In Silico Discovery and in Crystallo Validation." J. Med. Chem. 59: 9919-9927 (2016); Drouin L. et al. "Structure Enabled Design of BAZ2-ICR A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B." J.Med.Chem.58:2553-2559(2015); Chen P. et al. "Discovery and characterization ofGSK2801 a selective chemical probe for the bromodomains BAZ2A and BAZ2B." BAZ2B." J. Med. Chem. 59:1410-1424 (2016).

[0268] Figure 3BBBNon-limiting examples of BRD1 targeting ligands are provided, wherein R represents an exemplary point 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”, NM et al.); Crystal structure PDB5AMF (“Crystal Structure of the Bromodomain of Human Surface EpitopeEngineered Brd1A in Complex with 3D Consortium Fragment Ethyl 4 5 6 7-Tetrahydro-1H-Indazole-5-Carboxylate”, Pearce NM et al.); 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.); Filippakopoulos P. et al. "Histone recognition and large-scale structural analysis of the human bromodomain family." Cell, 149:214-231 (2012).

[0269] Figure 3CCC-3EEE Non-limiting examples of BRD2 bromodomain 1 targeting ligands are provided, wherein 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.

[0270] Figure 3FFF-3HHHNon-limiting examples of BRD2 bromodomain 2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 3oni; Filippakopoulos P. et al. "Selective Inhibition of BET Bromodomains." Nature 468:1067-1073 (2010); Crystal structure PDB 4j1p; McLure K.G. et al. "RVX-208: an Inducer of ApoA-Iin Humans is a BET Bromodomain Antagonist." Plos One 8:e83190-e83190 (2013); BaudM.G. et al. "Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes" Science 346:638-641 (2014); BaudM.G. et al. "New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo andExtra-Terminal(BET)Bromodomain Inhibition" J.Med.Chem.59:1492-1500(2016); Gosmini R. et al. "The Discovery of I-Bet726(Gsk1324726A)aPotentTetrahydroquinoline Apoa1 Up-Regulator and Selective Bet BromodomainInhibitor" J.Med.Chem.57:8111(2014); Crystal structure of the second bromodomain of human BRD2 in complex with a hydroquinolinoneinhibitor”, Tallant C. et al.); crystal structure PDB 5BT5; crystal structure PDB 5dfd; BaudM.G.et al. "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" J. Med. Chem. 59: 1492-1500 (2016).

[0271] Figure 3III-3JJJ Non-limiting examples of BRD4 bromodomain 1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 5WUU and crystal structure PDB 5F5Z.

[0272] Figure 3KKK-3LLL Non-limiting examples of BRD4 bromodomain 2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Chung CW et al. "Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains" J. Med. Chem. 54: 3827 (2011) and Ran X. et al. "Structure-Based Design of gamma-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors" J. Med. Chem. 58: 4927-4939 (2015).

[0273] Figure 3 MMM Non-limiting examples of BRDT targeting ligands are provided, 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.

[0274] Figure 3NNN-3QQQNon-limiting examples of BRD9 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For additional examples and related ligands, see crystal structure PDB 4nqn; crystal structure PDB 4uit; crystal structure PDB 4uiu; crystal structure PDB 4uiv; crystal structure PDB 4z6h; crystal structure PDB 4z6i; crystal structure PDB 5e9v; crystal structure PDB 5eu1; crystal structure PDB 5f1h; crystal structure PDB 5fp2, ("Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" J Med Chem., 2016, 59 (10), 4462; and WO2016139361).

[0275] Figure 3RRR Non-limiting examples of SMARCA4 PB1 and / or SMARCA2 targeting ligands are provided, wherein 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.

[0276] Figure 3SSS-3XXX Additional non-limiting examples of bromodomain targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Hewings et al. "3, 5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands." J. Med. Chem. 546761-6770 (2011); Dawson et al. "Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia." Nature, 478, 529-533 (2011); US2015 / 0256700; US2015 / 0148342; WO 2015 / 074064; WO 2015 / 067770; WO 2015 / 022332; WO 2015 / 015318; and WO 2015 / 011084.

[0277] Figure 3YYY Non-limiting examples of PB1 targeting ligands are provided, 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.

[0278] Figure 3ZZZ Non-limiting examples of SMARCA4 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See crystal structure 3uvd and crystal structure 5dkd for additional examples and related ligands.

[0279] Figure 3AAAA Non-limiting examples of SMARCA2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For additional examples and related ligands, see crystal structures 5dkc and 5dkh; and WO2020023657, US20200038378, WO2020010227, WO2020078933, WO2019207538, WO2016138114, WO2020035779, 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.

[0280] Figure 3BBBB Non-limiting examples of TRIM24 (TIF1a) and / or BRPF1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached, and m is 0 1 2 3 45 6 7 or 8.

[0281] Figure 3CCCC Non-limiting examples of TRIM24 (TIF1a) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Palmer WS et al. "Structure-Guided Design of IACS-9571: aSelective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor." J. Med. Chem. 59:1440-1454 (2016).

[0282] Figure 3DDDD-3FFFFNon-limiting examples of BRPF1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Crystal Structure PDB 4uye; Crystal Structure PDB 5c7n; Crystal Structure PDB 5c87; Crystal Structure PDB 5c89; Crystal Structure PDB 5d7x; Crystal Structure PDB 5dya; Crystal Structure PDB 5epr; Crystal Structure PDB 5eq1; Crystal Structure PDB 5etb; Crystal Structure PDB 5ev9; Crystal Structure PDB 5eva; Crystal Structure PDB 5ewv; Crystal Structure PDB 5eww; Crystal Structure PDB 5ffy; Crystal Structure PDB 5fg5; and Crystal Structure PDB 5g4r.

[0283] Figure 3GGGG Non-limiting examples of CECR2 targeting ligands are provided, wherein R represents an exemplary point to which a linker 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).

[0284] Figure 3HHHH-3OOOO Non-limiting examples of CREBBP targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached, A is N or CH, and m is 0 1 23 4 5 6 7 or 8. For additional examples and related ligands, see Crystal Structure 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 PDB4nyx; 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.

[0285] Figure 3 PPPP Non-limiting examples of EP300 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 5BT3.

[0286] Figure 3QQQQNon-limiting examples of PCAF targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See, e.g., M. Ghizzoni et al. Bioorg. Med. Chem. 18:5826-5834 (2010).

[0287] Figure 3RRRR Non-limiting example targeting ligands for PHIP are provided, 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).

[0288] Figure 3SSSS Non-limiting examples of TAF1 and TAF1L targeting ligands are provided, wherein 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).

[0289] Figure 3TTTT Provided are non-limiting examples of histone deacetylase 2 (HDAC2) targeting ligands, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Lauffer B. EJ Biol. Chem. 288: 26926-26943 (2013); Wagner FF Bioorg. Med. Chem. 24: 4008-4015 (2016); Bressi JC Bioorg. Med. Chem. Lett. 20: 3142-3145 (2010); and Lauffer B. EJ Biol. Chem. 288: 26926-26943 (2013).

[0290] Figure 3UUUU-3VVVV Non-limiting examples of histone deacetylase 4 (HDAC4) targeting ligands are provided, wherein 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 CAACS Med. Chem. Lett. 7: 34 (2016); Bottomley MJ J Biol. Chem. 283: 26694-26704 (2008).

[0291] Figure 3WWWWNon-limiting examples of histone deacetylase 6 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Harding RJ (forthcoming); Hai Y. Nat. Chem. Biol. 12: 741-747, (2016); and Miyake Y. Nat. Chem. Biol. 12: 748 (2016).

[0292] Figure 3XXXX-3YYYY Non-limiting examples of histone deacetylase 7 targeting ligands are provided, wherein 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).

[0293] Figure 3ZZZZ-3DDDDD Non-limiting examples of histone deacetylase 8 targeting ligands are provided, wherein 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 AA J Structure. Biol. 195:373-378 (2016); Dowling DP 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);SomozaJ.R.Biochemistry 12:1325-1334(2004);Decroos C.Biochemistry 54:6501-6513(2015);Decroos A.ACS Chem. Biol. 9:2157-2164 (2014); and Dowling DPBiochemistry 47:13554-13563 (2008).

[0294] Figure 3EEEEEProvided are non-limiting examples of histone acetyltransferase (KAT2B) targeting ligands, wherein 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).

[0295] Figure 3FFFFF-3GGGGG Provide non-limiting examples of histone acetyltransferase (KAT2A) targeting ligands, wherein 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).

[0296] Figure 3HHHHH Provide the non-limiting example of histone acetyltransferase B type catalytic unit (HAT1) targeting ligand, wherein R represents the exemplary point that linking group can be connected.For other examples and related ligands, refer to crystal structure PDB 2POW.

[0297] Figure 3IIIII I provides non-limiting examples of cyclic AMP-dependent transcription factor (ATF2) targeting ligands, wherein R represents an exemplary point to which a linker can be attached.

[0298] Figure 3JJJJJ Non-limiting examples of histone acetyltransferase (KAT5) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached.

[0299] Figure 3KKKKK-3MMMMMM Non-limiting examples of lysine-specific histone demethylase 1A (KDM1A) targeting ligands are provided, wherein 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).

[0300] Figure 3NNNNN Non-limiting examples of HDAC6 Zn finger domain targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0301] Figure 3OOOOOO-3PPPPPNon-limiting examples of general lysine methyltransferase targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0302] Figure 3QQQQQ-3TTTTT Non-limiting examples of DOT1L targeting ligands are provided, where R represents an exemplary point to which a linker can be attached, A is N or CH, and m is 0 1 23 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 structure 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 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 complexwith SS148” Yu W. et al. Structural Genomics Consortium), crystal structure PDB 6TE6 (“Dot1Lin complex with an inhibitor, compound 3”, Stauffer, F., et al., ACS Med Chem Lett., 2019, 10: 1655-1660).

[0303] Figure 3UUUUUNon-limiting examples of EHMT1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 5TUZ ("EHMT1 in complex within inhibitor MS0124", Babault N. et al.).

[0304] Figure 3VVVVV Non-limiting examples of EHMT2 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 5TUY ("EHMT2 in complex within inhibitor MS0124", Babault N. et al.); PDB crystal structure 5TTF ("EHMT2 in complex within 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 RF et al.).

[0305] Figure 3WWWWW Non-limiting examples of SETD2 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 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).

[0306] Figure 3XXXXX-3YYYYYNon-limiting examples of SETD7 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 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 JR 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).

[0307] Figure 3ZZZZZ Non-limiting examples of SETD8 targeting ligands are provided, wherein R represents an exemplary point 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.; forthcoming).

[0308] Figure 4A-4BNon-limiting examples of SETDB1 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 5KE2 ("SETDB1 in complex within 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 JR et al. Structural Genomics Consortium); and PDB crystal structure 5KCO ("SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide", Walker JR et al.).

[0309] Figure 4C-4PNon-limiting examples of SMYD2 targeting ligands are provided, 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 within inhibitor AZ13450370", Cowen SD et al.); PDB crystal structure 5KJM ("SMYD2 in complex with AZ931", Cowen SD et al.); PDB crystal structure 5KJN ("SMYD2 in complex with AZ506", Cowen SD 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 RF et al.); PDB crystal structure 4WUY (“SMYD2 in complex with LLY-507”, Nguyen H. et al.); and 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 AD et al.).

[0310] Figure 4Q-4RNon-limiting examples of SMYD3 targeting ligands are provided, wherein 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 GS et al.); crystal structure 5CCL ("SMYD3 in complex withoxindole compound", Mitchell LH et al.); and crystal structure 5CCM ("Crystal structure ofSMYD3 with SAM and EPZ030456").

[0311] Figure 4S Non-limiting examples of SUV4-20H1 targeting ligands are provided, wherein 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 KD et al.).

[0312] Figure 4T-4AANon-limiting examples of wild-type androgen receptor targeting ligands are provided, 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)benzonitrilederivatives”, 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-benzonitrilederivatives”, 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 RS et al.); PDB crystal structure 3V49 (“Androgen Receptor lbd with activator peptide and sarminhibitor 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 CE 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 CE et al.); Bohl CE et al. Bioorg. Med. Chem. Lett. 18:5567-5570 (2008); PDB crystal structure 2PIP ("Androgen Receptor ligand binding domain in complex with smallmolecule", Estebanez-Perpina E. et al.); Estebanez-Perpina.E. Proc. Natl. Acad. Sci. 104:16074-16079 (2007); PDB crystal structure 2PNU ("Androgen Receptor ligand binding domainin 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 other related ligands, see. Matias PM et al. "Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor(Ar(Ccr))Derived from an Androgen-IndependentProstate Cancer." J. Med. Chem. 45: 1439 (2002); Sack JS et al. "Crystallographic structures of the ligand-binding domains of the androgen receptor and itsT877Amutant complexed with the natural agonist dihydrotestosterone." Proc.Natl.Acad.Sci.98:4904-4909 (2001); He B.et al., “Structural basis for androgenreceptor interdomain and coactivator interactions suggests a transition innuclear receptor activation function dominance.” Mol. Cell 16:425-438 (2004); Pereira deJesus-Tran K. “Comparison of crystal structures of human androgenreceptor ligand-binding domain complexed with various agonists revealsmolecular determinants responsible for binding affinity.” Protein Sci. 15:987-999 (2006); BohlC.E. et al., “Structural Basis for Accommodation of NonsteroidalLigands in the Androgen Receptor.” Mol Pharmacol. 63(1):211-23 (2003); SunC. et al., “Discovery of potent orally-active and muscle-selective androgen receptormodulators based on an N-aryl-hydroxybicyclohydantoin scaffold.” J. Med. Chem. 49:7596-7599 (2006); Nirschl A.A. et al., “N-aryl-oxazolidin-2-iminemuscle selective androgen receptor modulators enhance potency throughpharmacophore reorientation.” J. Med. Chem. 52:2794-2798 (2009); BohlC.E.et al., “Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators.” Bioorg. Med. Chem. Lett. 18:5567-5570 (2008); Ullrich T. et al., “3-alkoxy-pyrrolo[1 2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration.” J. Med. Chem. 57:7396-7411 (2014); Saeed A. et al., “2-Chloro-4-[[(1R2R)-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); Nique et al., “Discovery of diarylhydantoins as new selective androgen receptor modulators.” J. Med. Chem. 55:8225-8235 (2012); and Michael E. Jung et al., “Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC).” J. Med. Chem. 53:2779–2796 (2010).

[0313] Figure 4BBNon-limiting examples of mutant T877A androgen receptor targeting ligands are provided, where R represents an example 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 CL et al.) and PDB crystal structure 2OZ7 ("Androgen Receptor T877A-AR-LBD", Bohl CE et al.).

[0314] Figure 4CC Non-limiting examples of mutant W741L androgen receptor targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 4OJB ("AndrogenReceptor T877A-AR-LBD", Hsu CL et al.).

[0315] Figure 4DD-4EE Non-limiting examples of estrogen and / or androgen targeting ligands are provided, where R represents an exemplary point to which a linker can be attached.

[0316] Figure 5A A non-limiting example of afatinib, a targeting ligand for EGFR and ErbB2 / 4 receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0317] Figure 5B A non-limiting example of axitinib (a targeting ligand for VEGFR1 / 2 / 3, PDGFRβ, and Kit receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0318] Figure 5C-5D A non-limiting example of bosutinib (a targeting ligand for BCR-Abl, Src, Lyn, and Hck receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0319] Figure 5E A non-limiting example of cabozantinib (a targeting ligand for RET, c-Met, VEGFR1 / 2 / 3, Kit, TrkB, Flt3, Axl, and Tie 2 receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0320] Fig. 5F A non-limiting example of Ceritinib, a targeting ligand for ALK, IGF-1R, InsR, and ROS1 receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0321] Figure 5GA non-limiting example of crizotinib, a targeting ligand for ALK, c-Met, HGFR, ROS1, and MST1R receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0322] Figure 5H A non-limiting example of dabrafenib, a targeting ligand for the B-Raf receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0323] Fig.5I A non-limiting example of dasatinib (a targeting ligand for BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0324] Figure 5J A non-limiting example of erlotinib, a targeting ligand for the EGFR receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0325] Figure 5K-5M A non-limiting example of everolimus (a targeting ligand for the HER2 breast cancer receptor, the PNET receptor, the RCC receptor, the RAML receptor, and the SEGA receptor) is provided. R represents an exemplary point to which a linker can be attached.

[0326] Figure 5N A non-limiting example of gefitinib, a targeting ligand for EGFR and PDGFR receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0327] Fig.5O A non-limiting example of ibrutinib, a targeting ligand for the BTK receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0328] Figure 5P-5Q A non-limiting example of imatinib, a targeting ligand for BCR-Abl, Kit, and PDGFR receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0329] Figure 5R-5S A non-limiting example of lapatinib, a targeting ligand for EGFR and ErbB2 receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0330] Figure 5T A non-limiting example of lenvatinib (a targeting ligand for VEGFR1 / 2 / 3, FGFR1 / 2 / 3 / 4, PDGFRα, Kit, and RET receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0331] Figure 5U-5VA non-limiting example of nilotinib (a targeting ligand for BCR-Abl, PDGRF, and DDR1 receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0332] Figure 5W-5X A non-limiting example of nintedanib, a targeting ligand for FGFR1 / 2 / 3, Flt3, Lck, PDGFRα / β, and VEGFR1 / 2 / 3 receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0333] Figure 5Y-5Z A non-limiting example of palbociclib, a targeting ligand for the CDK4 / 6 receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0334] Figure 5AA A non-limiting example of pazopanib (a targeting ligand for VEGFR1 / 2 / 3, PDGFRα / β, FGFR1 / 3, Kit, Lck, Fms, and Itk receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0335] Figure 5BB-5CC Non-limiting examples are provided for Ponatinib (a targeting ligand for BCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2, and Flt3 receptors). R represents an exemplary point to which a linker can be attached.

[0336] Figure 5DD A non-limiting example of regorafenib (a targeting ligand for VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα / β, RET, FGFR1 / 2, Tie2, and Eph2A) is provided. R represents an exemplary point to which a linker can be attached.

[0337] Figure 5EE A non-limiting example of ruxolitinib, a targeting ligand for the JAK1 / 2 receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0338] Figure 5FF-5GG A non-limiting example of sirolimus, a targeting ligand for the FKBP12 / mTOR receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0339] Figure 5HH A non-limiting example of sorafenib (a targeting ligand for B-Raf, CDK8, Kit, Flt3, RET, VEGFR1 / 2 / 3, and PDGFR receptors) is provided. R represents an exemplary point to which a linker can be attached.

[0340] Figure 5II-5JJ A non-limiting example of sunitinib (a targeting ligand for PDGFRα / β, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, RET) is provided. R represents an exemplary point to which a linker can be attached.

[0341] Figure 5KK-5LL A non-limiting example of temsirolimus (targeting ligand FKBP12 / mTOR) is provided. R represents an exemplary point to which a linker can be attached.

[0342] Figure 5MM A non-limiting example of tofacitinib, a targeting ligand for the JAK3 receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0343] Figure 5NN A non-limiting example of trametinib, a targeting ligand for the MEK1 / 2 receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0344] Figure 5OO-5PP A non-limiting example of vandetanib (a targeting ligand for EGFR, VEGFR, RET, Tie2, Brk, and EphR) is provided. R represents an exemplary point to which a linker can be attached.

[0345] Figure 5QQ A non-limiting example of vemurafenib, a targeting ligand for A / B / C-Raf, KSR1, and B-Raf (V600E) receptors, is provided. R represents an exemplary point to which a linker can be attached.

[0346] Figure 5RR A non-limiting example of Idelasib, a targeting ligand for the PI3Ka receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0347] Figure 5SS A non-limiting example of Buparlisib, a targeting ligand for the PI3Ka receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0348] Figure 5TT A non-limiting example of Taselisib, a targeting ligand for the PI3Ka receptor, is provided. R represents an exemplary point to which a linker can be attached.

[0349] Figure 5UU A non-limiting example of Copanlisib, a targeting ligand for PI3Ka, is provided. R represents an exemplary point to which a linker can be attached.

[0350] Figure 5VV A non-limiting example of apellisin, a targeting ligand for PI3Ka, is provided. R represents an exemplary point to which a linker can be attached.

[0351] Figure 5WW A non-limiting example of niclosamide, a targeting ligand for CNNTB1, is provided. R represents an exemplary point to which a linker can be attached.

[0352] Figure 6A-6B Non-limiting examples of BRD4 bromodomain targeting ligands for PCAF and GCN5 receptor 1 are provided, wherein 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 aPCAF 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, PG et al. J. Med. Chem. 60: 695 (2017).

[0353] Figure 6C-6DNon-limiting examples of G9a (EHMT2) targeting ligands are provided, wherein 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, RF et al. ACS Med Chem Lett 5:205 (2014).

[0354] Figure 6E-6GNon-limiting examples of EZH2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 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 HistoneMethyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas”); Vaswani, RG et al. J. Med. Chem. 59:9928 (2016); and PDB crystal structures 5ij8 and 5ls6.

[0355] Figures 6H-6I Non-limiting examples of EED targeting ligands are provided, where R represents an exemplary point 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.

[0356] Figure 6J Non-limiting examples of KMT5A (SETD8) targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See, e.g., PDB crystal structure 5t5g.

[0357] Figure 6K-6LNon-limiting examples of DOT1L targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 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, SR 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”); and Chen, C. et al. ACS Med. Chem. Lett. 7:735 (2016).

[0358] Figure 6M-6NNon-limiting examples of PRMT3 targeting ligands are provided, wherein 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, HU et al. Angew. Chem. Int. Ed. Engl. 54:5166 (2015).

[0359] Fig.6O Non-limiting examples of CARM1 (PRMT4) targeting ligands are provided, wherein 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, JS et al. Biochem. J. 436: 331 (2011).

[0360] Figure 6P Non-limiting examples of PRMT5 targeting ligands are provided, wherein 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 invivo and in vitro potency in MCL models". Chan-Penebre, E. Nat. Chem. Biol. 11: 432 (2015).

[0361] Figure 6QNon-limiting examples of PRMT6 targeting ligands are provided, wherein 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, LH et al. ACS Med. Chem. Lett. 6: 655 (2015).

[0362] Figure 6R Non-limiting examples of LSD1 (KDM1A) targeting ligands are provided, wherein 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).

[0363] Figure 6S-6TNon-limiting examples of KDM4 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 3rvh; PDB crystal structure 5a7p and related ligands described in "Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors." Korczynska, M., et al. J. Med. Chem. 59: 1580 (2016); 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).

[0364] Figure 6U Non-limiting examples of KDM5 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the PDB crystal structure 3fun and related ligands described in "Structural Analysis of Human Kdm5BGuides Histone Demethylase Inhibitor Development". Johansson, C. et al. Nat. Chem. Biol. 12: 539 (2016) and the 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).

[0365] Figure 6V-6WNon-limiting examples of KDM6 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the 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).

[0366] Figure 6X Non-limiting examples of L3MBTL3 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See, e.g., PDB crystal structure 4f16.

[0367] Figure 6Y Non-limiting examples of Menin targeting ligands are provided, wherein R represents an exemplary point at 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 structures 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).

[0368] Figure 6Z-6AA Non-limiting examples of HDAC6 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. See, e.g., PDB crystal structures 5kh3 and 5eei.

[0369] Figure 6BBNon-limiting examples of HDAC7 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For additional examples and related ligands, see "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) described in PDB crystal structure 3c10 and related ligands and "Selective Class Iia Histone Deacetylase Inhibition Via a Non-Chelating Zinc Binding Group". Lobera, M. et al. Nat. Chem. Biol. 9: 319 (2013) described in PDB crystal structure PDB 3zns and related ligands.

[0370] Figures 7A-7CNon-limiting examples of protein tyrosine phosphatase, non-receptor type 1, PTP1B targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see PDB crystal structure 1bzj described in "Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics" Groves, MR et al. Biochemistry 37:17773-17783 (1998); 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); PDB crystal structure 3cwe described in "Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors." Moretto, AF et al. Bioorg. Med. Chem. 14: 2162-2177 (2006) described in PDB crystal structures 2azr and 2b07; in "Structure-Based Design of Protein Tyrosine Phosphatase-1B Inhibitors". Black, E. et al. Bioorg. Med. Chem. Lett. 15: 2503 (2005) and "Structural Basis for Inhibition of Protein-Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics." Ala, PJ et al. J. Biol. Chem. 281: 32784 (2006) described in PDB crystal structures PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cmb, 2cmc; in "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatasePTP1Binhibitors".PDB crystal structures 2f6t and 2f6w described in Klopfenstein, SR et al. Bioorg. Med. Chem. Lett. 16: 1574-1578 (2006); PDB crystal structures 2h4g, 2h4k, 2hb1 described in "Monocyclic thiophenes as protein tyrosinephosphatase 1B inhibitors: Capturing interactions with Asp48." Wan, ZK et al. Bioorg. Med. Chem. Lett. 16: 4941-4945 (2006); PDB crystal structure 2zn7 described in "Structure-based optimization of protein tyrosine phosphatase-1B inhibitors: capturing interactions with arginine 24". Wan, ZK et al. Chem Med Chem. 3: 1525-9 (2008); PDB crystal structure 2zn7 described in "Probing acid replacements of thiophene PTP1B inhibitors." PDB crystal structures 2nt7, 2nta described in Wan, ZK et al. Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007); and WO 2008148744A1 assigned to Novartis AG, entitled "Thiadiazole derivatives as antidiabetic agents". See also PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 1l8g and described in "2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases". Andersen, HS 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, LF et al. J.Biol.Chem.275:10300-10307 (2000); and "Steric hindrance as a basis forstructure-based design of selective inhibitors of protein-tyrosinephosphatases". Iversen, LF et al. Biochemistry 40:14812-14820 (2001). .

[0371] Fig.7D Provided are non-limiting examples of tyrosine protein phosphatase non-receptor type 11, SHP2 targeting ligands, wherein R represents an exemplary point at which a linker can be connected. For additional examples and related ligands, see crystal structures PDB 4pvg and 305x and described in "Salicylic acid based small molecule inhibitor for theoncogenic Src homology-2domain containing protein tyrosine phosphatase-2 (SHP2)." Zhang, X. et al. J. Med. Chem. 53: 2482-2493 (2010); and crystal structure PDB 5ehr and related ligands are 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 Effective 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, YP et al. Nature 535:148-152 (2016).

[0372] Fig. 7E Non-limiting examples of non-receptor 22-type targeting ligands for tyrosine protein phosphatases are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see 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).

[0373] Figure 7F Provided are non-limiting examples of scavenger mRNA decapping enzyme DcpS targeting ligands, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb and related ligands described in "DcpS as a therapeutic target for spinalmuscular atrophy." Singh, J. et al. ACS Chem. Biol. 3: 711-722 (2008).

[0374] Figures 8A-8S Non-limiting examples of BRD4 bromodomain 1 targeting ligands are provided, wherein 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 described 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 structure PDB 3zyu and related ligands are described in Dawson, MAet al. "Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for Mll-Fusion Leukaemia." Nature 478:529 (2011); crystal structure PDB 4bw1 and related ligands are described in Mirguet, O. et al. "Naphthyridines as Novel Bet Family Bromodomain Inhibitors." Chemmedchem 9:589 (2014); crystal structure PDB 4cfl and related ligands described in Dittmann, A. et al. "The Commonly Used Pi3-Kinase Probe Ly294002is anInhibitor of Bet Bromodomains" ACS Chem. Biol. 9:495 (2014); Crystal structure PDB 4e96 and related ligands are described in Fish, PV et al. “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); Crystal structure PDB 4clb and related ligands are described in Atkinson, S.J. et al. “The Structure Based Design of Dual Hdac / Bet Inhibitors as Novel Epigenetic Probes.” Medchemcomm 5:342 (2014); Crystal structure PDB 4f3i and related ligands are described in Zhang, G. et al. "Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition." J. Biol. Chem. 287: 28840-28851 (2012); crystal structure PDB 4hxl and related ligands are described in Zhao,L."Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain." J. Med. Chem. 56: 3833-3851 (2013); Crystal structure PDB 4hxs and related ligands are described in Zhao, L. et al. "Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain." J. Med. Chem. 56: 3833-3851 (2013); Crystal structure PDB4lrg and related ligands are described in Gehling, VS et al. “Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.” ACS Med Chem Lett 4:835-840 (2013); Crystal structure PDB 4mep and related ligands are described in Vidler, LR "Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening." et al. J. Med. Chem. 56:8073-8088 (2013); the crystal structures PDB 4nr8 and PDB 4c77 and related ligands are described in Ember, SW et al. "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors". ACS Chem. Biol. 9: 1160-1171 (2014); crystal structure PDB 4o7a and related ligands are described in Ember, SW et al."Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors." ACS Chem. Biol. 9: 1160-1171 (2014); Crystal structure PDB 407b and related ligands are described in "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors." Ember, SW et al. (2014) ACS Chem. Biol. 9: 1160-1171; crystal structure PDB 4o7c and related ligands are described in Ember, SW et al. "Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors". ACS Chem. Biol. 9: 1160-1171 (2014); Crystal structure PDB 4gpj; Crystal structure PDB 4uix and related ligands are described in Theodoulou, NH et al. "The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein9 Inhibition". J. Med. Chem. 59: 1425 (2016); crystal structure PDB 4uiz and related ligands are described in Theodoulou, NH , 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 4wiv and related ligands are described in McKeown, MR et al."Biased multicomponent reactions to develop novel bromodomain inhibitors." J. Med. Chem. 57:9019-9027 (2014); crystal structure PDB 4x2i and related ligands are described in Taylor, A. M. et al. “Discovery ofBenzotriazolo[4,3-d][1,4]diazepines asOrally Active Inhibitors ofBETBromodomains.”ACS Med.Chem.Lett.7:145-150(2016); Crystal structure PDB 4yh3; and related ligands described in Duffy, BC "Discovery of a new chemical series of BRD4(1)inhibitors using protein-ligand docking and structure-guided design." Bioorg. Med. Chem. Lett. 25: 2818-2823 (2015); Crystal structure PDB 4yh4 and related ligands are described in Duffy, BC “Discovery of a new chemical series of BRD4(1)inhibitors using protein-ligand docking and structure-guided design.” Bioorg. Med. Chem. Lett. 25:2818-2823 (2015); crystal structure PDB4z1q and related ligands are described in Taylor, A.M. “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.” ACSMed.Chem.Lett.7:145-150(2016); Crystal structure PDB 4zw1; Crystal structure PDB 5a5s and related ligands described in Demont, EH "Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors. J. Med. Chem. 58:5649 (2015); Crystal structure PDB 5a85 and related ligands are described in Bamborough, P."Structure-Based Optimization of Naphthyridones Into PotentAtad2Bromodomain Inhibitors" J. Med. Chem. 58:6151 (2015); Crystal structure PDB 5acy and related ligands are described in Sullivan, JM "Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice." J. Exp. Med. 212: 1771 (2015); Crystal structure PDB 5ad2 and related ligands are described in Waring, MJ et al. "Potent and Selective Bivalent Inhibitors of Bet Bromodomains". Nat. Chem. Biol. 12: 1097 (2016); Crystal structure PDB 5cfw and related ligands are described in Chekler, E.L. et al. "Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities." Chem. Biol. 22: 1588-1596 (2015); Crystal structure PDB 5cqt and related ligands are described in Xue, X. et al. "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); Crystal structure PDB 5d3r and related ligands are described in Hugle, M. et al."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); Crystal structure PDB 5dlx and related ligands are described in Milhas, S. et al. "Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery." (2016) ACS Chem. Biol. 11: 2140-2148; Crystal structure PDB 5dlz and related ligands are described in Milhas, S. et al. "Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery." ACS Chem. Biol. 11: 2140-2148 (2016); Crystal structure PDB 5dw2 and related ligands are described in Kharenko, O.A. et al. "RVX-297-a novel BD2 selective inhibitor of BET bromodomains." Biochem. Biophys. Res. Commun. 477: 62-67 (2016); crystal structure PDB 5dlx; crystal structure PDB 5his and related ligands are described in Albrecht, BK et al. people "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); Crystal structure PDB 5ku3 and related ligands are described in Crawford, TD et al."Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP / EP300". J. Med. Chem. 59: 10549-10563 (2016); Crystal structure PDB 5lj2 and related ligands are described in Bamborough, P. et al. "A Chemical Probe for the ATAD2 Bromodomain." Angew. Chem. Int. Ed. Engl. 55: 11382-11386 (2016); Crystal structure PDB 5dlx and related ligands described in Wang, L. "Fragment-based, structure-enabled discovery of novel pyridones and pyridone macrocycles as potent bromodomain and extra-terminaldomain (BET) family bromodomain inhibitors". J. Med. Chem. 10.1021 / acs.jmedchem.7b00017 (2017); WO 2015169962 A1, entitled "Benzimidazole derivatives as BRD4 inhibitors and their preparation and use for treating cancer", has been assigned to Boehringer Ingelheim International GmbH, Germany; and WO 2011143669 A2, entitled " Azolodiazepinederivativesandtheir preparation,compositionsandmethodsfor treatingneoplasia,inflammatorydiseasea and other disorders ”, has been transferred to Dana-Farber Cancer Institute, Inc, USA Dana-Farber Cancer Institute, Inc, USA.

[0375] Figure 8T-8VNon-limiting examples of ALK targeting ligands are provided, where R represents an exemplary point 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, RT 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); Crystal structures PDB, 4cli, 4cmo and 4cnh and related ligands are described in Johnson, TW et al. "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); Crystal structure PDB 4fny and its related ligands are described in Epstein, LF et al. "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).Crystal structure PDB 4dce and related ligands are described in Bryan, MC et al. "Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors." J. Med. Chem. 55: 1698-1705 (2012); crystal structure PDB 4joa and related ligands are described in Gummadi, VR et al. "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; and crystal structure PDB 5iui and related ligands are described in Tu, CH et al. "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).

[0376] Figure 8W-8XNon-limiting examples of BTK targeting ligands are provided, 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, DJ 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); crystal structures PDB 5fbn and 5fbo and related ligands are described in Liu, J. et al. "Discovery of 8-Amino-imidazo [1, 5-a] pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis." ACSMed. Chem. Lett. 7: 198-203 (2016); crystal structure PDB 3pix and related ligands are described in 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); and the crystal structure PDB 3pij and related ligands are described in Bujacz, A. et al. "Crystal structures of the apoform of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose." Febs J. 278:1728-1744 (2011). .

[0377] Figure 8Y Non-limiting examples of FLT3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structures PDB 4xuf and 4rt7 and related ligands described in Zorn, JA et al. "Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)". PLoS One 10: e0121177-e0121177 (2015).

[0378] Figure 8Z-8AA Non-limiting examples of TNIK targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 2x7f; crystal structures 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).

[0379] Figure 8BB-8CCNon-limiting examples of NTRK1, NTRK2, and NTRK3 targeting ligands are provided, 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, SJ 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, HS 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); crystal structures PDB 4at5 and 4at3 and related ligands are described in Bertrand, T. et al. "The Crystal Structures of Trka and Trkb Suggest Key Regionsfor Achieving Selective Inhibition." J.Mol.Biol.423:439 (2012); and crystal structures PDB 3v5q and 4ymj and related ligands are 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).

[0380] Figure 8DD-8EENon-limiting examples of FGFR1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see 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); crystal structure PDB 4fb3; crystal structure PDB 4rwk and related ligands described in Harrison, C. et al. "Polyomavirus largeT antigen binds symmetrical repeats at the viral origin in an asymmetrical manner." J.Virol.87:13751-13759 (2013); crystal structure PDB 4rwl and related ligands are described in Sohl, CD et al. "Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy." ACS Chem. Biol. 10: 1319-1329 (2015); crystal structure PDB 4uwc; crystal structure PDB 4v01 and related ligands are described in Tucker, JA et al. "Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4." Structure 22: 1764 (2014).; crystal structure PDB 5a46 and related ligands are described in Klein, T.et al. "Structural and Dynamic Insights Into the Energetics of Activation Loop Rearrangement in Fgfr1 Kinase." Nat. Commun. 6:7877 (2015); and the crystal structure PDB 5ew8 and related ligands are described in. Patani, H. et al. "Landscape of activating cancermutations in FGFR kinases and their differential responses to inhibitors inclinical use." Oncotarget 7:24252-24268 (2016).

[0381] Figure 8FF Non-limiting examples of FGFR2 and FGFR3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structure 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 asnovel FGFR3 inhibitors with high selectivity over VEGFR2" Bioorg Med Chem2020,28,115453.

[0382] Figure 8GG Non-limiting examples of FGFR4 targeting ligands are provided, wherein 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 receptor4kinase." J. Mol. Biol. 426:3744-3756 (2014).

[0383] Figure 8HH-8IINon-limiting examples of MET Targeting Ligands are provided, 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; crystal structures PDB 4xmo, 4xyf and 3zcl and related ligands are described in Peterson, EA et al. "Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors." J. Med. Chem. 58:2417-2430 (2015) and Cui, JJ 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); crystal structure PDB 5eyd and related ligands are described in Boezio, AA et al. "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); crystal structure PDB 3ce3 and related ligands are described in Kim, KSet al. "Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase:synthesis,X-raycrystallographic analysis,and biological activities." J.Med.Chem.51:5330-5341(2008); the crystal structure PDB 2rfn and related ligands are described in Bellon, SF et al. "c-Met inhibitors with novel binding mode show activity against several hereditary papillary renalcell carcinoma-related mutations." J.Biol.Chem.283:2675-2683(2008); and the crystal structure PDB 5dg5 and related ligands are described in Smith, BD 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).

[0384] Figure 8JJNon-limiting examples of JAK1 targeting ligands are provided, 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-2Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1Inhibitors 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, MM et al. "Identification of azabenzimidazoles as potent JAK1selective 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); crystal structure PDB 5hx8 and related ligands are described in Caspers, NL et al. "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 Kettle, JG "Discovery of the JAK1selective kinase inhibitor AZD4205", AACR National Meeting, April 2017.

[0385] Figure 8KK-8LLNon-limiting examples of JAK2 targeting ligands are provided, 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 JAKinhibitors 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, AC 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, MG et al. "Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders" Bioorg. Med. Chem. 23: 2387 (2015); Crystal structure PDB 4ytf, 4yth, 4yti and related ligands are described in Farmer, LJ et al. "Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases." J. Med. Chem. 58: 7195-7216 (2015); Crystal structure PDB 4ytf, 4yth, 4yti and related ligands are described in Menet, CJ et al. "Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634." J. Med. Chem. 57: 9323-9342 (2014); Crystal structure PDB 4ji9 and related ligands are described in Siu, M. et al. "2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2inhibitors." Bioorg.Med.Chem.Lett.23:5014-5021(2013); and crystal structures PDB 3io7 and 3iok and related ligands are described in Schenkel, LB et al. "Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors." J.Med.Chem.54:8440-8450(2011). .

[0386] Figure 8MM Non-limiting examples of JAK3 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see crystal structure PDB 3zc6 and related ligands described in Lynch, SM 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 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-phenylethers,as potent JAK3 kinase inhibitors." Bioorg. Med. Chem. Lett. 23:2522-2526 (2013).

[0387] Figure 8NN-8OONon-limiting examples of KIT targeting ligands are provided, wherein 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, CD et al. "Structural basis for the autoinhibition and STI-571inhibition of c-Kit tyrosine kinase." J. Biol. Chem. 279: 31655-31663 (2004); and the crystal structure PDB 4u0i and related ligands described in Garner, AP 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).

[0388] Figure 88PP-8VV provides non-limiting examples of EGFR 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 5hcy, 4rj4 and 5cav; Heald, R., "Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: ALead Optimization Case Study", J. Med. Chem. 58, 8877–8895 (2015); Hanano, EJ, "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, BK et al. "Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor" J. Med. Chem. 59, 9080 (2016); crystal structure PDB 5d41 and related ligands are described in Jia, Y. et al., "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors" Nature534, 129 (2016); Ward, RA "Structure-and reactivity-based development ofcovalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor(EGFR)"J.Med.Chem.56, 7025-7048 (2013); crystal structure PDB 4zau and related ligands are described in “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); crystal structure PDB 5em7 and related ligands are described in Bryan, MC et al. “Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR” ACS Med. Chem. Lett., 7 (1), 100–104 (2016); crystal structure PDB 3IKA and related ligands are described in Zhou, W. et al. “Novel mutant-selective EGFR kinase inhibitors against EGFR T790M” Nature 462(7276), 1070–1074(2009); crystal structure see PDB 5feq and related ligands described in Lelais, G., J. “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 Cancer” Cancers" Med. Chem., 59(14), 6671–6689(2016); Lee, H.-J. "Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M" Cancer Discov.3(2):168–181 (2013); Crystal structure PDB 5j7h and related ligands are described in Huang, WS. et al. "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase." J. Med. Chem. 59:4948-4964 (2016); Crystal structure PDB 4v0g and related ligands are described in Hennessy, EJ et al."Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation." ACS. Med. Chem. Lett. 7: 514-519 (2016); Crystal structure PDB5hg7 and its related ligands are described in Cheng, H." 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 FactorReceptor(EGFR)Inhibitors against L858R / T790M Resistance Mutation." J.Med.Chem.59:7111-7124(2016);Crystal structures PDB 5ug8, 5ug9 and 5ugc and related ligands are described in Planken,S."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 structure PDB 5gnk and its associated ligand are described in Wang, A. "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 Juchum, M. "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).

[0389] Figure 8WW-8XXNon-limiting examples of PAK1 targeting ligands are provided, wherein R represents an exemplary point 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).

[0390] Figure 8YY Non-limiting examples of PAK4 targeting ligands are provided, wherein R represents an exemplary point 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).

[0391] Figure 8ZZ-8AAANon-limiting examples of IDO targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Yue, EW; 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, MR et al. "NLG919, anovelindoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy" Abstract 491, AACR 104th Annual Meeting 2013; April 6-10, 2013; Washington, DC; and WO2012142237, entitled "Fused imidazole derivatives useful as IDO inhibitors".

[0392] Figure 8BBB-8EEENon-limiting examples of ERK1 and ERK2 targeting ligands are provided, 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 their related ligands described in Blake, JF 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 structure PDB 5BVF and related ligands described in Bagdanoff, JT et al. "Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase" Bioorg. Med. Chem. Lett. 25, 3788-3792 (2015); crystal structure PDB 4QYY and related ligands are described in Deng, Y. et al. "Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase" J. Med. Chem. 57: 8817-8826 (2014); crystal structures PDB 5HD4 and 5HD7 and related ligands are described in Jha, S. et al. "Dissecting Therapeutic Resistance to ERK Inhibition" Mol. Cancer Ther. 15: 548-559 (2016); crystal structure PDB 4XJ0 and related ligands are 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); crystal structures PDB 4ZZM, 4ZZN, 4ZZO and related ligands are described in Ward, RAet al. "Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1 / 2." J. Med. Chem. 58:4790 (2015); Burrows, F. et al. "KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors" Poster #5168, AACR National Meeting 2017; Bhagwat, SV et al. "Discovery of LY3214996, a selective and novel ERK1 / 2 inhibitor with potentantitumor activities in cancer models with MAPK pathway alterations." AACR National Meeting 2017; Crystal structures PDB 3FHR and 3FXH and related ligands are described in Cheng, R. et al. "High-resolution crystal structure of human Mapkap kinase 3in complex with ahigh affinity ligand" Protein Sci.19:168-173 (2010); Crystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP and 5NHV and related ligands are described in Ward, RA et al. "Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1 / 2from a Modestly Active and Promiscuous Chemical Start Point." J. Med. Chem. 60, 3438–3450 (2017); Crystal structures PDB 3SHE and 3R1N and related ligands are described in Oubrie, A. et al. "Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout theseries." Bioorg. Med.Chem.Lett.22:613-618(2012);"Structure-Guided Design ofPotent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase(ERK)Using Conformational Control" J Med Chem 2009,52(20),6362;WO2015051341;"Discovery of a Potent and Selective Oral Inhibitor of ERK1 / 2 (AZD0364) That Is Efficacious in Both Monotherapy and CombinationTherapy 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.

[0393] Figure 8FFF-8III Non-limiting examples of ABL1 targeting ligands are provided, where R represents an exemplary point 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 abelsontyrosine kinase”, Science 289:1938-1942 (2000); and Horio, T. et al. "Structural factors contributing to the Abl / Lyn dual inhibitory activity of 3-substitutedbenzamide derivatives", Bioorg. Med. Chem. Lett. 17: 2712-2717 (2007); crystal structures PDB 2hzn and 2hiw and related ligands are described in Cowan-Jacob, SW et al."Structural biology contributes 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); the crystal structure PDB 3cs9 and related ligands are described in Weisberg, E. et al. "Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl", Cancer Cell 7:129-14 (2005); the crystal structure PDB 3ik3 and related ligands are described in O'Hare, T. et al. "AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance", Cancer Cell 16:401-412 (2009); crystal structure PDB 3mss and related ligands are described in Jahnke, W. et al. "Binding or bending: distinction of allosteric Abl kinaseagonists from antagonists by an NMR-based conformational assay", J. Am. Chem. Soc. 132:7043-7048 (2010); crystal structure PDB 3oy3 and related ligands are described in Zhou, T. et al. "Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance", Chem. Biol. Drug Des. 77:1-11 (2011); crystal structure PDB 3qri and 3qrk and related ligands are described in Chan, WWet al. "Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315IMutant, by the Switch-Control Inhibitor DCC-2036", Cancer Cell 19: 556-568 (2011); Crystal structure PDB 5hu9 and 2f4j and related ligands are 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 Young, MA 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); Crystal structure PDB 2gqg and 2qoh and related ligands are described in Tokarski, JS et al. "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 Zhou, T. et al. "Crystal Structure of the T315I Mutant of Abl Kinase", Chem. Biol. Drug Des. 70: 171-181 (2007); Crystal structure PDB 2gqg and 2qoh and related ligands are described in Tokarski, JSet al. "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 Zhou, T. et al. "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 ligands are described in Tokarski, JS et al. "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 Zhou, T. et al. "Crystal Structure of the T315I Mutant of Abl Kinase", Chem.Biol.Drug Des.70:171-181 (2007); the crystal structures PDB 3dk3 and 3dk8 and related ligands are described in Berkholz, DS et al. "Catalytic cycle of human glutathione reductase near 1A resolution" J.Mol.Biol.382:371-384 (2008); the crystal structure PDB 3ue4 and related ligands are described in Levinson, NM et al. "Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer ofbosutinib binding to the abl tyrosine kinase domain", PLoS One 7:e29828-e29828(2012); Crystal structure PDB 4cy8 and related ligands are described in Jensen, CNet al. "Structures of the Apoand Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase(Hbpa)Locate Activity Hotspots Identified by Using Directed Evolution", Chembiochem 16:968(2015); Crystal structure PDB 2hz0 and related ligands are described in Cowan-Jacob, SW et al. "Structural biology contributions to the discovery of drugs to treat chronic myelogenousleukaemia", Acta Crystallogr D Biol Crystallogr.63(Pt 1):80-93(2007); Crystal structure PDB 3pyy and related ligands are described in Yang, J. et al. "Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the MyristoylBinding Site”, Chem.Biol.18:177-186 (2011); and the crystal structure PDB 5k5v and related ligands are described in Kim, MK, et al. “Structural basis for dual specificity of yeast N-terminalamidase in the N-end rule pathway”, Proc.Natl.Acad.Sci.USA113:12438-12443 (2016).

[0394] Figure 8JJJNon-limiting examples of ABL2 targeting ligands are provided, 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, BH 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", to be published.

[0395] Figure 8KKK-8MMMNon-limiting examples of AKT1 targeting ligands are provided, 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 structurebased optimization of novel Akt inhibitors Bioorg. Med. Chem. Lett. 18:3359-3363 (2008); Freeman-Cook, KD et al. "Design of selective, ATP-competitive inhibitors of Akt", J. Med. Chem. 53:4615-4622 (2010); Blake, JF et al. "Discovery of pyrrolopyrimidine inhibitors of Akt", Bioorg. Med. Chem. Lett. 20:5607-5612 (2010); Kallan, NC 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 ThatRestricts 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); Wu, WI, et al. "Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Plos One5: 12913-12913 (2010); Ashwell, MAet 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); and Lapierre, J.M. et al., "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).

[0396] Figure 8NNN-8OOONon-limiting examples of AKT2 Targeting Ligands are provided, 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, TG 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); crystal structure PDB 3d03 and related ligands are described in Hadler, KS et al. "Substrate-promoted formation of a catalytically competent binuclear center and regulation of reactivity in aglycerophosphodiesterase from Enterobacter aerogenes', J. Am. Chem. Soc. 130: 14129-14138 (2008); and crystal structures PDB 3e87, 3e8d and 3e88 and related ligands are described in Rouse, MB et al. "Aminofurazans as potent inhibitors of AKT kinase" Bioorg. Med. Chem. Lett. 19: 1508-1511 (2009).

[0397] Figure 8 PPPNon-limiting examples of BMX targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 3sxr and 3sxr and related ligands described in Muckelbauer, J. et al. "X-ray crystal structure of bone marrow kinase in the xchromosome: a Tec family kinase", Chem.Biol.Drug Des.78:739-748 (2011).

[0398] Figure 8QQQ-8SSSNon-limiting examples of CSF1R targeting ligands are provided, 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 structure 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 MT, McKay, DB Overgaard, "Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon”, forthcoming; crystal structures PDB 3krj and 3krl and related ligands are described in Illig, CR 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”, J. Med. Chem. 54:7860-7883 (2011); crystal structure PDB 4r7h and related ligands are described in Tap, WDet al. "Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor:, N Engl J Med 373:428-437 (2015); the crystal structures PDB 3lcd and 3lcoa and related ligands are described in Meyers, MJ et al. "Structure-based drug design enables conversion of a DFG-inbinding CSF-1R kinase inhibitor to a DFG-out binding mod", Bioorg. Med. Chem. Lett. 20:1543-1547 (2010); the crystal structure PDB 4hw7 and related ligands are described in Zhang, C. et al. "Design and pharmacology of a highly specific dual FMS and KITkinase inhibitor", Proc. Natl. Acad. Sci. USA 110:5689-5694 (2013); and the crystal structure PDB4r7i and related ligands are described in Tap, WD et al. "Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor", N Engl J Med 373:428-437 (2015). .

[0399] Figure 8 TTT Non-limiting examples of CSK targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Levinson, NM et al. "Structural basis for the recognition of c-Src by its inactivator Csk", Cell 134: 124-134 (2008).

[0400] Figure 8UUU-8YYYNon-limiting examples of DDR1 targeting ligands are provided, wherein R represents an exemplary point 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 structure 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, CW et al. "Fragment-Based Discovery of Potent and Selective DDR1 / 2 Inhibitors", ACS Med.Chem.Lett.6:798-803(2015); crystal structure PDB 5fdp and related ligands are described in Wang, Z. et al. “Structure-Based Design of Tetrahydroisoquinoline-7-carboxamidesas Selective Discoidin Domain Receptor 1(DDR1)Inhibitors”, J.Med.Chem.59:5911-5916(2016); and crystal structure PDB 5fdx and related ligands are described in Bartual, SG et al. “Structure ofDDR1 receptor tyrosine kinase in complex with D2164 inhibitor at2.65Angstroms resolution”, to be published.

[0401] Figure 8ZZZ-8CCCCNon-limiting examples of EPHA2 targeting ligands are provided, where R represents an exemplary point 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). Structural Biology DefineEPHA2Inhibition by Clinical Kinase Drug", ACS Chem. Biol. 11: 3400-3411 (2016).

[0402] Figure 8DDDD-8FFFFNon-limiting examples of EPHA3 targeting ligands are provided, 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". Mode Validation by X-ray Crystallography”, J. Med. Chem. 56: 84-96 (2013); crystal structures PDB 4p4c and 4p5q and related ligands are 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); crystal structure PDB 4p5z and related ligands are described in Unzue, A. et al.et al. "Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2and 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 related ligands are 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); the crystal structure PDB 3dzq and related ligands are described in Walker, JR "Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex with ALW-II-38-3", to be published. .

[0403] Figure 8GGGG Non-limiting examples of EPHA4 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see the crystal structure PDB 2y60 and related ligands described in Clifton, IJ et al. "The Crystal Structure of Isopenicillin N Synthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals ThioetherCoordination to Iron", Arch.Biochem.Biophys.516:103 (2011) and the crystal structure PDB 2xyu and related ligands described in Van Linden, OP et al. "Fragment Based Lead Discovery of SmallMolecule Inhibitors for the Epha4Receptor Tyrosine Kinase", Eur.J.Med.Chem.47:493 (2012).

[0404] Figure 8HHHHNon-limiting examples of EPHA7 targeting ligands are provided, wherein 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 Walker, JR et al. "Kinase domain of human ephrin type-a receptor 7 (epha7) in complex with ALW-II-49-7", forthcoming.

[0405] Figure 8III-8LLLLNon-limiting examples of EPHB4 targeting ligands are provided, 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); the crystal structure PDB 2xvd and related ligands described in Barlaam, B. et al. "Inhibitors of the Tyrosine Kinase Ephb4. Part 4: Discovery and Optimization of a Benzylic Alcohol Series”, Bioorg. Med. Chem. Lett. 21: 2207 (2011); crystal structure PDB 3zew and related ligands are described in Overman, RC et al. “Completing the Structural Family Portrait of the Human Ephb Tyrosine Kinase Domains”, Protein Sci. 23: 627 (2014); crystal structure PDB 4aw5 and related ligands are described in Kim, MH et al. “The Design, Synthesis, and Biological Evaluation of Potent Receptor Tyrosine Kinase Inhibitors”, Bioorg. Med. Chem. Lett. 22: 4979 (2012); crystal structure PDB 4bb4 and related ligands are described in Vasbinder, MMet al. "Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600ESelective Kinase Inhibitors" J. Med. Chem. 56: 1996.", (2013); crystal structures PDB 2vwu, 2vwv and 2vww and related ligands are described in Bardelle, C. et al. "Inhibitors of the Tyrosine Kinase Ephb4. Part 1: Structure-Based Design and Optimization of a Series of 2,4-Bis-Anilinopyrimidines", Bioorg. Med. Chem. Lett. 18: 2776-2780 (2008); crystal structures PDB 2vwx, 2vwy and 2vwz and related ligands are 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); and the crystal structure PDB 2vxo and related ligands are described in Welin, M. et al. "Substrate Specificity and Oligomerization of Human Gmp Synthetas", J. Mol. Biol. 425: 4323 (2013).

[0406] Figure 8MMMMNon-limiting examples of ERBB2 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see the crystal structure 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 the crystal structure and related ligands described in 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).

[0407] Figure 8NNNN Non-limiting examples of ERBB3 targeting ligands are provided, wherein R represents an exemplary point to which a linker 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).

[0408] Figure 8OOOONon-limiting examples of ERBB4 targeting ligands are provided, wherein R represents an exemplary point to which a linker 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, ER et al. "6-Ethynylthieno[3,2-d]-and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines astunable covalent modifiers of ErbB kinases", Proc. Natl. Acad. Sci. Usa 105:2773-2778 (2008).

[0409] Figure 8PPPP-8QQQQ Non-limiting examples of FES targeting ligands are provided, wherein R represents an exemplary point to which a linker 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).

[0410] Figure 8RRRR Non-limiting examples of FYN targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see Kinoshita, T. et al. "Structure of human Fynkinase domain complexed with staurosporine", Biochem. Biophys. Res. Commun. 346: 840-844 (2006).

[0411] Figure 8SSSS-8VVVVNon-limiting examples of GSG2 (Haspin) targeting ligands are provided, 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 Filippakopoulos, P. et al. "Crystal Structure of Human Haspin with apyrazolo-pyrimidine ligand", to be published; crystal structure PDB 3iq7 and related ligands described in Eswaran, J. et al. "Structure and functional characterization of the atypical human kinase haspin", Proc. Natl. Acad. Sci. USA 106:20198-20203 (2009); and crystal structure PDB 4qtc and related ligands described in Chaikuad, A. et al. "A unique inhibitor binding site inERK1 / 2is associated with slow binding kinetics", Nat. Chem. Biol. 10:853-860 (2014).

[0412] Figure 8WWWW-8AAAAANon-limiting examples of HCK targeting ligands are provided, 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-FamilySelective 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); crystal structures PDB 3vry, 3vs3, 3vs6 and 3vs7 and related ligands are described in Saito, Y. et al. "APyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo", Sci Transl Med 5: 181ra52-181ra52 (2013); and crystal structure PDB 4lud and related ligands are described in Parker, LJ et al. "Kinase crystal identification and ATP-competitive inhibitorscreening using the fluorescent ligand SKF86002", Acta Crystallogr., Sect. D70: 392-404 (2014).

[0413] Figure 8BBBBB-8FFFFFNon-limiting examples of IGF1R targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples and related ligands, see 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); crystal structure PDB 3i81 and related ligands described in Wittman, MD 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); crystal structure PDB 3nw5 and related ligands are described in Sampognaro, AJ et al. “Proline isosteres in aseries of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase”, Bioorg. Med. Chem. Lett. 20: 5027-5030 (2010); crystal structure PDB 3qqu and related ligands are described in Buchanan, JL 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); crystal structure PDB 4d2r and related ligands are described in Kettle, JGet al. “Discovery and Optimization of a Novel Series of Dyrk1B KinaseInhibitors to Explore a Mek Resistance Hypothesis”. J. Med. Chem. 58: 2834 (2015); Crystal structure PDB 3fxq and related ligands are 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); Crystal structure PDB 5fxs and related ligands are described in Degorce, S. et al. “Discovery of Azd9362, a Potent Selective Orally Bioavailable and Efficacious NovelInhibitor of Igf-R1”, to be published; Crystal structure PDB 2zm3 and related ligands are described in Mayer, SC 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); crystal structure PDB 3f5p and related ligands are 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); crystal structure PDB 3lvp and related ligands are described in Nemecek, C.et al. "Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles" Chem. Biol. Drug Des. 76: 100-106 (2010); crystal structure PDB 3o23 and related ligands are described in Lesuisse, D. et al. "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); crystal structure PDB 3d94 and related ligands are described in Wu, J. et al. "Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor", Embo J. 27: 1985-1994 (2008); and crystal structure PDB 5hzn and related ligands are described in Stauffer, F. et al. "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).

[0414] Figure 8GGGGG-8JJJJJNon-limiting examples of INSR targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see 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); crystal structure PDB 3ekk and related ligands described in Chamberlain, SD 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; crystal structure PDB 3ekn and related ligands described in Chamberlain, SD 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); crystal structure PDB 5e1s and related ligands are described in Sanderson, MP et al. “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); crystal structure PDB 3eta and related ligands are described in Patnaik, S.et al. "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 are described in Stauffer, F. et al. "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 the crystal structure PDB 4ibm and related ligands are described in Anastassiadis, T. et al. "A highly selective dualinsulin receptor (IR) / insulin-like growth factor-1 receptor tyrosine kinase", Bioorg. Med. Chem. Lett. 26:2065-2067 (2016). factor 1receptor(IGF-1R)inhibitorderived from an extracellular signal-regulated kinase(ERK)inhibitor”, J.Biol.Chem.288:28068-28077(2013).

[0415] Figure 8KKKKK-8PPPPPNon-limiting examples of HBV targeting ligands are provided, wherein 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. USA, 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, XY; et al. "In vitro inhibition of HBV replication by a novel compound, GLS4, and its Efficacy against adefovir-dipivoxil-resistant HBVmutations." 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 Bvirus (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." Bioorg. Med. Chem. Lett. 20, 299-301 (2010); Campagna, MR; et al. "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis Bvirus nucleocapsids." J. Virol. 87, 6931-6942 (2013); Campagna, MR; et al. "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids." J. Virol. 87, 6931-6942 (2013); WO 2013096744A1, entitled "Hepatitis B antiviral drugs"; WO 2015138895, entitled "Hepatitis B core protein allosteric modulators"; Wang, YJ; et al. "Anovel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation." Antimicrob. Agents Chemother. 59, 7061-7072 (2015); WO 2014033167, entitled "Fused bicyclic sulfonamide derivatives for the treatment of hepatitis"; US20150132258, entitled "Azepane derivatives and methods for treating hepatitis B infection"; and WO2015057945 "Hepatitis B virus assembly effectors". .

[0416] Fig. 9 A dendrogram of the human bromodomain protein family, divided into eight subfamilies, which are involved in epigenetic signaling and chromatin biology. Fig. 9 Any protein in the bromodomain protein family can be selected as the target protein of the present invention.

[0417] Fig. 10A and Fig. 10B Non-limiting examples of CBP and / or P300 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For example, additional examples of targeting ligands are described in "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, WO2018073586; FT-7051 and WO2019055869.

[0418] Fig.11A and 11B Non-limiting examples of BRD9 targeting ligands are provided, wherein R is the point of attachment of the linker. For additional examples, see: "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" J Med Chem 2016, 59(10), 4462; WO2016139361.

[0419] Figures 12A-12C Non-limiting examples of CBL-B targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see WO201914800).

[0420] Fig.13Non-limiting examples of ERK targeting ligands are provided, wherein R is the point of attachment of the linker. 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; WO2015051341; "Discovery of a Potent and Selective Oral Inhibitor of ERK1 / 2(AZD0364)That Is Efficacious in BothMonotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer(NSCLC)"J Med Chem 2019,62(24),11004;"ERK Inhibitor LY3214996 Targets ERKPathway–Driven Cancers:ATherapeutic Approach Toward Precision Medicine"MolCancer Ther2020,19,325.

[0421] Figures 14A-14CNon-limiting examples of WDR5 targeting ligands are provided, 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; WO2017147700; "Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with PicomolarAffinity" Cell Rep 2019,26(11),2916; "Discovery and Optimization of SalicylicAcid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYCProtein–Protein Interaction" JMed Chem 2019,62(24),11232).

[0422] Fig.15 Non-limiting examples of NSP3 targeting ligands are provided, wherein 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-rayStructure and Biological Evaluation", J Med Chem 2010, 53, 4968; "X-rayStructural and Biological Evaluation of a Series of Potent and HighlySelective Inhibitors of Human Coronavirus Papain-like Proteases", J Med Chem 2014, 57, 2393).

[0423] Fig.16Non-limiting examples of RET targeting ligands are provided, wherein 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, WO2018071447; "APyrazolo [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).

[0424] Figures 17A-17C Non-limiting examples of CTNNB1 targeting ligands are provided, wherein 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.

[0425] Figures 18A-18CNon-limiting examples of IRAK4 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples and related ligands, see the crystal structures PDB 6UYA, 4YP8, 5UIU and 6F3I in the corresponding references (Rajapaksa NS et al. "Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity." ACS Med. Chem. Lett. 11:327-333 (2020); McElroy WT 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 SL et al. "Optimization of permeability in a series of pyrrolotriazine inhibitors ofIRAK4". Bioorg. Med. Chem. 26:913-924 (2018); WO2019099926 and WO2019133531.

[0426] Figures 19A-19D Non-limiting examples of FGFR2 and FGFR3 targeting ligands are provided, wherein R is the point of attachment of the linker. 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.

[0427] Figures 20A-20DNon-limiting examples of SMARCA2 targeting ligands are provided, wherein R is the point to which the linker is attached. For additional examples, see: WO2020023657, US20200038378, WO2020010227, WO2020078933, WO2019207538, WO2016138114, "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; 2) WO2020035779.

[0428] Figures 21A-21JNon-limiting examples of NRAS targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see “Small-molecule Ligands Bing to a Distinct Pocketin 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 structure PDB 6GQY, 6GQT, (“Structure-based development of new RAS-effectorinhibitors from a combination of active and inactive RAS-binding compounds” 2019 PNAS 116 (7), 2545-2550); crystal structure PDB 6FA4, 1HE8, (“Small molecule inhibitorsof RAS-effector protein interactions derived using an intracellular antibodyfragment" 2018Nature Communications 9(1),3169); and "Discovery of High-AffinityNoncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding" ACSOmega 2019,4,2921-2930.

[0429] Fig. 22Non-limiting examples of ADAR targeting ligands are provided, wherein R represents an exemplary point at which a linker can be connected. For other examples, see crystal structure PDB 6VFF, (Thuy-Boun, AS, et al., Nucleic Acids Res, 2020, 48, 7958-7972); and crystal structure PDB 5HP2, 5HP3, 5ED1, 5ED2 (Mathews, MM, et al., Nat Struct Mol Biol., 2016, 23, 426-433).

[0430] Fig.23 Non-limiting examples of NSD2 or WHSC1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 6XCG (Zhou, MQ, et al., "Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934", forthcoming); crystal structure PDB 6UE6 (Liu, Y et al., "PWWP1 domain of NSD2 in complex with MR837", forthcoming); crystal structure 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).

[0431] Fig.24 Non-limiting examples of PI3KCA targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 3HHM, 3HIZ (Mandelker, D., et al., "A frequent kinase domain mutation that changes the interaction between PI3K{alpha}andthe membrane.", Proc Natl Acad Sci US A., 2009, 106: 16996-17001).

[0432] Fig.25Non-limiting examples of RIT1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 4KLZ (Shah, DM, et al., "Inhibition of SmallGTPases by Stabilization of the GDP Complex, a Novel Approach applied to Rit1, a Target for Rheumatoid Arthritis", forthcoming).

[0433] Fig.26 Non-limiting examples of WRN targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples, see crystal structure PDB 2FC0 (Perry, JJ, et al., "WRN exonuclease structure and molecular mechanism imply an editing role in DNA endprocessing." ', Nat Struct Mol Biol., 2006, 13: 414-422); and crystal structure PDB 6YHR (Newman, JA, et al., "Crystal structure of Werner syndrome helicase", forthcoming).

[0434] Fig. 27Non-limiting examples of ALK fusion targeting ligands are provided, 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 structures PDB 4CGB, 4CGC (Richards, MW, et al., “Microtubule Association of Eml Proteins and the Eml4-Alk Variant3 Oncoprotein Require an N-Terminal Trimerization Domain”, Biochem J., 2015, 467:529); crystal structure PDB 3AOX (Sakamoto, H., et al., “CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant”, Cancer Cell, 2011, 19:679-690); crystal structure PDB 6MX8 (Huang, WS, et al., “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase”, J Med Chem., 2016, 59: 4948-4964); 4Z55 (Michellys, PY, et al., "Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.", Bioorg Med Chem Lett., 2016, 26: 1090-1096); and crystal structure PDB 4FOB, 4FOC, 4FOD (Lewis, RT, et al., "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.", J Med Chem., 2012, 55: 6523-6540).

[0435] Fig.28 Non-limiting examples of BAP1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 2W12, 2W13, 2W14, 2W15 (Lingott, TJ et al., "High-Resolution Crystal Structure of the Snake Venom Metalloproteinase Bap1 Complexed with a Peptidomimetic: Insight into Inhibitor Binding", Biochemistry, 2009, 48: 6166).

[0436] Fig.29 Non-limiting examples of EPAS1 or HIF2α targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 5UFP (Cho, H., et al., "On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models.", Nature, 2016, 539: 107-111); crystal structure PDB 6D09 Du, X, ("Crystal structure of PT1940 bound to HIF2a-B*:ARNT-B* complex," forthcoming); crystal structure PDB 5TBM (Wallace, EM, et al., "A Small-Molecule Antagonist of HIF2 alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.", Cancer Res., 2016, 76: 5491-5500); and crystal structures PDB 6E3S, 6E3T, 6E3U (Wu, D., et al., "Bidirectional modulation of HIF-2 activity through chemical ligands.", Nat Chem Biol., 2019, 15: 367-376).

[0437] Fig. 30A and Fig. 30BNon-limiting examples of GRB2 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 1CJ1 (Furet, P., et al., "Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic", J Med Chem., 1999, 42: 2358-2363); crystal structure PDB 2AOA, 2AOB (Phan, J., et al., "Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2SH2 Domain", J Mol Biol., 2005, 353: 104-115); crystal structure PDB 3KFJ, 3IN7, 3IMJ, 3IMD, 3IN8 (Delorbe, JE, et al., "Thermodynamic and Structural Effects of Conformational Constraints in Protein-Ligand Interactions. Entropic Paradoxy Associated with LigandPreorganization.", J Am Chem Soc., 2009, 131: 16758-16770); crystal structure PDB 2HUW, 3C71 (Benfield, AP, et al., "Ligand Preorganization May Be Accompanied by EntropicPenalties 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", to be published).

[0438] Fig.31Non-limiting examples of KMT2D or MLL2 / MLL4 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 7BRE (Li, Y., et al., "Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases.", Structure, 2020); crystal structure PDB 4ZAP (Zhang, Y., et al., "Evolving Catalytic Properties of the MLL Family SETDomain.", Structure, 2015, 23: 1921-1933); crystal structure PDB 6KIZ (Xue, H., et al., "Structural basis of nucleosome recognition and modification by MLLmethyltransferases.", Nature, 2019, 573: 445-449); and crystal structure PDB 3UVK (Zhang, P., et al., "The plasticity of WDR5peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases.", Nucleic Acids Res., 2012, 40: 4237-4246).

[0439] Fig.32Non-limiting examples of MLLT1 or ENL targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 6HT0, 6HT1 (Moustakin, M. et al., "Discovery of an MLLT1 / 3 YEATSDomain Chemical Probe", Angew Chem Int Ed Engl., 2018, 57: 16302-16307); crystal structures PDB 6T1I, 6T1J, 6TIL, 6T1M, 6T1N, 6T1O (Ni, X., et al., "Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATSDomain Binders in MLLT1", ACS Med Chem Lett., 2019, 10: 1661-1666); and crystal structures PDB 6HPW, 6HPY, 6HPX, 6HPZ (Heidenreich, D., et al., "Structure-Based Approach toward Identification of Inhibitory Fragments for Eleven-Nineteen-LeukemiaProtein(ENL)", J Med Chem., 2018, 61: 10929-10934).

[0440] Fig.33Non-limiting examples of NSD3 targeting ligands are provided, wherein 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)", forthcoming); and crystal structure PDB 6CEN (Morrison, MJ, et al., "Identification of a peptide inhibitor for the histonemethyltransferase WHSC1", PLoS One,2018,13:e0197082-e0197082).

[0441] Fig.34 Non-limiting examples of PPM1D or WIP1 targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 3UYH, ADA3, 4DAQ (Micco, M., et al., "Structure-based design and evaluation of naphthalene diimide g-quadruplexligands as telomere targeting agents in pancreatic cancer cells", J Med Chem., 2013, 56: 2959-2974).

[0442] Figures 35A-35BNon-limiting examples of SOS1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For additional examples, see crystal structures PDB 5OVE, 5OVF, 5OVG, 5OVH, 5OVI, (Hillig, RC, et al., "Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction", Proc Natl Acad Sci US A., 2019, 116: 2551-2560); crystal structure PDB 6F08 (Ballone, A., et al., "Structural characterization of 14-3-3zeta in complex with the human Son of sevenless homolog 1 (SOS1)", J Struct Biol., 2018, 202: 210-215); crystal structure PDB 6D5E, 6D5G, 6D5H, 6D5J, 6D5L, 6D5M, 6D5V, 6D5W, 6D55, 6D59, (Hodges, TR 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 structure PDB 6SCM, 6SFR (Kessler, D., et al., "SOS1 in Complex with Inhibitor BI-3406", forthcoming); Crystal structure PDB 6V94, 6V9J, 6V9L, 6V9M, 6V9N (Sarkar, D., et al., "Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-BasedMethods.", J Med Chem., 2020, 63: 8325-8337).

[0443] Fig.36ANon-limiting examples of TBXT or Brachyury targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples, see crystal structures PDB 5QS6, 5QSC, 5QSE, 5QSF, 5QRW, (Newman, JA, et al., "PanDDA analysis group deposition", forthcoming); and crystal structure PBD 6ZU8 (Newman, JA, et al., "Crystal structure of human BrachyuryG177D variant in complex with Afatinib", forthcoming).

[0444] Figures 37A-37C Non-limiting examples of USP7 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For additional examples, see crystal structures PDB 5UQV, 5UQX (Kategaya, L., et al., "USP7 small-molecule inhibitors interfere with ubiquitin binding", Nature, 2017, 550: 534-538); crystal structures PDB 6VN2, 6VN3, 6VN4, 6VN5, 6VN6 (Leger, PR, et al., "Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antitumor Activity.", J Med Chem., 2020, 63: 5398-5420); and crystal structures PDB 5N9R, 5N9T (Gavory, G., et al., "Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.", Nat Chem Biol., 2018, 14: 118-125); and crystal structures PDB 5NGE, 5NGF (Turnbull, AP, et al., "Molecular basis of USP7 inhibition by selective small-molecule inhibitors", Nature, 2017, 550: 481-486).

[0445] Fig.38Non-limiting examples of BKV and JCV targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 5J4V, 5J4Y (Bonafoux, D., et al., "Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.", J Med Chem., 2016, 59: 7138-7151).

[0446] Fig.39 Non-limiting examples of CK1α (casein kinase 1α) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 5ML5, 5MQV (Halekotte, J., et al., "Optimized 4,5-Diarylimidazoles as Potent / Selective Inhibitors of Protein Kinase CK1delta and Their Structural Relation to p38 alpha MAPK.", Molecules, 2017, 22).

[0447] Fig.40 Non-limiting examples of GSPT1 / ERF3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 5LZT, 5LZS, 5LZV, 5LZU, 5LZX, 5LZW, 5LZZ, 5LZY (Shao, S., et al., "Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes", Cell, 2016, 167: 1229-1240.e15).

[0448] Fig.41Non-limiting examples of IFZV targeting ligands are provided, wherein R represents an exemplary point at which a linker can be attached. For additional examples, see the crystal structure PDB (Iyer, S., et al., "The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0A resolution.", J Biol Chem., 2001, 276: 12153-12161); and the crystal structure PDB IRV6 (Christinger, HW, et al., "The crystal structure of placental growth factor incomplex with domain 2 of vascular endothelial growth factor receptor-1", J Biol Chem., 2004, 279: 10382-10388).

[0449] Fig.42 Non-limiting examples of NSD2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 6XCG (Zhou, MQ, "Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934", forthcoming); and crystal structure PDB6UE6 (Liu, Y., et al., "PWWP1 domain of NSD2 in complex with MR837", forthcoming).

[0450] Fig.43 Non-limiting examples of TAU targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 6VA2, 6VA3 (Chen, JL et al., "Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.", J Am Chem Soc., 2020, 142: 8706-8727).

[0451] Fig.44Non-limiting examples of CYP17A1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 3RUK, 3SWZ (Devore, NM et al., "Structures of cytochrome P45017A1 with prostate cancer drugs abiraterone and TOK-001", Nature, 2012, 482: 116-119); and crystal structures PDB 6CHI, 6CIZ, (Fehl, C., et al., "Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2", J Med Chem., 2018, 61: 4946-4960).

[0452] Fig.45 Non-limiting examples of SALL4 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For further examples, see crystal structures PDB 7BQU, 7BQV (Furihata, H., et al., "Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide", Nat Commun., 2020, 11: 4578-4578); and crystal structure PDB 6UML (Matyskiela, ME, et al., "Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex", Nat Struct Mol Biol., 2020, 27: 319-322).

[0453] Fig.46 Non-limiting examples of FAM38 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 6KG7 (Wang, L., et al., "Structure and mechanogating of the mammalian tactile channel PIEZO2.", Nature, 2019, 573: 225-229).

[0454] Fig.47Non-limiting examples of CYP20A1 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see Durairaj et al., Biological Chemistry, 2020, 401(3), 361-365.

[0455] Fig.48 Non-limiting examples of HTT targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 5XI1 (Khan, E., et al., "Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington's Disease (HD) and Spino Cerebellar Ataxia (SCAs). ", ACS Chem Biol., 2018, 13: 180-188).

[0456] Fig.49 Non-limiting examples of KRAS targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structure PDB 6CU6 (Hobbs, GA, et al., "Atypical KRASG12RMutant Is Impaired in PI3KSignaling and Macropinocytosis in Pancreatic Cancer.", Cancer Discov., 2020, 10: 104-123); crystal structure PDB 6GJ5, 6GJ6, 6GJ8, 6JG7, ("Drugging an Undruggable Pocket on KRAS" PNAS 2019 116 (32) 15823-15829); and crystal structure PDB 6BP1 (Lu, J., et al., "KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation.", Biochemistry, 2018, 57: 324-333).

[0457] Fig.50Non-limiting examples of NRF2 (NFE2L2) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. For further examples, see crystal structure PDB 5CGJ (Winkel, AF, et al., "Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling.", J Biol Chem., 2015, 290: 28446-28455); and 6TYM, 6TYP (Ma, B., et al., "Design, synthesis and identification of novel, generally bioavailable non-covalent Nrf2 activators", Bioorg Med Chem Lett., 2020, 30: 126852-126852).

[0458] Fig.51 Non-limiting examples of P300 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be connected. For other examples, see 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 crystal structure PDB 6PGU (Gardberg, AS, et al., "Make the right measurement: Discovery of an allostericinhibition site for p300-HAT", Struct Dyn., 2019, 6: 054702-054702).

[0459] Fig.52Non-limiting examples of PIK3CA targeting ligands are provided, wherein R represents an exemplary point at which a linker can be connected. For further 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 IPI3K and mTOR Kinase", J Med Chem., 2019, 62: 6241-6261); and crystal structure PDB 5SX8, 5SWP (Miller, MS et al., "Identification of allosteric binding sites for PI3K alpha oncogenic mutant specific inhibitor design.", Bioorg Med Chem., 2017, 25: 1481-1486).

[0460] Fig.53 Non-limiting examples of SARM1 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be connected. For additional examples, see crystal structure PDB 6QWV (Sporny, M., et al., "Structural Evidence for an Octameric Ring Arrangement of SARM1", J Mol Biol., 2019, 431: 3591-3605); and crystal structure PDB 6O0Q, 6O0R, 6O0T, 6O0V, 6O0W (Horsefield, S., et al., "NAD+cleavageactivity by animal and plant TIR domains in cell death pathways", Science, 2019, 365: 793-799).

[0461] Fig.54Non-limiting examples of SNCA targeting ligands are provided, where R represents an exemplary point to which a linker can be attached. For additional examples, see crystal structures PDB 4I5M, 4I5P, 4I6B, 4I6F, 4I6H (Aubele, DL, et al., "Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain", Chem Med Chem., 2013, 8: 1295-1313).

[0462] Fig.55 Non-limiting examples of MAPT targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. 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, SA, 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).

[0463] Fig.56 Non-limiting examples of PTPN2 or TCPTP targeting ligands are provided, 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).

[0464] Fig.57 Non-limiting examples of STAT3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be connected. The examples shown here are derived from 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 theSTAT3 DNA-Binding Domain, Theranostics 2017, 7 (18): 4632 and US2006 / 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.

[0465] Fig.58 Non-limiting examples of MyD88 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. The examples shown here are derived from compounds in Sucking, C. et al. Small Molecule Analogues of theparasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibitpro-inflammatory signaling (2018) 8: 2123 and Loiarro, M. et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by anovel peptidomimetic compound. Journal of Leukocyte Biology, (2007) 82: 801-810.

[0466] Fig.59Non-limiting examples of PTP4A3 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. The examples shown here are derived from compounds in Ahn, J. et al. Synthesis and Biological Evaluation of Rhodanine D derivatives as PRL-3 Inhibitors Bioorganic & Medicinal Chemistry Letters (2006) 16 (11): 2996-2999 and Min, G. et al. Rhodanine-Based PRL-3 Inhibitors Blocked the Migration and Invasion of Metastatic Cancer Cells Bioorganic & Medicinal Chemistry Letters (2013) 23 (13): 3769-3774. For additional examples, see Tasker, N. et al. Tapping the Therapeutic Potential of Protein Tyrosine Phosphatase 4A with Small Molecule Inhibitors Bioorganic & Medicinal Chemistry Letters (2019) 29 (16): 2008-2015.

[0467] Fig.60Non-limiting examples of SF3B1 targeting ligands are provided, wherein R represents an exemplary point at which a linker can be connected. The examples shown here are derived from 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.

[0468] Fig.61 Non-limiting examples of ARID1B and ARID2 targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see Chory et al. ACS Chemical Biology 2020, 15(6), 1685.

[0469] Fig.62 Non-limiting examples of class II BRAF mutant targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. For additional examples, see Cho et al. Biochemical and Biophysical Research Communications 2020, 352(2), 315.

[0470] Fig.63 Provided by NRAS Q61K Non-limiting examples of targeting ligands, wherein 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.

[0471] Figures 64A-64ENon-limiting examples of ataxia telangiectasia mutated (ATM) kinase targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Other examples are provided in J Med Chem, 2019, 62: 2988-3008.

[0472] Figures 65A-65B Non-limiting examples of ATR targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Additional examples are provided in Journal of Molecular Biology, Vol. 429, No. 11, June 2, 2017, pp. 1684-1704.

[0473] Figures 66A-66C Non-limiting examples of BPTF targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Additional examples are provided in Organic & Biomolecular Chemistry 2020, 18(27): 5174-5182.

[0474] Figures 67A-67B Non-limiting examples of DNA-PK targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Additional examples are provided in J. Med. Chem. 2020, 63, 7, 3461-3471.

[0475] Figures 68A-68B Non-limiting examples of elf4E targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Additional examples are provided in J. Am. Chem. Soc. 2020, 142, 4960-4964.

[0476] Fig.69 Non-limiting examples of TEADs, such as TEAD1, TEAD2, TEAD3, and / or TEAD4 targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker.

[0477] Fig.70 Non-limiting examples of YAP targeting ligands are provided, where R represents an exemplary point of attachment of a linker.

[0478] Fig.71 Non-limiting examples of formulas for degrons of the invention are provided.

[0479] Fig.72 Non-limiting examples of B-cell lymphoma 6 protein (BCL6) targeting ligands are provided, wherein R represents an exemplary point of attachment of a linker. Additional examples are provided in J. Bio. Chem. 2021, 297, 2, 100928 and Cancer Lett. 2022, 529, 100-111.

[0480] Fig.73A and Fig.73B Non-limiting examples of HDAC-co-repressor or repressor element-1 silencing transcription factor (CoREST) ​​targeting ligands or CoREST complex targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in ACS Chem. Neurosci. 2019, 10, 1729-1743.

[0481] Figures 74A-74M Non-limiting examples of colony stimulating factor 1 receptor (CSF1R) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in Expert Opin. on Ther. Pat. 2021, 31, 2, 107-117 and Nature Communications 2019, 10, 3758. Crystal structures associated with these targeting ligands include PDB code 3krj and PDB code 4r7h.

[0482] Fig.75A and Fig.75B Non-limiting examples of diacylglycerol kinase (DGK) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in Cell Chem. Biol. 2017, 24, 870-880, WO2022 / 187406, and WO2021 / 127554.

[0483] Fig.76 Non-limiting examples of sevenless homolog 1 (SOS1) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Crystal structures associated with these targeting ligands include 5ovi, 6scm, and 7ukr.

[0484] Fig.77 Non-limiting examples of tyrosine kinase 2 (TYK2) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in J. Med. Chem. 2023, 66, 4378-4416.

[0485] Fig.78 Non-limiting examples of ubiquitin-specific peptidase 1 (USP1) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in WO2021 / 163530.

[0486] Figures 79A-79JNon-limiting examples of hematopoietic progenitor kinase (HPK1) targeting ligands are provided, wherein R represents an exemplary point to which a linker can be attached. Additional examples are provided in Expert Opin. on Ther. Pat. 2021, 31, 10, 893-910. DETAILED DESCRIPTION OF THE INVENTION

[0488] I. Definitions

[0489] The compounds are described using standard nomenclature. Unless defined otherwise, 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 belongs.

[0490] The compounds of any formula described herein may be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; for example, rotamers, as if each were specifically described unless clearly excluded by the context.

[0491] The terms "a" and "an" do not represent a limitation of quantity, but rather represent the presence of at least one of the cited items. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of numerical ranges is intended only as a shorthand method for individually citing each individual numerical value within the range, and each individual numerical value is incorporated into the specification as if it were individually listed herein. The endpoints of all ranges are included within the range and are independently combinable. Unless otherwise specified herein or the context is clearly contradictory, all methods described herein can be performed in a suitable order. The use of examples or exemplary language (e.g., "for example") is intended only to better illustrate the present invention, and unless otherwise stated, will not limit the scope of the present invention.

[0492] The present invention includes degradant and degradant compounds having at least one desired isotopically substituted atom in an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons.

[0493] Examples of isotopes that may be incorporated into the compounds of the 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. In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (e.g., 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiotherapy for patients. In particular, 18 F-labeled compounds may be particularly useful in PET or SPECT studies.Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0494] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution refers to that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotopic enrichment of the isotope at any position of interest is 90%, 95% or 99% or more. In a non-limiting embodiment, the enrichment of deuterium at the desired position is 90%, 95% or 99%.

[0495] In a non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom can be at any suitable position of the degron or degrader compound.

[0496] In a non-limiting embodiment, the replacement of a hydrogen atom with a deuterium atom occurs within one or more groups selected from any R' or variable, linker, and targeting ligand described herein. For example, when any group is methyl, ethyl, or methoxy or contains methyl, ethyl, or methoxy, for example by substitution, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH 2 , CD 2 H.CD 3、 CH 2 CD 3 , CD 2 CD 3 、CHDCH 2 D. CH 2 CD 3 ,CHD CHD 2 , OCDH 2 , OCD 2 H or OCD 3 In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

[0497] The compounds of the present invention can form solvates with solvents (including water). Therefore, in a non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salt) and 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 comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent may be isotopically substituted (e.g., D 2 O、d 6 -acetone, d 6 The solvate may be in liquid or solid form.

[0498] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH 2 Attachment is through the carbon of the carbonyl (C=O) group.

[0499] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 or C 1 -C 6 As used herein, a specified range means that the alkyl group has each member of the range described as a separate species. For example, as used herein, the term C 1 -C 6 Alkyl means a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to indicate that each of these is described as a separate species and each subset is therefore considered to be disclosed separately. For example, as used herein, the term C 1 -C 4Alkyl represents a straight or branched alkyl group with 1, 2, 3 or 4 carbon atoms, and means that each of these alkyls is described as a separate species. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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 using a term including "alkyl (alk)", "cycloalkyl" or "carbocycle" can be considered as part of the definition unless the context clearly excludes. For example, but not limited to, the term alkyl, alkoxy, haloalkyl, etc. can all be considered to include a cyclic form of an alkyl, unless the context clearly excludes.

[0500] In one embodiment, "alkyl" is C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 alkyl.

[0501] In one embodiment, an "alkyl" group has one carbon.

[0502] In one embodiment, an "alkyl" group has two carbons.

[0503] In one embodiment, an "alkyl" group has three carbons.

[0504] In one embodiment, an "alkyl" group has four carbons.

[0505] In one embodiment, an "alkyl" group has five carbons.

[0506] In one embodiment, an "alkyl" group has six carbons.

[0507] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0508] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0509] Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0510] Additional non-limiting examples of "alkyl" include: tert-butyl, tert-amyl, and tert-hexyl.

[0511] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activepentyl.

[0512] In one embodiment, "cycloalkyl" is C 3 -C 8 Cycloalkyl, C 3 -C 7 Cycloalkyl, C 3 -C 6 Cycloalkyl, C 3 -C 5 Cycloalkyl, C 3 -C 4 Cycloalkyl, C 4 -C 8 Cycloalkyl, C 5 -C 8 Cycloalkyl or C 6 -C 8 Cycloalkyl.

[0513] In one embodiment, a "cycloalkyl" group has three carbons.

[0514] In one embodiment, a "cycloalkyl" group has four carbons.

[0515] In one embodiment, a "cycloalkyl" group has five carbons.

[0516] In one embodiment, a "cycloalkyl" group has six carbons.

[0517] In one embodiment, a "cycloalkyl" group has seven carbons.

[0518] In one embodiment, a "cycloalkyl" group has eight carbons.

[0519] In one embodiment, a "cycloalkyl" group has nine carbons.

[0520] In one embodiment, a "cycloalkyl" group has ten carbons.

[0521] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0522] Additional non-limiting examples of "cycloalkyl" include indane and tetralin, wherein the point of attachment of each group is on the cycloalkyl ring.

[0523] For example: is a "cycloalkyl" group.

[0524] However, is an "aryl" group.

[0525] "Alkenyl" is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain. As used herein, a specified range means that the alkenyl group has each member of the range described as a separate species, as described above for the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans" alkenyl geometries, or "E" and "Z" alkenyl geometries. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0526] "Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may occur at stable points along the chain. As used herein, a specific range means that the alkynyl group has each member of the range described as a separate species, as described above for the alkyl portion. 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.

[0527] "Alkylene" is a divalent saturated hydrocarbon. Alkylene can be, for example, 1, 2, 3, 4, 5, 6, 7 to 8 carbon moieties, 1 to 6 carbon moieties, or a specified number of carbon atoms, such as C 1 -C 2 Alkylene, C 1 -C 3 Alkylene, C 1 -C 4 Alkylene, C 1 -C 5 Alkylene or C 1 -C 6 Alkylene.

[0528] "Alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylene can be, for example, 2 to 8 carbon moieties, 2 to 6 carbon moieties, or a specified number of carbon atoms, such as C 2 -C 4 Alkenylene.

[0529] "Alkyne" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkyne can be, for example, 2 to 8 carbon moieties, 2 to 6 carbon moieties, or a specified number of carbon atoms, such as C2 -C 4 Alkyne group.

[0530] "Halo" and "halogen" refer to fluoro, chloro, bromo or iodo.

[0531] "Haloalkyl" is a branched or straight chain alkyl group substituted by one or more of the above-mentioned halogen atoms (up to the maximum allowed 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" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0532] In one embodiment, "haloalkyl" is C 1 -C 10 Haloalkyl, C 1 -C 9 Haloalkyl, C 1 -C 8 Haloalkyl, C 1 -C 7 Haloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 5 Haloalkyl, C 1 -C 4 Haloalkyl, C 1 -C 3 Haloalkyl and C 1 -C 2 Halogenated alkyl.

[0533] In one embodiment, a "haloalkyl" group has one carbon.

[0534] In one embodiment, a "haloalkyl" group has one carbon and one halogen.

[0535] In one embodiment, a "haloalkyl" group has one carbon and two halogens.

[0536] In one embodiment, a "haloalkyl" group has one carbon and three halogens.

[0537] In one embodiment, a "haloalkyl" group has two carbons.

[0538] In one embodiment, a "haloalkyl" group has three carbons.

[0539] In one embodiment, a "haloalkyl" group has four carbons.

[0540] In one embodiment, a "haloalkyl" group has five carbons.

[0541] In one embodiment, a "haloalkyl" group has six carbons.

[0542] Non-limiting examples of "haloalkyl" include:

[0543] Additional non-limiting examples of "haloalkyl" include:

[0544] Additional non-limiting examples of "haloalkyl" include:

[0545] Additional non-limiting examples of "haloalkyl" include:

[0546] "Chain" refers to a straight chain, and all other chains (long chains, short chains or both) can be regarded as pendants. When two or more chains can be equally regarded as the main chain, "chain" refers to the chain that results in the simplest representation of the molecule.

[0547] "Haloalkoxy" means a haloalkyl group as defined herein attached through an oxygen bridge (the oxygen of the alcohol group).

[0548] "Heterocycloalkyl" is an alkyl group, as defined herein, substituted with a heterocyclo group, as defined herein.

[0549] "Aralkyl" is an alkyl group, as defined herein, substituted with an aryl group, as defined herein.

[0550] Non-limiting examples of "aralkyl" include:

[0551]

[0552] In one embodiment, "aralkyl" is

[0553] In one embodiment, "aralkyl" refers to a 2-carbon alkyl group substituted with an aryl group.

[0554] Non-limiting examples of "aralkyl" include:

[0555]

[0556] In one embodiment, "aralkyl" refers to a 3 carbon alkyl group substituted with an aryl group.

[0557] "Heteroaralkyl" is an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0558] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) radical having 6-14 ring carbon atoms and no heteroatoms ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 In some embodiments, an aryl group has 10 ring carbon atoms (“C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in this case, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups, which optionally contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron to form, for example, a 3,4-methylenedioxyphenyl group. In a non-limiting embodiment, the aryl group is a side chain. An example of a side chain ring is a phenyl group substituted with a phenyl group. In certain embodiments, the aryl group is an unsubstituted C 6-14 Aryl.

[0559] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0560] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0561] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the aromatic ring.

[0562] For example "Aryl" groups.

[0563] However, It is a "heterocyclic" group.

[0564] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indane and tetrahydronaphthalene, wherein the point of attachment of each group is on the aromatic ring.

[0565] For example is an "aryl" group.

[0566] but, is a "cycloalkyl" group.

[0567] The terms "heterocyclyl", "heterocycle" and "heterocyclo" include saturated and partially saturated heteroatom-containing ring groups, wherein the heteroatom can be selected from nitrogen, sulfur and oxygen. Heterocycle includes monocyclic 3, 4, 5, 6, 7, 8, 9 or 10-membered rings, and 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16-membered bicyclic ring systems (which can include bridged fused and spiro fused bicyclic ring systems). It does not include rings containing -OO-, -OS- or -SS- moieties.

[0568] 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]; 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 heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.

[0569] 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, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro -1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, 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.

[0570] The terms "heterocyclyl", "heterocycle" and "heterocyclo" groups also include moieties in which a heterocyclic group is fused / condensed with an aryl or heteroaryl group: for example, unsaturated condensed heterocyclic groups containing 1, 2, 3, 4 or 5 nitrogen atoms (e.g., indoline, isoindoline), unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms, unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0571] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0572] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0573] In one embodiment, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0574] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0575] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0576] Non-limiting examples of "heterocycle" include aziridine, oxirane, thioethane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0577] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0578] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0579] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, cyclopentane sulfide, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0580] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is located on the heterocycle.

[0581] For example, It is a "heterocyclic" group.

[0582] However, is an "aryl" group.

[0583] Non-limiting examples of "heterocycle" also include:

[0584]

[0585] Additional non-limiting examples of "heterocycle" include:

[0586]

[0587] Additional non-limiting examples of "heterocycle" include:

[0588]

[0589] Non-limiting examples of "heterocycle" also include:

[0590]

[0591] Non-limiting examples of "heterocycle" also include:

[0592]

[0593] Additional non-limiting examples of "heterocycles" include:

[0594]

[0595] Additional non-limiting examples of "heterocycles" include:

[0596]

[0597] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in the cyclic array) and 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, 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 oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing sulfur atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc. Cyclic groups, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 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 to 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]. Further examples include 8-, 9- or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolyl, isoquinolyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl and triazolopyridinyl.

[0598] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3 or 4 nitrogen atoms.

[0599] 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.

[0600] Additional non-limiting examples of 5-membered "heteroaryl" groups include:

[0601]

[0602] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0603] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0604]

[0605] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0606] Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0607] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0608]

[0609] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0610]

[0611] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0612]

[0613] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0614] Non-limiting examples of "heteroaryl" groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0615] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0616]

[0617] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0618] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0619] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0620] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0621] "Aliphatic" refers to saturated or unsaturated straight chain, branched or cyclic hydrocarbons. "Aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties, and therefore comprises each of these definitions. In one embodiment, "aliphatic" is used to represent those aliphatic groups with 1-20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated or polyunsaturated or alkynyl. Unsaturated aliphatic groups can be cis or trans configurations. In one embodiment, aliphatic groups contain 1 to about 12 carbon atoms, more generally contain 1 to about 6 carbon atoms or 1 to about 4 carbon atoms.

[0622] In one embodiment, aliphatic groups contain 1 to about 8 carbon atoms. In certain embodiments, aliphatic groups are C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 or C 1 -C 6 As used herein, a designated range indicates that an aliphatic group has each member of the range described as a separate species. For example, as used herein, the term C 1 -C 6 Aliphatic refers to a straight or branched chain alkyl, alkenyl or alkynyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as a separate species. For example, as used herein, the term C 1 -C 4 Aliphatic means a straight or branched chain alkyl, alkenyl or alkynyl group having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of these groups is described as a separate species. In one embodiment, the aliphatic group is substituted with one or more functional groups to form a stable moiety.

[0623] The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in the chain, for example, an amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom replacing a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur.

[0624] "Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to refer to heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, and the like.

[0625] "Dosage form" refers to the unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, etc. "Dosage form" may also include implants, such as optical implants.

[0626] As used herein, an "effective amount" refers to an amount that provides a therapeutic or prophylactic benefit.

[0627] As used herein, "endogenous" refers to any substance that originates from or is produced within an organism, cell, tissue, or system.

[0628] As used herein, the term "exogenous" refers to any substance introduced or generated from outside an organism, cell, tissue or system.

[0629] As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of a subject's response compared to the subject's response level in the absence of a treatment or compound, and / or compared to the level of response of an otherwise identical but untreated subject. The term encompasses perturbing and / or influencing a natural signal or response, thereby mediating a beneficial therapeutic response in a subject, preferably a human.

[0630] "Parenteral" administration of the pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection or infusion techniques.

[0631] As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably and refer to compounds consisting 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 a protein or peptide sequence is generally comparable to the number of amino acids found in nature. Polypeptides include any peptide or protein consisting of two or more amino acids interconnected by peptide bonds. As used herein, the term refers to both short chains, which are also commonly referred to in the art as, for example, peptides, oligopeptides and oligomers, and long chains, which are commonly referred to in the art as proteins, of which there are many types. "Polypeptide" includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, etc. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0632] As the term is 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 effects of the disease or disorder (i.e., disease-modifying treatment).

[0633] Throughout this disclosure, various aspects of the present invention may be presented in the form of a range. It should be understood that the description in the form of a range is only for convenience and should not be construed as limiting the scope of the invention. The range description should be deemed to have clearly disclosed all possible sub-ranges and single numerical values ​​within the range. For example, the description of a range (e.g., from 1 to 6) should be deemed to have clearly disclosed sub-ranges (e.g., from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc.) and single numbers within the range (e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6). This applies regardless of the width of the range.

[0634] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance (e.g., a carrier). A "pharmaceutical combination" is a combination of at least two active agents, which may be combined in a single dosage form, or may be provided together in separate dosage forms with instructions that the active agents are to be used together to treat any of the disorders described herein.

[0635] As used herein, "pharmaceutically acceptable salts" are derivatives of disclosed compounds, wherein the parent compound is modified by preparing its inorganic and organic, nontoxic acid or base addition salts. The salts of the compounds of the present invention can be synthesized from the parent compound containing an alkaline or acidic part by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent, or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical where feasible. The salts of the compounds of the present invention further include solvates of the compounds and solvates of the compound salts.

[0636] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include conventional non-toxic salts formed, for example, from non-toxic inorganic or organic acids and the quaternary ammonium salts of the parent compound. For example, conventional non-toxic acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH 2 ) n -COOH (wherein n is 0-4), etc., or using a different acid that produces the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0637] The term "carrier" as applied to the pharmaceutical composition / combination of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

[0638] "Pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition / combination, which is generally safe, non-toxic, and biologically or otherwise suitable for administration to a host (usually a human being). In one embodiment, the excipient used is acceptable for veterinary use.

[0639] A "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, e.g., by modulation of a native (wild-type) or modified (non-wild-type) protein that can be degraded according to the invention, thereby producing a therapeutic effect. Typically, 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.

[0640] A "therapeutically effective amount" of the pharmaceutical composition / combination of the present invention refers to an amount effective to provide a therapeutic benefit (eg, improving symptoms or alleviating or reducing the disease itself) when administered to a host.

[0641] II. Compounds of the Invention

[0642] In certain aspects, a degron compound of Formula IAa, Formula IAb or Formula IAc is provided:

[0643]

[0644] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0645] where all variables are defined as above.

[0646] In certain aspects, the degron compounds of the invention are selected from

[0647]

[0648]

[0649] or a pharmaceutically acceptable salt thereof.

[0650] In certain aspects, the degron compounds of the invention are selected from

[0651]

[0652]

[0653] or a pharmaceutically acceptable salt thereof.

[0654] In certain aspects, the degron compounds of the invention are selected from

[0655]

[0656]

[0657] or a pharmaceutically acceptable salt thereof.

[0658] In certain aspects, the degron compounds of the invention are selected from

[0659]

[0660]

[0661]

[0662] or a pharmaceutically acceptable salt thereof.

[0663] In certain aspects, the degron compounds of the invention are selected from

[0664]

[0665]

[0666]

[0667] or a pharmaceutically acceptable salt thereof.

[0668] In another aspect, a degron compound of Formula IIAa, Formula IIAb or Formula IIAc is provided:

[0669]

[0670] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0671] where all variables are defined as above.

[0672] In another aspect, a degron compound of Formula IIIAa, Formula IIIAb or Formula IIIAc is provided:

[0673]

[0674] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0675] where all variables are defined as above.

[0676] In another aspect, a degron compound of Formula IVAa, Formula IVAb or Formula IVAc is provided:

[0677]

[0678] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0679] where all variables are defined as above.

[0680] In certain embodiments, the compounds of the invention have the formula:

[0681]

[0682] or a pharmaceutically acceptable salt thereof.

[0683] In certain embodiments, the compounds of the invention have the formula:

[0684]

[0685]

[0686] or a pharmaceutically acceptable salt thereof.

[0687] In another aspect, the degron compound of Formula VAa, Formula VAb or Formula VAc:

[0688]

[0689] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0690] where all variables are defined as above.

[0691] In another aspect, a degron compound of Formula VIAa, Formula VIAb or Formula VIAc:

[0692]

[0693] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0694] where all variables are defined as above.

[0695] In another aspect, a degron compound of Formula VIIAa, Formula VIIAb or Formula VIIAc is provided:

[0696]

[0697] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0698] where all variables are defined as above.

[0699] In another aspect, a degron compound of Formula VIIIAa, Formula VIIIAb, or Formula VIIIAc is provided:

[0700]

[0701] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0702] where all variables are defined as above.

[0703] In certain aspects, a degron compound of Formula IXAa, Formula IXAb, or Formula IXAc is provided:

[0704]

[0705] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0706] where all variables are defined as above.

[0707] In certain aspects, provided are degron compounds of Formula XAa, Formula XAb, or Formula XAc:

[0708]

[0709] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0710] where all variables are defined as above.

[0711] In certain aspects, provided are degron compounds of Formula XIAa, Formula XIAb, or Formula XIAc:

[0712]

[0713] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0714] where all variables are defined as above.

[0715] In certain aspects, a degron compound of Formula XIIAa, Formula XIIAb, or Formula XIIAc is provided:

[0716]

[0717] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0718] where all variables are defined as above.

[0719] In certain aspects, provided are degron compounds of Formula XIIIAa, Formula XIIIAb, or Formula XIIIAc:

[0720]

[0721] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0722] where all variables are defined as above.

[0723] In certain aspects, a degron compound of Formula XIVAa, Formula XIVAb, or Formula XIVAc is provided:

[0724]

[0725] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0726] where all variables are defined as above.

[0727] In certain aspects, provided are degron compounds of Formula XVAa, XVAb or XVAc:

[0728]

[0729] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0730] where all variables are defined as above.

[0731] In certain aspects, provided are degron compounds of Formula XVIAa, XVIAb or XVIAc:

[0732]

[0733] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0734] where all variables are defined as above.

[0735] In certain aspects, a degron compound of Formula XVIIAa, Formula XVIIAb, Formula XVIIAc, Formula XVIIAd, or Formula XVIIAe is provided:

[0736]

[0737] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0738] where all variables are defined as above.

[0739] In certain embodiments, the present invention is a compound of formula IA:

[0740]

[0741]

[0742]

[0743] or a pharmaceutically acceptable salt thereof.

[0744] In certain embodiments, the compounds of the invention are selected from:

[0745]

[0746]

[0747] or a pharmaceutically acceptable salt thereof.

[0748] In certain embodiments, the compound of the invention is a compound of Formula IIA selected from:

[0749]

[0750]

[0751] or a pharmaceutically acceptable salt thereof.

[0752] In certain embodiments, the compounds of the invention are selected from:

[0753]

[0754]

[0755]

[0756] or a pharmaceutically acceptable salt thereof.

[0757] In certain embodiments, the compound of the invention is a compound of formula IIIA selected from:

[0758]

[0759]

[0760]

[0761]

[0762] or a pharmaceutically acceptable salt thereof.

[0763] In certain embodiments, the compounds of the invention are selected from:

[0764]

[0765] or a pharmaceutically acceptable salt thereof.

[0766] In certain embodiments, the compounds of the invention are selected from:

[0767]

[0768] or a pharmaceutically acceptable salt thereof.

[0769] In another aspect, a degradant compound of 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 is provided:

[0770]

[0771]

[0772]

[0773]

[0774]

[0775] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0776] where all variables are defined as above.

[0777] In certain embodiments, Selected from:

[0778]

[0779] In certain embodiments, Selected from:

[0780]

[0781] In certain embodiments, Selected from:

[0782]

[0783] In certain embodiments, Selected from:

[0784]

[0785] In certain embodiments, the compound of the invention is a compound of formula VA selected from:

[0786]

[0787]

[0788]

[0789] or a pharmaceutically acceptable salt thereof.

[0790] In certain embodiments, a degrader compound of the formula:

[0791]

[0792] wherein the degron is a degron as described herein and the point of attachment to the linker is located on the bicyclic ring, ring A or ring B. In a preferred embodiment, the degron is attached to the linker on the A ring.

[0793] Alternative Linker, A-Ring and B-Ring Positions

[0794] In alternative aspects, compounds are provided in which the A ring, B ring, or linker is bonded to a position to the left or right of its drawn position. If the previous bonding position was a carbon on an aromatic ring, that carbon may be replaced by X. 5 Substitute, where X 5 is N, CH or CR 5 .

[0795] For example, in this regard, the compound of formula I may be:

[0796]

[0797]

[0798] or a pharmaceutically acceptable salt thereof.

[0799] Additional non-limiting formulae in this regard include:

[0800]

[0801]

[0802]

[0803] or a pharmaceutically acceptable salt thereof.

[0804] Additional non-limiting formulae in this regard include:

[0805]

[0806]

[0807] or a pharmaceutically acceptable salt thereof.

[0808] In certain embodiments, the compounds of the invention have the formula

[0809]

[0810]

[0811]

[0812]

[0813] or a pharmaceutically acceptable salt thereof.

[0814] In certain embodiments, the compounds of the invention have the formula

[0815]

[0816]

[0817] or a pharmaceutically acceptable salt thereof.

[0818] In certain embodiments, the compounds of the invention have the formula

[0819]

[0820]

[0821] or a pharmaceutically acceptable salt thereof.

[0822] R 1 Implementation plan

[0823] In certain embodiments, R 1 For hydrogen.

[0824] In certain embodiments, R 1 It is an alkyl group.

[0825] In certain embodiments, R 1 It is an alkenyl group.

[0826] In certain embodiments, R 1 It is an alkynyl group.

[0827] In certain embodiments, R 1 It is a halogen.

[0828] R 2 Implementation plan

[0829] In certain embodiments, R 2 For hydrogen.

[0830] In certain embodiments, R 2 It is an alkyl group.

[0831] In certain embodiments, R 2 It is a halogenated alkyl group.

[0832] In certain embodiments, R 2 It is an alkenyl group.

[0833] In certain embodiments, R 2 It is an alkynyl group.

[0834] In certain embodiments, R 2 It is an aromatic group.

[0835] In certain embodiments, R 2 It is a heteroaryl group.

[0836] In certain embodiments, R 2 It is a heterocyclic ring.

[0837] In certain embodiments, R 2 -C(O)R 9 .

[0838] R 5 Implementation plan

[0839] In certain embodiments, R 5 For hydrogen.

[0840] In certain embodiments, R 5 It is an alkyl group.

[0841] In certain embodiments, R 5 It is a halogenated alkyl group.

[0842] In certain embodiments, R 5 It is an alkenyl group.

[0843] In certain embodiments, R 5 It is an alkynyl group.

[0844] In certain embodiments, R 5 It is a halogen.

[0845] In certain embodiments, R 5 It is an aromatic group.

[0846] In certain embodiments, R 5 It is a heteroaryl group.

[0847] In certain embodiments, R 5 It is a heterocyclic ring.

[0848] In certain embodiments, R 5 It is cyano.

[0849] In certain embodiments, R 5 For nitro.

[0850] In certain embodiments, R 5 For-NR 7 R 8 .

[0851] In certain embodiments, R 5 For-OR 7 .

[0852] In certain embodiments, R 5 For-SR 7 .

[0853] In certain embodiments, R 5 -C(O)R 9 .

[0854] In certain embodiments, R 5 -C(S)R 9 .

[0855] In certain embodiments, R 5 -S(O)R 9 .

[0856] In certain embodiments, R 5 -S(O) 2 R 9 .

[0857] In certain embodiments, R 5 -OC(S)R 9 .

[0858] In certain embodiments, R 5 For-NR 7 S(O)R 9 .

[0859] In certain embodiments, R 5 For-NR 7 S(O) 2 R 9 .

[0860] In certain embodiments, R 5 -P(O)(R 9 ) 2 .

[0861] In certain embodiments, R 5 SP(O)(R 9 ) 2 .

[0862] In certain embodiments, R 5 NR 7 P(O)(R 9 ) 2 .

[0863] In certain embodiments, R 5 -OP(O)(R 9 ) 2 .

[0864] R 5b Implementation plan

[0865] In certain embodiments, R 5b For hydrogen.

[0866] In certain embodiments, R 5b It is an alkyl group.

[0867] In certain embodiments, R 5b It is an alkenyl group.

[0868] In certain embodiments, R 5b It is an alkynyl group.

[0869] In certain embodiments, R 5b It is an aromatic group.

[0870] In certain embodiments, R 5b It is a heteroaryl group.

[0871] In certain embodiments, R5b It is a heterocyclic ring.

[0872] In certain embodiments, R 5b It is -C(O)alkyl.

[0873] In certain embodiments, R 5b -C(S)R 9 .

[0874] In certain embodiments, R 5b -S(O)R 9 .

[0875] In certain embodiments, R 5b -S(O) 2 R 9 .

[0876] R 5c Implementation plan

[0877] In certain embodiments, R 5c For hydrogen.

[0878] In certain embodiments, R 5c It is an alkyl group.

[0879] In certain embodiments, R 5c It is a halogenated alkyl group.

[0880] In certain embodiments, R 5c It is an alkenyl group.

[0881] In certain embodiments, R 5c It is an alkynyl group.

[0882] In certain embodiments, R 5c It is a halogen.

[0883] In certain embodiments, R 5c It is an aromatic group.

[0884] In certain embodiments, R 5c It is a heteroaryl group.

[0885] In certain embodiments, R 5c It is a heterocyclic ring.

[0886] In certain embodiments, R 5c It is cyano.

[0887] In certain embodiments, R 5c For nitro.

[0888] In certain embodiments, R 5c For-OR 7 .

[0889] In certain embodiments, R 5c For-SR 7 .

[0890] In certain embodiments, R 5c -C(O)R 9 .

[0891] In certain embodiments, R 5c -C(S)R 9 .

[0892] In certain embodiments, R 5c -S(O)R 9 .

[0893] In certain embodiments, R 5c -S(O) 2 R 9 .

[0894] In certain embodiments, R 5c -OC(S)R 9 .

[0895] In certain embodiments, R 5c For-NR 7 S(O)R 9 .

[0896] In certain embodiments, R 5c For-NR 7 S(O) 2 R 9 .

[0897] In certain embodiments, R 5c -P(O)(R 9 ) 2 .

[0898] In certain embodiments, R 5c SP(O)(R 9 ) 2 .

[0899] In certain embodiments, R 5c NR 7 P(O)(R 9 ) 2 .

[0900] In certain embodiments, R 5c -OP(O)(R 9 ) 2 .

[0901] R6 Implementation plan

[0902] In certain embodiments, R 6 For hydrogen.

[0903] In certain embodiments, R 6 It is an alkyl group.

[0904] In certain embodiments, R 6 It is an alkenyl group.

[0905] In certain embodiments, R 6 It is an alkynyl group.

[0906] In certain embodiments, R 6 It is a halogen.

[0907] R 7 Implementation plan

[0908] In certain embodiments, R 7 For hydrogen.

[0909] In certain embodiments, R 7 It is an alkyl group.

[0910] In certain embodiments, R 7 It is a halogenated alkyl group.

[0911] In certain embodiments, R 7 It is an alkenyl group.

[0912] In certain embodiments, R 7 It is an alkynyl group.

[0913] In certain embodiments, R 7 It is an aromatic group.

[0914] In certain embodiments, R 7 It is a heteroaryl group.

[0915] In certain embodiments, R 7 It is a heterocyclic ring.

[0916] In certain embodiments, R 7 C(O)R 14 .

[0917] R 8 Implementation plan

[0918] In certain embodiments, R 8 For hydrogen.

[0919] In certain embodiments, R 8 It is an alkyl group.

[0920] In certain embodiments, R 8 It is a halogenated alkyl group.

[0921] In certain embodiments, R 8 It is an alkenyl group.

[0922] In certain embodiments, R 8 It is an alkynyl group.

[0923] In certain embodiments, R 8 It is an aromatic group.

[0924] In certain embodiments, R 8 It is a heteroaryl group.

[0925] In certain embodiments, R 8 It is a heterocyclic ring.

[0926] In certain embodiments, R 8 C(O)R 14 .

[0927] R 9 Implementation plan

[0928] In certain embodiments, R 9 For hydrogen.

[0929] In certain embodiments, R 9 It is an alkyl group.

[0930] In certain embodiments, R 9 It is a halogenated alkyl group.

[0931] In certain embodiments, R 9 It is an alkenyl group.

[0932] In certain embodiments, R 9 It is an alkynyl group.

[0933] In certain embodiments, R 9 It is an aromatic group.

[0934] In certain embodiments, R 9 It is a heteroaryl group.

[0935] In certain embodiments, R 9 It is a heterocyclic ring.

[0936] In certain embodiments, R 9 For-NR 7 R 8 .

[0937] In certain embodiments, R 9 For-OR 7 .

[0938] In certain embodiments, R 9 For-SR 7 .

[0939] R 10 Implementation plan

[0940] In certain embodiments, R 10 For hydrogen.

[0941] In certain embodiments, R 10 It is an alkyl group.

[0942] In certain embodiments, R 10 It is a halogenated alkyl group.

[0943] In certain embodiments, R 10 It is an alkenyl group.

[0944] In certain embodiments, R 10 It is an alkynyl group.

[0945] In certain embodiments, R 10 It is a halogenated alkyl group.

[0946] In certain embodiments, R 10 It is a halogen.

[0947] In certain embodiments, R 10 It is an aromatic group.

[0948] In certain embodiments, R 10 It is a halogenated alkyl group.

[0949] In certain embodiments, R 10 It's hydrogen.

[0950] In certain embodiments, R 10 It is an alkyl group.

[0951] In certain embodiments, R 10 It is a heteroaryl group.

[0952] In certain embodiments, R 10 It is a heterocyclic ring.

[0953] In certain embodiments, R 10 It is cyano.

[0954] In certain embodiments, R 10 For nitro.

[0955] In certain embodiments, R 10 For-NR 11 R 13 .

[0956] In certain embodiments, R 10 For-OR 11 .

[0957] In certain embodiments, R 10 For-SR 11 .

[0958] In certain embodiments, R 10 -C(O)R 14 .

[0959] In certain embodiments, R 10 -C(S)R 14 .

[0960] In certain embodiments, R 10 -S(O)R 14 .

[0961] In certain embodiments, R 10 -S(O) 2 R 14 .

[0962] In certain embodiments, R 10 For-NR 11 S(O) 2 R 14 .

[0963] In certain embodiments, R 10 -P(O)(R 14 ) 2 .

[0964] In certain embodiments, R 10 For-NR 11 P(O)(R 14 ) 2 .

[0965] In certain embodiments, R 10 -OP(O)(R 14 ) 2 .

[0966] R 11 Implementation plan

[0967] In certain embodiments, R 11 For hydrogen.

[0968] In certain embodiments, R 11 It is an alkyl group.

[0969] In certain embodiments, R 11 It is a halogenated alkyl group.

[0970] In certain embodiments, R 11 It is an alkenyl group.

[0971] In certain embodiments, R 11 It is an alkynyl group.

[0972] In certain embodiments, R 11 It is an aromatic group.

[0973] In certain embodiments, R 11 It is a heteroaryl group.

[0974] In certain embodiments, R 11 It is a heterocyclic ring.

[0975] In certain embodiments, R 11 -C(O)R 14 .

[0976] In certain embodiments, R 11 -C(S)R 14 .

[0977] In certain embodiments, R 11 -S(O)R 14 .

[0978] In certain embodiments, R 11 -S(O) 2 R 14 .

[0979] In certain embodiments, R 11 -P(O)(R 14 ) 2 .

[0980] R 12 Implementation plan

[0981] In certain embodiments, R 12 For hydrogen.

[0982] In certain embodiments, R 12 It is an alkyl group.

[0983] In certain embodiments, R 12 It is a halogenated alkyl group.

[0984] In certain embodiments, R 12 It is an alkenyl group.

[0985] In certain embodiments, R 12 It is an alkynyl group.

[0986] In certain embodiments, R 12 It is an alkynyl group.

[0987] In certain embodiments, R 12 It is a halogen.

[0988] In certain embodiments, R 12 It is an aromatic group.

[0989] In certain embodiments, R 12 It is a heterocyclic ring.

[0990] In certain embodiments, R 12 It is a heteroaryl group.

[0991] In certain embodiments, R 12 It is cyano.

[0992] In certain embodiments, R 12 It's nitro.

[0993] In certain embodiments, R 12 For-NR 11 R 13 .

[0994] In certain embodiments, R 12 For-OR 11 .

[0995] In certain embodiments, R 12 For-SR 11 .

[0996] R 13 Implementation plan

[0997] In certain embodiments, R 13 For hydrogen.

[0998] In certain embodiments, R 13 It is an alkyl group.

[0999] In certain embodiments, R 13 It is a halogenated alkyl group.

[1000] In certain embodiments, R 13 It is an alkenyl group.

[1001] In certain embodiments, R 13 It is an alkynyl group.

[1002] In certain embodiments, R 13 It is an aromatic group.

[1003] In certain embodiments, R 13 It is a heteroaryl group.

[1004] In certain embodiments, R 13It is a heterocyclic ring.

[1005] In certain embodiments, R 13 -C(O)R 14 .

[1006] In certain embodiments, R 13 -C(S)R 14 .

[1007] In certain embodiments, R 13 -S(O)R 14 .

[1008] In certain embodiments, R 13 -S(O) 2 R 14 .

[1009] In certain embodiments, R 13 -P(O)(R 14 ) 2 .

[1010] R 14 Implementation plan

[1011] In certain embodiments, R 14 For hydrogen.

[1012] In certain embodiments, R 14 It is an alkyl group.

[1013] In certain embodiments, R 14 It is a halogenated alkyl group.

[1014] In certain embodiments, R 14 It is an alkenyl group.

[1015] In certain embodiments, R 14 It is an alkynyl group.

[1016] In certain embodiments, R 14 It is an aromatic group.

[1017] In certain embodiments, R 14 It is a heteroaryl group.

[1018] In certain embodiments, R 14 It is a heterocyclic ring.

[1019] In certain embodiments, R 14 It's amino.

[1020] In certain embodiments, R 14 It is hydroxyl.

[1021] In certain embodiments, R14 It is an alkoxy group.

[1022] In certain embodiments, R 14 It is -N(H)(alkyl).

[1023] In certain embodiments, R 14 -N(alkyl) 2 .

[1024] R 15a Implementation plan

[1025] In certain embodiments, R 15a For hydrogen.

[1026] In certain embodiments, R 15a It is an alkyl group.

[1027] In certain embodiments, R 15a It is a halogenated alkyl group.

[1028] In certain embodiments, R 15a It is an alkenyl group.

[1029] In certain embodiments, R 15a It is an alkynyl group.

[1030] In certain embodiments, R 15a It is a halogen.

[1031] In certain embodiments, R 15a It is an aromatic group.

[1032] In certain embodiments, R 15a It is a heteroaryl group.

[1033] In certain embodiments, R 15a It is a heterocyclic ring.

[1034] In certain embodiments, R 15a It is cyano.

[1035] In certain embodiments, R 15a For nitro.

[1036] In certain embodiments, R 15a It is amino.

[1037] In certain embodiments, R 15a It is hydroxyl.

[1038] In certain embodiments, R 15a It is an alkoxy group.

[1039] In certain embodiments, R 15a It is -N(H)(alkyl).

[1040] In certain embodiments, R 15a -N(alkyl) 2 .

[1041] R 15b Implementation plan

[1042] In certain embodiments, R 15b For hydrogen.

[1043] In certain embodiments, R 15b It is an alkyl group.

[1044] In certain embodiments, R 15b It is a halogenated alkyl group.

[1045] In certain embodiments, R 15b It is an alkenyl group.

[1046] In certain embodiments, R 15b It is an alkynyl group.

[1047] In certain embodiments, R 15b It is a halogen.

[1048] In certain embodiments, R 15b It is an aromatic group.

[1049] In certain embodiments, R 15b It is a heteroaryl group.

[1050] In certain embodiments, R 15b It is a heterocyclic ring.

[1051] In certain embodiments, R 15b It is cyano.

[1052] In certain embodiments, R 15b For nitro.

[1053] In certain embodiments, R 15b It is amino.

[1054] In certain embodiments, R 15b It is hydroxyl.

[1055] In certain embodiments, R 15b It is an alkoxy group.

[1056] In certain embodiments, R 15b It is -N(H)(alkyl).

[1057] In certain embodiments, R 15b -N(alkyl) 2 .

[1058] R 15c Implementation plan

[1059] In certain embodiments, R 15c For hydrogen.

[1060] In certain embodiments, R 15c It is an alkyl group.

[1061] In certain embodiments, R 15c It is a halogenated alkyl group.

[1062] In certain embodiments, R 15c It is an alkenyl group.

[1063] In certain embodiments, R 15c It is an alkynyl group.

[1064] In certain embodiments, R 15c It is a halogen.

[1065] In certain embodiments, R 15c It is an aromatic group.

[1066] In certain embodiments, R 15c It is a heteroaryl group.

[1067] In certain embodiments, R 15c It is a heterocyclic ring.

[1068] In certain embodiments, R 15c It is cyano.

[1069] In certain embodiments, R 15c For nitro.

[1070] In certain embodiments, R 15c It is amino.

[1071] In certain embodiments, R 15c It is hydroxyl.

[1072] In certain embodiments, R 15c It is an alkoxy group.

[1073] In certain embodiments, R 15c It is -N(H)(alkyl).

[1074] In certain embodiments, R 15c -N(alkyl) 2 .

[1075] R 15d Implementation plan

[1076] In certain embodiments, R 15dFor hydrogen.

[1077] In certain embodiments, R 15d It is an alkyl group.

[1078] In certain embodiments, R 15d It is a halogenated alkyl group.

[1079] In certain embodiments, R 15d It is an alkenyl group.

[1080] In certain embodiments, R 15d It is an alkynyl group.

[1081] In certain embodiments, R 15d It is a halogen.

[1082] In certain embodiments, R 15d It is an aromatic group.

[1083] In certain embodiments, R 15d It is a heteroaryl group.

[1084] In certain embodiments, R 15d It is a heterocyclic ring.

[1085] In certain embodiments, R 15d It is cyano.

[1086] In certain embodiments, R 15d For nitro.

[1087] In certain embodiments, R 15d It is amino.

[1088] In certain embodiments, R 15d It is hydroxyl.

[1089] In certain embodiments, R 15d It is an alkoxy group.

[1090] In certain embodiments, R 15d It is -N(H)(alkyl).

[1091] In certain embodiments, R 15d -N(alkyl) 2 .

[1092] R 15e Implementation plan

[1093] In certain embodiments, R 15e For hydrogen.

[1094] In certain embodiments, R 15e It is an alkyl group.

[1095] In certain embodiments, R 15e It is a halogenated alkyl group.

[1096] In certain embodiments, R 15e It is an alkenyl group.

[1097] In certain embodiments, R 15e It is an alkynyl group.

[1098] In certain embodiments, R 15e It is a halogen.

[1099] In certain embodiments, R 15e It is an aromatic group.

[1100] In certain embodiments, R 15e It is a heteroaryl group.

[1101] In certain embodiments, R 15e It is a heterocyclic ring.

[1102] In certain embodiments, R 15e It is cyano.

[1103] In certain embodiments, R 15e For nitro.

[1104] In certain embodiments, R 15e It is amino.

[1105] In certain embodiments, R 15e It is hydroxyl.

[1106] In certain embodiments, R 15e It is an alkoxy group.

[1107] In certain embodiments, R 15e It is -N(H)(alkyl).

[1108] In certain embodiments, R 15e -N(alkyl) 2 .

[1109] R 15f Implementation plan

[1110] In certain embodiments, R 15f For hydrogen.

[1111] In certain embodiments, R 15f It is an alkyl group.

[1112] In certain embodiments, R 15f It is a halogenated alkyl group.

[1113] In certain embodiments, R 15fIt is an alkenyl group.

[1114] In certain embodiments, R 15f It is an alkynyl group.

[1115] In certain embodiments, R 15f It is a halogen.

[1116] In certain embodiments, R 15f It is an aromatic group.

[1117] In certain embodiments, R 15f It is a heteroaryl group.

[1118] In certain embodiments, R 15f It is a heterocyclic ring.

[1119] In certain embodiments, R 15f It is cyano.

[1120] In certain embodiments, R 15f For nitro.

[1121] In certain embodiments, R 15f It is amino.

[1122] In certain embodiments, R 15f It is hydroxyl.

[1123] In certain embodiments, R 15f It is an alkoxy group.

[1124] In certain embodiments, R 15f It is -N(H)(alkyl).

[1125] In certain embodiments, R 15f -N(alkyl) 2 .

[1126] R 15g Implementation plan

[1127] In certain embodiments, R 15g For hydrogen.

[1128] In certain embodiments, R 15g It is an alkyl group.

[1129] In certain embodiments, R 15g It is a halogenated alkyl group.

[1130] In certain embodiments, R 15g It is an alkenyl group.

[1131] In certain embodiments, R 15g It is an alkynyl group.

[1132] In certain embodiments, R 15g It is a halogen.

[1133] In certain embodiments, R 15g It is an aromatic group.

[1134] In certain embodiments, R 15g It is a heteroaryl group.

[1135] In certain embodiments, R 15g It is a heterocyclic ring.

[1136] In certain embodiments, R 15g It is cyano.

[1137] In certain embodiments, R 15g For nitro.

[1138] In certain embodiments, R 15g It is amino.

[1139] In certain embodiments, R 15g It is hydroxyl.

[1140] In certain embodiments, R 15g It is an alkoxy group.

[1141] In certain embodiments, R 15g It is -N(H)(alkyl).

[1142] In certain embodiments, R 15g -N(alkyl) 2 .

[1143] R 16 Implementation plan

[1144] In certain embodiments, R 16 For hydrogen.

[1145] In certain embodiments, R 16 It is an alkyl group.

[1146] In certain embodiments, R 16 It is a halogenated alkyl group.

[1147] In certain embodiments, R 16 It is an alkenyl group.

[1148] In certain embodiments, R 16 It is an alkynyl group.

[1149] In certain embodiments, R 16 It is a halogen.

[1150] In certain embodiments, R 16 It is an aromatic group.

[1151] In certain embodiments, R 16 It is a heteroaryl group.

[1152] In certain embodiments, R 16 It is a heterocyclic ring.

[1153] In certain embodiments, R 16 It is cyano.

[1154] In certain embodiments, R 16 For nitro.

[1155] In certain embodiments, R 16 For-NR 11 R 13 .

[1156] In certain embodiments, R 16 For-OR 11 .

[1157] In certain embodiments, R 16 For-SR 11 .

[1158] In certain embodiments, R 16 -C(O)R 14 .

[1159] In certain embodiments, R 16 -OC(S)R 14

[1160] In certain embodiments, R 16 -OS(O)R 14 .

[1161] In certain embodiments, R 16 For OS(O)R 14 .

[1162] In certain embodiments, R 16 For-OS(O) 2 R 14 .

[1163] In certain embodiments, R 16 For-NR 11 C(O)R 14 .

[1164] In certain embodiments, R 16 For-NR 11 C(S)R 14 .

[1165] In certain embodiments, R16 For-NR 11 S(O)R 14 .

[1166] In certain embodiments, R 16 -P(O)(R 14 ) 2 .

[1167] In certain embodiments, R 16 For-NR 11 P(O)(R 14 ) 2 .

[1168] In certain embodiments, R 16 -OP(O)(R 14 ).

[1169] R 17 Implementation plan

[1170] In certain embodiments, R 17 For hydrogen.

[1171] In certain embodiments, R 17 It is an alkyl group.

[1172] In certain embodiments, R 17 It is a halogenated alkyl group.

[1173] In certain embodiments, R 17 It is an alkenyl group.

[1174] In certain embodiments, R 17 It is an alkynyl group.

[1175] In certain embodiments, R 17 It is a halogen.

[1176] In certain embodiments, R 17 It is an aromatic group.

[1177] In certain embodiments, R 17 It is a heteroaryl group.

[1178] In certain embodiments, R 17 It is a heterocyclic ring.

[1179] In certain embodiments, R 17 -C(O)R 14 .

[1180] In certain embodiments, R 17 -C(S)R 14 .

[1181] In certain embodiments, R 17 -S(O)R 14 .

[1182] In certain embodiments, R 17 S(O) 2 R 14 .

[1183] In certain embodiments, R 17 -P(O)(R 14 ).

[1184] R 18 Implementation plan

[1185] In certain embodiments, R 18 For hydrogen.

[1186] In certain embodiments, R 18 It is an alkyl group.

[1187] In certain embodiments, R 18 It is a halogenated alkyl group.

[1188] In certain embodiments, R 18 It is an alkenyl group.

[1189] In certain embodiments, R 18 It is an alkynyl group.

[1190] In certain embodiments, R 18 It is a halogen.

[1191] In certain embodiments, R 18 It is an aromatic group.

[1192] In certain embodiments, R 18 It is a heteroaryl group.

[1193] In certain embodiments, R 18 It is a heterocyclic ring.

[1194] In certain embodiments, R 18 It is cyano.

[1195] In certain embodiments, R 18 For nitro.

[1196] In certain embodiments, R 18 For-NR 11 R 13 .

[1197] In certain embodiments, R 18 For-OR 11 .

[1198] In certain embodiments, R 18 For-SR 11 .

[1199] In certain embodiments, R 18 -OC(O)R 14 .

[1200] In certain embodiments, R 18 -OC(S)R 14 .

[1201] In certain embodiments, R 18 -OS(O)R 14 .

[1202] In certain embodiments, R 18 For OS(O) 2 R 14 .

[1203] In certain embodiments, R 18 For-NR 11 C(O)R 14 .

[1204] In certain embodiments, R 18 For-NR 11 C(S)R 14 .

[1205] In certain embodiments, R 18 -P(O)(R 14 ) 2 .

[1206] In certain embodiments, R 18 NR 11 P(O)(R 14 ) 2 .

[1207] In certain embodiments, R 18 -OP(O)(R 14 ) 2 .

[1208] In one embodiment, the targeting ligand is a small molecule that binds to the targeting protein.

[1209] In one embodiment, the target protein is a mediator of abnormal cellular proliferation in a host in need of such therapy.

[1210] Examples of degradation agent compounds according to the present invention are:

[1211]

[1212] or a pharmaceutically acceptable salt thereof.

[1213] In another aspect, provided are compounds of Formula IA or Formula IB:

[1214]

[1215] wherein the linker is a bond or a divalent or multivalent chemical group that connects the degron to the targeting ligand described herein;

[1216] The tail is selected from -(tail) as defined herein. The tail is covalently linked to at least one degron and is not linked to a targeting ligand.

[1217] Targeting ligands are molecules that bind to target proteins, where the target protein is a mediator of disease in the host;

[1218] For example, the degron compound can be sel...

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt thereof; in m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; p is 0 or 1; Q is O, S, NR 17 or CR 17 R 18 ; X 1 , X 2 and X 3 Independently selected from N, CH and CR 5 ; X 4 is N, CH or CR 5 ; is cycloalkyl, heterocyclic or heteroaryl; R 1 and R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl and halogen; or R 1 With R 6 Combine to form a CH2 or CH2CH2 bridge; Each R 2 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted; Each R 5 are independently selected from 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; wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted; R 7 and R 8 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle and C(O)R 14 Each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 16 Substituents are substituted; Each R 9 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 、-OR 7 and-SR 7 ; each of which is optionally 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted; Each R 10 are independently selected from 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; wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15a Substituents are substituted; R 11 and R 13 is independently selected from 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; each of which is optionally 1, 2, 3 or 4 independently selected from R 15b Substituents are substituted; Each R 12 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 、-OR 11 and-SR 11 ;in Each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 groups independently selected from R 15c Substituents are substituted; Each R 14 independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxy, alkoxy, -N(H)(alkyl) and -N(alkyl)2, wherein each of the radicals other than hydrogen is optionally replaced by 1, 2, 3 or 4 radicals independently selected from R 15d Substituents are substituted; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f and R 15g is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxy, alkoxy, -N(H)(alkyl), and -N(alkyl); Each R 16 are independently selected from 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; wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15e Substituents are substituted; Each R 17 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, -C(O)R 14 、-C(S)R 14 、-S(O)R 14 and -S(O)2R 14 wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 15f Substituents are substituted; 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)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; wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 15g Substituents are substituted; X 3b is N, CH or CR 5b ; R 5b is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)alkyl, -C(S)R 9 、-S(O)R 9 and -S(O)2R 9 wherein each of the above except hydrogen is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted; R 5c is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -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; wherein each of the groups except hydrogen, halogen, cyano and nitro is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 substituted with a substituent; and R 9b are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 and-SR 7 , each of which is optionally replaced by 1, 2, 3 or 4 independently selected from R 10 substituted by a substituent.

2. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound has the formula: or a pharmaceutically acceptable salt thereof.

8. Compounds of the formula: or a pharmaceutically acceptable salt thereof, in Z 1 and Z 2 Independently selected from CH, CR 5 and N; Z 3 is S, O, NH or NR 17 ;and All other variables are as defined in claim 1.

9. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: Z 3b Selected from O, NH and NR 17 ; Z 4b Selected from S, NH and NR 17 ; Z 5 and Z 6 Independently selected from CH, CR 5 and N; Z 4 Selected from S, O, NH and NR 17 ; is a 5-membered heterocyclic ring, a 5-membered heteroaryl, a pyrimidinyl group, a pyridazinyl group or a pyrazinyl group; and All other variables are as defined in claim 1.

10. The compound according to any one of claims 1 to 9, wherein ring A is selected from pyrrolidine, piperidine and piperazine, and is optionally substituted with 1, 2, 3 or 4 groups R as long as the valence permits. 2 replace.

11. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: The tail is selected from X 31 Selected from a bond, heterocycle, aryl, heteroaryl, bicyclic, -NR 27 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-, -C(S)-, -S(O)-, -S(O)2- and -S-; wherein each of the heterocyclic, aryl, heteroaryl and bicyclic rings is 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted; X 22 YesR 5 ; R 20 , R 21 , R 22 , R 23 and R 24 is independently selected at each occurrence from 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 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted; R 26 is independently selected at each occurrence from hydrogen, alkyl, aralkyl, heteroaralkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 40 is independently selected at each occurrence from hydrogen, R 27 , alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl; R 41 is aliphatic, aryl, heteroaryl or hydrogen; And all other variables are as defined in claim 1.

12. The compound of claim 11, wherein X 22 It is a heterocycle.

13. The compound of claim 11, wherein X 22 It is a heteroaryl group.

14. The compound of claim 11, wherein X 22 It's a halogen.

15. The compound of claim 11, wherein X 22 It's amino.

16. The compound of claim 11, wherein X 22 It's a hydroxyl group.

17. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: Targeting ligands are chemical moieties that bind to target proteins; The target protein is a selected protein that causes or contributes to the disease; and the linker is a divalent chemical moiety of formula LI: in X 31 and X 32 is independently selected at each occurrence from a bond, heterocycle, aryl, heteroaryl, bicyclic, -NR 27 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-, -C(S)-, -S(O)-, -S(O)2-, and -S-; wherein each of heterocyclic, aryl, heteroaryl and bicyclic is substituted by 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted; R 20 , R 21 , R 22 , R 23 and R 24 is independently selected at each occurrence from 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 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 Substituents are substituted; R 26 is independently selected at each occurrence from hydrogen, alkyl, aralkyl, heteroaralkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 27 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 40 is independently selected at each occurrence from hydrogen, R 27 , alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl; and R 41 is aliphatic, aryl, heteroaryl or hydrogen; and wherein all other variables are as defined in claim 1.

18. The compound of claim 17, which has the formula: or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17, which has the formula: or a pharmaceutically acceptable salt thereof.

20. The compound of claim 17, having the formula: or a pharmaceutically acceptable salt thereof.

21. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: Z 1 and Z 2 Independently selected from CH, CR 5 and N; Z 3 is S, O, NH or NR 17 ;and All other variables are as defined in claim 1.

22. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: Z 5 and Z 6 Independently selected from CH, CR 5 and N; Z 4 Selected from S, O, NH and NR 17 ;and All other variables are as defined in claim 1.

23. The compound of any one of claims 11-22, wherein A is 24. The compound of any one of claims 1-23, wherein m is 0.

25. The compound of any one of claims 1-23, wherein m is 1.

26. The compound of any one of claims 1-23, wherein m is 2.

27. The compound of any one of claims 1-23, wherein m is 3.

28. The compound of any one of claims 1-27, wherein R 2 It's a halogen.

29. The compound of any one of claims 1-27, wherein R 2 It is an alkyl group.

30. The compound of any one of claims 1-29, wherein p is 1.

31. The compound of any one of claims 1-29, wherein p is 0.

32. The compound of any one of claims 1-30, wherein R 6 and R 1 Together they form a CH2 bridge.

33. The compound of any one of claims 1-31, wherein R 6 and R 1 It's hydrogen.

34. The compound of claim 17, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 17-34, wherein the targeting ligand is a means of binding to a target protein, wherein the targeting ligand is a chemical moiety.

36. The compound of claim 35, wherein the linker has the formula:

37. The compound of any one of claims 11-16, 35 and 36, wherein X 31 is the key.

38. The compound of any one of claims 11-16, 35 and 36, wherein X 31 It is a heterocycle.

39. The compound of any one of claims 11-16, 35 and 36, wherein X 31 YesNR 2 .

40. The compound of any one of claims 11-16, 35 and 36, wherein X 31 It is C(O).

41. The compound of any one of claims 35-40, wherein X 32 is the key.

42. The compound of any one of claims 35-40, wherein X 32 It is a heterocycle.

43. The compound of any one of claims 35-40, wherein X 32 YesNR 2 .

44. The compound of any one of claims 35-40, wherein X 32 It is C(O).

45. The compound of any one of claims 11-16 and 35-44, wherein R 20 is the key.

46. ​​The compound of any one of claims 11-16 and 35-44, wherein R 20 It is CH2.

47. The compound of any one of claims 11-16 and 35-44, wherein R 20 It is a heterocycle.

48. The compound of any one of claims 11-16 and 35-44, wherein R 20 It is an aromatic group.

49. The compound of any one of claims 11-16 and 35-44, wherein R 20 It is phenyl.

50. The compound of any one of claims 11-16 and 35-44, wherein R 20 It's a double ring.

51. The compound of any one of claims 11-16 and 35-50, wherein R 21 is the key.

52. The compound of any one of claims 11-16 and 35-50, wherein R 21 It is CH2.

53. The compound of any one of claims 11-16 and 35-50, wherein R 21 It is a heterocycle.

54. The compound of any one of claims 11-16 and 35-50, wherein R 21 It is an aromatic group.

55. The compound of any one of claims 11-16 and 35-50, wherein R 21 It is phenyl.

56. The compound of any one of claims 11-16 and 35-50, wherein R 21 It's a double ring.

57. The compound of claim 35, wherein the linker has the formula:

58. The compound of any one of claims 11-16 and 35-57, wherein R 22 is the key.

59. The compound of any one of claims 11-16 and 35-57, wherein R 22 It is CH2.

60. The compound of any one of claims 11-16 and 35-57, wherein R 22 It is a heterocycle.

61. The compound of any one of claims 11-16 and 35-57, wherein R 22 It is an aromatic group.

62. The compound of any one of claims 11-16 and 35-57, wherein R 22 It is phenyl.

63. The compound of any one of claims 11-16 and 35-57, wherein R 22 It's a double ring.

64. The compound of claim 35, wherein the linker has the formula:

65. The compound of any one of claims 11-16 and 35-64, wherein R 23 is the key.

66. The compound of any one of claims 11-16 and 35-64, wherein R 23 It is CH2.

67. The compound of any one of claims 11-16 and 35-64, wherein R 23 It is a heterocycle.

68. The compound of any one of claims 11-16 and 35-64, wherein R 23 It is an aromatic group.

69. The compound of any one of claims 11-16 and 35-64, wherein R 23 It is phenyl.

70. The compound of any one of claims 11-16 and 35-64, wherein R 23 It's a double ring.

71. The compound of claim 35, wherein the linker has the formula:

72. The compound of any one of claims 11-16 and 35-71, wherein R 24 is the key.

73. The compound of any one of claims 11-16 and 35-71, wherein R 24 It is CH2.

74. The compound of any one of claims 11-16 and 35-71, wherein R 24 It is a heterocycle.

75. The compound of any one of claims 11-16 and 35-71, wherein R 24 It is an aromatic group.

76. The compound of any one of claims 11-16 and 35-71, wherein R 24 It is phenyl.

77. The compound of any one of claims 11-16 and 35-71, wherein R 24 It's a double ring.

78. The compound of any one of claims 17-78, wherein the targeting ligand is a chemical moiety depicted in the accompanying drawings.

79. The compound of any one of claims 17-78, wherein the target protein is selected from the group consisting of: AATK, ABL, ABL2, ALK, AXL, BLK, BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, ILK, IN SR, INSRR, IRAK4, ITK, JAK1, JAK2, JAK3, KDR, KIT, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MET, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB , PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1 and ZAP70.

80. The compound of any one of claims 17-78, wherein the target protein is a serine or threonine kinase.

81. The compound of any one of claims 17-78, wherein the target protein is selected from the group consisting of casein kinase 2, protein kinase A, protein kinase B, protein kinase C, Raf kinase, CaM kinase, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, Aurora A, Aurora B, Aurora C. CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1, ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAPKAPK, MNK1, MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5 , RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-β, TLK2, TSSK1, TSSK2, ULK1 and ULK2.

82. The compound of any one of claims 17-78, wherein the target protein is a cyclin-dependent kinase.

83. The compound of any one of claims 17-78, wherein the target protein is selected from the group consisting of: CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, and CDK13. E 84. The compound of any one of claims 17-78, wherein the target protein is a BET bromodomain-containing protein.

85. The compound of any one of claims 17-78, wherein the target protein is selected from the group consisting of: ASH1L, ATAD2, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8, BRD9, BRD10, BRDT, BRPF1, BRPF3, BRWD3, CECR2, CREBBP, EP300, FALZ, GCN5L2, KIAA1240, LOC93349, MLL, PB1, PCAF, PHIP, PRKCBP1, SMARCA2, SMARCA4, SP100, SP110, SP140, TAF1, TAF1L, TIF1a, TRIM28, TRIM33, TRIM66, WDR9, ZMYND11, and MLL4.

86. The compound of any one of claims 17-78, wherein the target protein is a nucleoprotein.

87. The compound of any one of claims 17-78, wherein the target protein is selected from the group consisting of Antennapedia homeodomain protein, BRCA1, BRCA2, CCAAT enhanced binding protein, histone, polycomb group protein, high mobility group protein, telomere binding protein, FANCA, FANCD2, FANCE, FANCF, hepatocyte nuclear factor, Mad2, NF-κB, nuclear receptor coactivator, CREB binding protein, p55, p107, p130, Rb protein, p53, c-fos, c-jun, c-mdm2, c-myc and c-rel.

88. The compound of any one of claims 17-78, wherein the target protein is a retinoid x receptor protein.

89. The compound of any one of claims 17-78, wherein the target protein is a phosphatase.

90. The compound of any one of claims 17-78, wherein the target protein is the androgen receptor.

91. The compound of any one of claims 17-78, wherein the target protein is an estrogen receptor.

92. The compound of any one of claims 17-78, wherein the target protein is a viral protein.

93. The compound of any one of claims 17-78, wherein the target protein is a viral protease, a viral integrase, or a viral nonstructural protein.

94. The compound of any one of claims 17-78, wherein the target protein is HIV protease, HIV integrase, HCV protease, coronavirus nonstructural protein, or coronavirus nonstructural protein 3.

95. The compound of any one of claims 17-78, wherein the target protein is BaDHFR, HSP90, HDM2, MDM2, DOTL1, CBP, WDR5, BRAF, KRAS, MCL1, HER2, SHOC2, UCHL1, USP6, USP30, USP1, USP2, USP4, USP7, USP8, USP9, USP10, USP11, USP13, USP14, USP17, USP28, or SMARCA2.

96. The compound of any one of claims 17-78, wherein the target protein is CK1a, GSPT1, STAT protein, SALL4, PLZF, p63, NRAS, BRD9, P13KCA, RET, RIT1, MCL1, ARID1B, P300, ARID2, FAM38, NSD2, CSK, CBLB, EGFR, WRN, NTRK, ADAR, SOS1, KRAS, WDR5, ALK, CTNNB1, FGFR, ROS1, MYD88, HER2, TBXT, PTP4A3, MET, USP7, NRF2, SF 3B1, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, MEN1, JCV, CYP17A1, BKV, MEK1, MEK2, Ataxin-2, JAK2, ERK1, ERK2, BRAF, ERBB3, GRB2, CBP, ATAD 2. BAP1, BRPF1, BRD4, EPAS1, KMT2D, Menin, MLLT1, DOT1L, NSD2, TAU, HTT, NSD3, SNCA, SMARCA2, SMARCA4, BTK, TAF1, IRAK4, SARM1 or PPM1D.

97. The compound of any one of claims 17-78, wherein the target protein is a retinoid X receptor (RXR), dihydrofolate reductase (DHFR), Bacillus anthracis dihydrofolate reductase (BaDHFR), heat shock protein 90 (HSP90), tyrosine kinase, Aurora kinase, ALK, ABL, JAK2, MET, mTORC1, mTORC2, mast cell / stem cell growth factor receptor (SCFR), IGF1R, HDM2, MDM2, HDAC, RAF receptor, androgen receptor, estrogen receptor, thyroid hormone receptor, HIV protease, H IV integrase, AP1, AP2, MCL-1, IDH1, RAS, RASK, MERTK, MER, EGFR, FLT3, SMARCA2, cyclin-dependent kinase 9 (CDK9), cyclin-dependent kinase 12, cyclin-dependent kinase 13, glucocorticoid receptor, RasG12C, Her3, Bcl-2, Bcl-XL, PPAR-γ, BCR-ABL, BRAF, LRRK2, PDGFRα, RET, fatty acid binding protein, 5-lipoxygenase activating protein (FLAP), Kringle domain V 4BVV, lactoylglutathione lyase, mPGES-1, factor Xa, kallikrein 7, cathepsin K, cathepsin L, cathepsin S, MTH1, MDM4, PARP1, PARP2, PARP3, PARP14, PARP15, PDZ domain, phospholipase A2 domain, protein S100-A72WOS, sapogenin-B, Sec7, pp60 Src, Tank1, Ubc9 SUMOE2 ligase SF6D, Src, Src-AS1, Src-AS2, JAK3, MEK1, KIT, KSR1, CTNNB1, BCL6, PAK1, PAK4, TNIK, MEN1, ERK1, IDO1, CBP, ASH1L, ATAD2, BAZ2A, BAZ2B, BDRT, BDR9, SMARCA4, PB1, TRIM24 (TIF1a), BRPF1, CECR2, CREBBP, PCAF, PHIP, TAF1, histone deacetylase 2, histone deacetylase 4, histone deacetylase 6, histone deacetylase 7, histone deacetylase 8, histone acetyltransferase (K AT2B), histone acetyltransferase (KAT2A), histone acetyltransferase type B catalytic unit (HAT1), cyclic AMP-dependent transcription factor (ATF2), histone acetyltransferase (KAT5), lysine-specific histone demethylase 1A (KDM1A), DOT1L, EHMT1, SETD2, SETD7, SETD8, SETDB1, SMYD2, SMYD3, SUV4-20H1, ErbB2 receptor, ErbB4 receptor, VEGFR1 receptor, VEGFR2 receptor, VEGFR3 receptor, PDGFRβ receptor, receptor, Lyn receptor, Hck receptor, c-Met receptor, TrkB receptor, Axl receptor, Tie 2 receptor, Ros1 receptor, HGFR receptor, MST1R receptor, Lck receptor, Yes receptor, HER2, PNET receptor, RCC receptor, RAML receptor, SEGA receptor, PDGFR receptors, ErbB2 receptor, FGFR1 receptor, FGFR2 receptor, FGFR3 receptor, FGFR4 receptor, PDGRF receptor, DDR1 receptor, PDGRα receptor, PDGRβ receptor, CDK4 receptor, CDK6 receptor, Fms receptor, T315I VEGFR receptor, FGFR receptor, Flt 3 receptor, Eph2A receptor, JAK1 receptor, FKBP12 receptor, mTOR receptor, CDK8 receptors, CSF-1R receptor, MEK2 receptor, Brk receptor, PI3Ka receptor, GCN5 receptor, G9a (EHMT2), EZH2, EED, PRMT3, PRMT4, PRMT5, PRMT6, KDM1, KDM4, KDM5, KDM6, L3MBTL3, Menin, HDAC6, HDAC7, PTP1B, SHP2, scavenger mRNA decapping enzyme DcpS, ALK, BTK, NTRK1, NTRK2, NTRK3, IDO, ERK2, ABL1, ABL2, ATK1, ATK2, BMX, CSK, EPHA3, EPHA4, EPHA7, EPHB4, FES, FYN, GSG2, INSR, HBV, CBL-B, ERK, WDR 5. NSP3, IRAK4, NRAS, ADAR, NSD2, WHSC1, RIT1, WRN, BAP1, EPAS1, HIF2α, GRB2, KMT2D, MLL2, MLL4, MLLT1, ENL, NSD3, PPM1D, WIP1, SOS1, TBXT, Brachyury, USP7, BKV, JCV, CK1α, GSPT1, ERF3, IFZV, TAU, CYP17A1, SALL4, FAM38, CYP20A1, HTT, NRF2, NFE2L2, P300, PIK3CA, SARM1, SNCA, MAPT, TCPTP, STAT3, MyD88, PTP4A3, SF3B1, ARID1B, or ARID2.

98. The compound of any one of claims 1-97, wherein X 1 It is CH.

99. The compound of any one of claims 1-98, wherein X 2 It is CH.

100. The compound of any one of claims 1-99, wherein X 3 It is CH.

101. The compound of any one of claims 1-100, wherein Q is O or S.

102. The compound of any one of claims 1-101, wherein at least one R 2 It's fluorine.

103. The compound of any one of claims 1-101, wherein at least one R 2 It is -CH2COOH.

104. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

105. A compound selected from: or a pharmaceutically acceptable salt thereof; wherein the compound is substituted with a tail as defined in any one of claims 11-16.

106. The compound of the formula or a pharmaceutically acceptable salt thereof.

107. A pharmaceutical composition comprising a compound according to any one of claims 17 to 106 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

108. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

109. A method for treating a disorder mediated by a target protein in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 1-16 or a pharmaceutical composition of claim 108, wherein the target protein is degraded or down-regulated by the compound.

110. The method of claim 109, wherein the patient is a human.

111. The method of claim 109 or 110, wherein the disorder is abnormal cell proliferation.

112. The method of claim 109 or 110, wherein the disorder is a neurodegenerative disorder.

113. The method of claim 109 or 110, wherein the disorder is an immune system disorder.

114. The method of any one of claims 109-113, wherein the target protein is selected from 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-FGF R1, ZMYM2-FLT3, ZNF198, ZNF276, ZNF276, ZNF517, ZNF582, ZNF653, ZNF654, ZNF692, ZNF787, ZNF827 and ZNF98.

115. The method of any one of claims 109-113, wherein the target protein is selected from ARID2, b-catenin, CDK12, NRF2, PDE6D, CK1α, cyclin K, GSPT1, FAM83, ILF2, ZBTB16, and ZMYM2.

116. The method of any one of claims 109-113, wherein the target protein is ARID2.

117. The method of any one of claims 109-113, wherein the target protein is b-catenin.

118. The method of any one of claims 109-113, wherein the target protein is CDK12.

119. The method of any one of claims 109-113, wherein the target protein is NRF2.

120. The method of any one of claims 109-113, wherein the target protein is PDE6D.

121. The method of any one of claims 109-113, wherein the target protein is CK1α.

122. The method of any one of claims 109-113, wherein the target protein is cyclin K.

123. The method of any one of claims 109-113, wherein the target protein is GSPT1.

124. The method of any one of claims 109-113, wherein the target protein is FAM83.

125. The method of any one of claims 109-113, wherein the target protein is ILF2.

126. The method of any one of claims 109-113, wherein the target protein is ZBTB16.

127. The method of any one of claims 109-113, wherein the target protein is ZMYM2.

128. A compound for use in the preparation of a medicament for treating a disorder mediated by a target protein in a human, wherein the compound is selected from any one of claims 1-16 or a pharmaceutically acceptable salt or composition thereof.

129. The compound for use of claim 128, wherein the disorder is abnormal cell proliferation.

130. The compound for use of claim 128, wherein the disorder is a neurodegenerative disorder.

131. The compound for use of claim 128, wherein the disorder is an immune system disorder.

132. The compound for use of any one of claims 128-131, wherein the target protein is selected from 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-ZBTB 16. RBM23, RBM39, RBM39, RNF166, SALL4, WBP4, ZBTB16, ZBTB16-RARα, ZBTB39, ZFP91, ZFP91, ZFP91, ZMYM2-FG FR1, ZMYM2-FLT3, ZNF198, ZNF276, ZNF276, ZNF517, ZNF582, ZNF653, ZNF654, ZNF692, ZNF787, ZNF827 and ZNF98.

133. The compound for use of any one of claims 128-131, wherein the target protein is selected from ARID2, b-catenin, CDK12, NRF2, PDE6D, CK1α, cyclin K, GSPT1, FAM83, ILF2, ZBTB16, and ZMYM2.

134. The compound for use of any one of claims 128-131, wherein the target protein is ARID2.

135. The compound for use of any one of claims 128-131, wherein the target protein is b-catenin.

136. The compound for use of any one of claims 128-131, wherein the target protein is CDK12.

137. The compound for use of any one of claims 128-131, wherein the target protein is NRF2.

138. The compound for use of any one of claims 128-131, wherein the target protein is PDE6D.

139. The compound for use of any one of claims 128-131, wherein the target protein is CK1α.

140. The compound for use of any one of claims 128-131, wherein the target protein is cyclin K.

141. The compound for use of any one of claims 128-131, wherein the target protein is GSPT1.

142. The compound for use of any one of claims 128-131, wherein the target protein is FAM83.

143. The compound for use of any one of claims 128-131, wherein the target protein is ILF2.

144. The compound for use of any one of claims 128-131, wherein the target protein is ZBTB16.

145. The compound for use of any one of claims 128-131, wherein the target protein is ZMYM2.

146. Use of a compound for treating a disorder mediated by a target protein in a human, wherein the compound is selected from any one of claims 1-16 or a pharmaceutically acceptable salt or composition thereof.

147. The use of claim 146, wherein the disorder is abnormal cell proliferation.

148. The use of claim 146, wherein the disorder is a neurodegenerative disorder.

149. The use of claim 146, wherein the disorder is an immune system disorder.

150. The use of any one of claims 146-149, wherein the target protein is selected from 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-FGF R1, ZMYM2-FLT3, ZNF198, ZNF276, ZNF276, ZNF517, ZNF582, ZNF653, ZNF654, ZNF692, ZNF787, ZNF827 and ZNF98.

151. The use of any one of claims 146-149, wherein the target protein is selected from ARID2, b-catenin, CDK12, NRF2, PDE6D, CK1α, cyclin K, GSPT1, FAM83, ILF2, ZBTB16 and ZMYM2.

152. The use of any one of claims 146-149, wherein the target protein is ARID2.

153. The use of any one of claims 146-149, wherein the target protein is b-catenin.

154. The use of any one of claims 146-149, wherein the target protein is CDK12.

155. The use of any one of claims 146-149, wherein the target protein is NRF2.

156. The use of any one of claims 146-149, wherein the target protein is PDE6D.

157. The use of any one of claims 146-149, wherein the target protein is CK1α.

158. The use of any one of claims 146-149, wherein the target protein is cyclin K.

159. The use of any one of claims 146-149, wherein the target protein is GSPT1.

160. The use of any one of claims 146-149, wherein the target protein is FAM83.

161. The use of any one of claims 146-149, wherein the target protein is ILF2.

162. The use of any one of claims 146-149, wherein the target protein is ZBTB16.

163. The use of any one of claims 146-149, wherein the target protein is ZMYM2.

164. A method of treating a disorder mediated by a target protein in a patient in need thereof, comprising administering an effective amount of a compound of any one of claims 17-106 or a pharmaceutical composition of claim 107.

165. The method of claim 164, wherein the patient is a human.

166. The method of claim 164 or 165, wherein the disorder is abnormal cell proliferation.

167. The method of claim 164 or 165, wherein the disorder is a neurodegenerative disorder.

168. The method of claim 164 or 165, wherein the disorder is an immune system disorder.

169. A compound for use in the preparation of a medicament for treating a disorder mediated by a target protein in a human, wherein the compound is selected from any one of claims 17-106 or a pharmaceutically acceptable salt or composition thereof.

170. The compound for use of claim 169, wherein the disorder is abnormal cell proliferation.

171. The compound for use of claim 169, wherein the disorder is a neurodegenerative disorder.

172. The compound for use of claim 169, wherein the disorder is an immune system disorder.

173. Use of a compound for treating a disorder mediated by a target protein in a human, wherein the compound is selected from any one of claims 17-106 or a pharmaceutically acceptable salt or composition thereof.

174. The use of claim 173, wherein the disorder is abnormal cell proliferation.

175. The use of claim 173, wherein the disorder is a neurodegenerative disorder.

176. The use of claim 173, wherein the disorder is an immune system disorder.

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