Targeted protein degradation

Abstract

The present invention provides pharmaceutical protein degrading agents and E3 ubiquitin ligase binding agents for therapeutic applications as further described herein.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of December 20, 2019, application number 201980092615.2, and invention name “Targeted Protein Degradation”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 783,004, filed December 20, 2018. The entire contents of that application are hereby incorporated by reference for all purposes. Technical Field

[0004] The present invention provides drug degraders and E3 ubiquitin ligase binders (degrons) for therapeutic applications as further described herein. Background Art

[0005] Protein degradation is a highly regulated process that is essential for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to regulating nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve 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.

[0006] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags proteins for proteasomal degradation, where they are digested into small peptides and ultimately into their constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0007] 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, 03, 15; 166: 65-74; R. Verma et al., “Identification of a Cereblon-Independent Protein Degradation Pathway in Residual Myeloma Cells Treated with Immunomodulatory Drugs” Blood (2015) 126(23): 913; 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” 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 mechanism of action of thalidomide, lenalidomide, and pomalidomide is unknown, these compounds have demonstrated activity. Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and alter its ubiquitination activity (see Ito, T. et al., “Identification of a primary target of thalidomide teratogenicity” Science, 2010, 327: 1345).Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA binding protein 1 to form an E3 ubiquitin ligase complex with Cullin 4 and the 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, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al., "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins" Science, 2014, 343: 305-309;. J. et al., "Lenalidomide causessselective degradation of IKZF1 and IKZF3 in multiple myeloma cells" Science, 2014, 343: 301-305).

[0008] The publication of thalidomide binding to the cereblon E3 ubiquitin ligase has led to research into incorporating thalidomide and certain derivatives into compounds for targeted protein destruction. Celgene has disclosed imides with similar uses, including those in the following 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; 7,874,98 4; 7,959,566; 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; and 9,101,622, 9,587,281, 9,857,359 and 10,092,555.

[0009] Patent applications filed by C4 Therapeutics, Inc. that describe compounds capable of binding to E3 ubiquitin ligases and target proteins for degradation include: WO / 2019 / 204354, entitled “Spirocyclic Compounds”; WO / 2019 / 191112, entitled “Cereblon Binders for the Degradation of Ikaros”; WO / 2019 / 099868, entitled “Degraders and Degrons for Targeted Protein Degradation”; WO / 2018 / 237026, entitled “N / O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017 / 197051, entitled “Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation”; and WO 2017 / 197055, entitled “Heterocyclic Degronimers for Target Protein Degradation.” Degradation”; WO 2017 / 197036, entitled “Spirocyclic Degronimers for Target Protein Degradation”; WO 2017 / 197046, entitled “C3-CarbonLinked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017 / 197056, entitled “Bromodomain Targeting Degronimers for Target Protein Degradation.”

[0010] Other patent applications describing compounds that degrade proteins 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 / 176708; WO 2017 / 180417; WO 2018 / 053354; WO 2018 / 071606; WO 2018 / 102067; WO 2018 / 102725; WO2018 / 118598; WO 2018 / 119357; WO 2018 / 119441; WO 2018 / 119448; WO 2018 / 140809; WO2018 / 144649; WO 2018 / 119448; WO 2018 / 226542, WO 2019 / 023553, WO 2019 / 195201, WO2019 / 199816 and WO 2019 / 099926.

[0011] It is an object of the present invention to provide novel compounds, methods, compositions and preparations that can be used to degrade selected proteins in vivo. Summary of the Invention

[0012] Provided are compounds that can cause selected protein degradation by the ubiquitin proteasome pathway (UPP), and their uses and preparation. Degradation determinant compounds of formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII that bind to E3 ligases (typically cereblon subunits) are described. Degradants of formulas I, II, III, IV, V, VI, VII, VIII, IX, X, and XI are disclosed, including a "targeting ligand" that binds to a selected target protein, a "degrader" that binds to an E3 ligase (typically through a cereblon subunit), and optionally a linker that covalently links the targeting ligand to the degrader.

[0013] The degraders provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, can be used to treat diseases mediated by a selected target protein bound to a targeting ligand. Thus, in some embodiments, a method of treating a host suffering from a disease mediated by a target protein is provided, comprising administering to the host, typically a human, an effective amount of a degrader described herein, or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition.

[0014] In one embodiment, the selected target protein is derived from a gene that has undergone amplification, translocation, rearrangement, copy number variation, change, deletion, mutation or inversion events, and the gene causes a medical disease or is caused by a medical disease. In some aspects, the selected target protein is post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation (farnesylation), geranylation (geranylation), ubiquitination, ubiquitination-like or sulfation, which causes a medical disease or is caused by a medical disease. In another embodiment, the target protein can be covalently modified by a targeting ligand, and the targeting ligand has been functionalized to produce a covalent bond with the target protein, and the covalent bond can be irreversible or reversible.

[0015] In one aspect, compounds of Formula I or Formula II are provided:

[0016]

[0017] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0018] in:

[0019] R 1 and R 2 independently selected from hydrogen and fluorine;

[0020] Each are independently a single bond or a double bond;

[0021] R 3 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4 '),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azido, nitro and R 5 ;

[0022] Wherein for the compounds of Formula I and Formula II at least one R 3 Selected from R 5 ;

[0023] m is 1, 2, 3, or 4;

[0024] n is 1, 2, 3, 4, 5, or 6;

[0025] o is 1, 2, or 3;

[0026] X A is CH or N, where if X A is N, then yes and if X A is CH, then yes Or if the valence state allows, X A The adjacent carbon to which it is attached forms a carbon-carbon double bond, e.g. Can be

[0027] If X A R 3 Replace, then X A It's CR 3 ;

[0028] X B selected from NH and CH2;

[0029] If X B R 3 Replace, then X B It is NR 3 or CHR 3 ;

[0030] R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl (e.g., methyl, ethyl, cyclopropyl, or C1-C3 alkyl), C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ;

[0031] Each R 5 Independently selected from -Linker-Targeting Ligand and -(Linker) B ;

[0032] R 6is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2;

[0033] A linker is a divalent chemical group that connects R 5 The attached atom is connected to the targeting ligand; and

[0034] -(Connector) B is a group that is covalently attached to at least one degron and is not attached to a targeting ligand.

[0035] In one embodiment, the linker is a divalent chemical group that attaches the degron to the targeting ligand.

[0036] In one embodiment, the linker is selected from in

[0037] X 1 and X 2 are independently selected from a bond, NR 4 , CH2, CHR 4 、C(R 4 )2, O and S;

[0038] R 20 、R 21 、R 22 、R 23 and R 24 independently selected from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-、-CH(-NR 4 R 4’ )-、-C(-OR 26 )alkyl-, -C(-NR 4 R 4’ )alkyl-, -C(R 40 R 40 )-、-alkyl(R 27 )-alkyl(R 28 )-、-C(R27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-、-NR 4 C(O)NR 4’ -, alkene, haloalkyl, alkoxy, alkynyl, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -、-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH- and -NH-(CH2) 1-12 -S-; wherein 1-6 can independently be 1, 2, 3, 4, 5 or 6; wherein 1-12 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and wherein one or more CH2 or NH groups can be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc. as described herein, and optionally inserting heteroatoms, heteroalkyl, aryl, heteroaryl or cycloaliphatic groups in the chain.

[0039] Some non-limiting examples include -O-CH(CH3)-CH(CH3)CH-O-, -O-CH2-CH(CH3)CH-O- or -O-CH(CH3)-CH2CH-O-, etc.

[0040] Each R 20 、R 21 、R 22 、R 23 and R 24 Optionally one or more selected from R 101 or substituted with a substituent as described in the definition section;

[0041] R 101is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic;

[0042] R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclyl, aliphatic, and heteroaliphatic;

[0043] R 27 and R 28 are independently selected from hydrogen, alkyl and amine; or together with the carbon atom to which they are attached form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings; and

[0044] R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclyl), -N(alkyl)SO2(aryl, heteroaryl or heterocyclyl), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclyl and carbocycle.

[0045] -(Connector) B is a group that is covalently attached to at least one degron and is not attached to a targeting ligand.

[0046] In one embodiment, -(linker) B Selected from

[0047] in

[0048] X 22 It's X 22a or X 22b ;

[0049] X 22a Selected from the following: halogen, -NH2, -NHR 4 、-N(R 4 )2, hydroxyl, mercapto, -B(OH)2, -Sn(R 6)3、-Si(R 6 )3, -OS(O)2 alkyl, -OS(O)2 haloalkyl, alkenyl, alkynyl, ethynyl, vinyl, -C(O)H, -NR 4 C(O)olefins, -NR 4 C(O)alkyne, cyano, OC(O)alkyl, heterocyclyl, and -C(O)OH; and

[0050] X 22b is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocyclyl; and wherein all other variables are as defined above.

[0051] Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of a host disease.

[0052] In one embodiment, the targeting ligand is a small molecule that binds to the targeted protein.

[0053] In one embodiment, the targeted protein is a mediator of abnormal cell proliferation in a host in need of such treatment.

[0054] In another aspect, provided are compounds of Formula III:

[0055]

[0056] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0057] in:

[0058] Y 1 is CH, N or CR 3 ;

[0059] R 8 is hydrogen, C1-C6 alkyl (e.g., methyl, ethyl, cyclopropyl or C1-C3 alkyl) or R 5 ;

[0060] Wherein for the compound of formula III, if R 8 Not R 5 , then at least one R 3 Selected from R 5 ;and

[0061] All other variables are as defined above.

[0062] In another aspect, provided are compounds of formula IV:

[0063]

[0064] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0065] Wherein for the compound of formula IV, at least one R 3 It is R 5 ;and

[0066] All variables are as defined above.

[0067] In another aspect, a compound of Formula V is provided:

[0068]

[0069] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0070] wherein for the compound of formula V, at least one R 3 It is R 5 ;

[0071] p is 1, 2, 3, 4, or 5; and

[0072] All other variables are as defined above.

[0073] In another aspect, compounds of Formula VI or Formula VII are provided:

[0074]

[0075] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0076] If R 8 Not R 5 , then at least one R 3 It is R 5 ;

[0077] q is 1 or 2; and

[0078] All other variables are as defined above.

[0079] In another aspect, provided is a compound of Formula VIII:

[0080]

[0081] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0082] wherein for the compound of formula VIII, at least one R 3 It is R 5 ;

[0083] R 9 and R 9’ independently selected from hydrogen, C1-C6 alkyl (e.g., methyl, ethyl, cyclopropyl, or C1-C3 alkyl), and C1-C3 haloalkyl;

[0084] or R 9 and R 9’ may be joined together with the carbon to which they are attached to form a cyclopropyl ring; and

[0085] All other variables are as defined above.

[0086] In one embodiment, R 9’ It's hydrogen.

[0087] In one embodiment, C1-C3 haloalkyl is C1-C3 alkyl substituted with 1, 2 or 3 F atoms.

[0088] In another aspect, provided are compounds of Formula IX:

[0089]

[0090] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0091] wherein for the compound of formula IX, at least one R 3 It is R 5 ;and

[0092] All other variables are as defined above.

[0093] In another aspect, compounds of Formula X or Formula XI are provided:

[0094]

[0095] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0096] Wherein for the compound of Formula X or Formula XI, at least one R 3 It is R 5 ;and

[0097] All other variables are as defined above.

[0098] 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 this end, each R group described herein must be sufficiently stable to maintain the corresponding desired shelf life of at least two, three, four, or five months under ambient conditions. One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are unstable or too reactive under appropriate conditions.

[0099] If necessary to achieve the desired effect, the degraders (degraders, linkers, and targeting ligands) comprising any of the "R" groups defined herein can be optionally substituted as described in the definitions in Section I below, resulting in a stable R moiety and a final compound that makes chemical sense to one skilled in the art and, if used therapeutically, is pharmaceutically acceptable. Furthermore, all R groups, whether with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted by alkyl is redundant; however, for example, alkoxy substituted by alkoxy is not redundant).

[0100] In one aspect, the degraders of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI are bifunctional compounds having an E3 ubiquitin ligase targeting moiety (degrader) linked to a protein targeting ligand (described in more detail below), which functions to recruit the target protein for degradation, typically by a cereblon-containing E3 ubiquitin ligase. A non-limiting example of a disease that can be treated by such compounds is abnormal cell proliferation, such as a tumor or cancer, wherein the target protein is an oncogenic protein or signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0101] Based on this discovery, compounds and methods for treating patients suffering from diseases mediated by proteins targeted for selective degradation are proposed, comprising administering to a patient (typically a human) in need thereof an effective amount of one or a combination of degraders of Formula I, II, III, IV, IV, V, VI, VII, VIII, IX, X, or XI as described herein, optionally in a pharmaceutically acceptable carrier (composition).

[0102] In certain embodiments, the disease is selected from benign growths, neoplasms, tumors, cancers, abnormal cell proliferation, immune diseases, inflammatory diseases, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based protein diseases, proteinopathy, or fibrotic diseases. In typical embodiments, the patient is a human.

[0103] In one embodiment, the present invention provides a degron covalently linked to a targeting ligand via a linker of variable length and functionality. In one embodiment, the resulting degron-linker-targeting ligand compound is used to treat a disorder as described herein. In one embodiment, the degron is directly linked to the targeting ligand (i.e., the linker is a bond).

[0104] In certain embodiments, the linker can be any chemically stable group that attaches the degron to the targeting ligand. The linker can be any linker described in Section IV (Linkers). In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms, one or more of which can be replaced by heteroatoms (such as 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.

[0105] 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 comprise 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 non-continuous 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 atoms.

[0106] In one embodiment, the target protein is a protein that is not druggable in the classical sense because it does not have a binding pocket or active site that can be inhibited or otherwise bound and is not susceptible to allosteric control. In another embodiment, the target protein is a protein that is druggable in the classical sense. Examples of target proteins are provided below.

[0107] In another embodiment, the degron described herein can be used alone (i.e., not as part of a degrader) as an in vivo binder of cereblon, which can be administered to a host in need thereof, such as a human, in an effective amount, optionally in the form of 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 comprising cereblon, including but not limited to known uses for the following cereblon binders: thalidomide, pomalidomide, and lenalidomide.

[0108] In certain embodiments, the degron described herein can activate, reduce, or alter the native activity of cereblon. Non-limiting examples of uses of cereblon binders are for the treatment of multiple myeloma, hematological disorders such as 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.

[0109] Thus in one aspect there is provided a compound of formula XII or XIII:

[0110]

[0111] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0112] in:

[0113] R 3a is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azide, and nitro groups;

[0114] X 1a is CH or N, where if X 1a is N, then yes and if X 1a is CH, then yes or

[0115] When the valence state allows, X 1a It forms a carbon-carbon double bond with the adjacent carbon to which it is attached, e.g. Can be

[0116] If X 1a R 3a Replace, then X 1a It's CR 3a ;

[0117] X 2a is CH2 or NH;

[0118] If X 2a R 3a Replace, then X 2a It is NR 3a or CHR 3a ;and

[0119] All other variables are as defined above.

[0120] In another aspect, provided is a compound of Formula XIV:

[0121]

[0122] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0123] in:

[0124] Y 1a is N, CH or CR 3a ;

[0125] R 8a is hydrogen or C1-C6 alkyl (e.g., methyl, ethyl, cyclopropyl, or C1-C3 alkyl); and

[0126] All other variables are as defined above.

[0127] In another aspect, provided is a compound of Formula XV:

[0128]

[0129] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition; wherein all variables are as defined above.

[0130] In another aspect, provided is a compound of Formula XVI:

[0131]

[0132] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0133] where all variables are as defined above.

[0134] In another aspect, provided are compounds of Formula XVII or XVIII:

[0135]

[0136] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0137] where all variables are as defined above.

[0138] In another aspect, provided is a compound of Formula XIX:

[0139]

[0140] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0141] where all variables are as defined above.

[0142] In another aspect, a compound of formula XX is provided:

[0143]

[0144] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0145] in:

[0146] X 1b is CH or N, where if X 1b is N, then yes and if X 1b is CH, then yes or

[0147] When the valence state allows, X 1b It forms a carbon-carbon double bond with the adjacent carbon to which it is attached, e.g. Can be

[0148] If X 1b R 3a Replace, then X 1b It's CR 3a ;

[0149] X 2b is NH or CH2;

[0150] If X 2b R 3a Replace, then X 2b It is NR 3a or CHR 3a ;

[0151] If X 1b is N, then X 2b cannot be CH2; and

[0152] All other variables are as defined above.

[0153] In another aspect, provided are compounds of Formula XXI or XXII:

[0154]

[0155] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0156] in

[0157] X 1c is CH or N, where if X 1c is N, then yes and if X 1c is CH, then yes or

[0158] When the valence state allows, X 1c It forms a carbon-carbon double bond with the adjacent carbon to which it is attached, e.g. Can be

[0159] If X 1c R 3a Replace, then X 1c It's CR 3a ;

[0160] X 2c is NH or CH2;

[0161] If X 2c R 3a Replace, then X 2c It is NR 3a or CHR 3a ;

[0162] If X 1c is N, then X 2c Cannot be NH or NR 3a ;and

[0163] All other variables are as defined above.

[0164] The compounds of Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, and Formula XXII do not include a targeting ligand.

[0165] In certain embodiments, the compound of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII is capable of activating, reducing, or altering the native activity of cereblon.

[0166] When administered in an effective amount to a host (typically a human), the compounds of Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI and Formula XXII can be used as therapeutic agents to treat medical conditions that can be treated with thalidomide, pomalidomide or lenalidomide, and / or include but are not limited to abnormal cell proliferation, including tumors or cancers, or myeloproliferative or lymphoproliferative diseases, such as B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom macroglobulin immune disorders, including autoimmune diseases such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes mellitus; cardiac dysfunction including hypercholesterolemia; infectious diseases including viral or bacterial infections; and inflammatory diseases including asthma, chronic peptic ulcer disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0167] In certain embodiments, the present invention provides for administering an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII to treat a patient (e.g., a human) suffering from an infectious disease, wherein the therapy targets a target protein of the infectious agent or a target protein of the host (Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI), or acts by binding to cereblon or its E3 ubiquitin ligase (Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII), or acts by an independent mechanism, optionally in combination with another biologically active agent.

[0168] The disease state or condition may be caused by a microbial agent or other exogenous agent, such as a virus (as a non-limiting example, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, pestivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, enveloped virus, orthomyxovirus, retrovirus or hepadnavirus), bacteria (including but not limited to Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, meningitis, gonorrhea, Chlamydia, Mycoplasma, etc.), fungus, protozoa, helminth, worm, prion, parasite or other microorganism.

[0169] In certain embodiments, the compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII have at least one desired isotopic substitution at an amount above the natural abundance of that isotope, i.e., are enriched.

[0170] In one embodiment, the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII includes a deuterium atom or multiple deuterium atoms.

[0171] The compounds of the present invention may provide important clinical benefits to patients, particularly for the treatment of disease states and conditions modulated by the protein of interest.

[0172] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which this application belongs. In this specification, the singular also includes the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein are not considered to be prior art of the claimed application. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be restrictive.

[0173] Other features and advantages of the application will be apparent from the following detailed description, and from the claims.

[0174] Therefore, the present invention includes at least the following features:

[0175] (a) a degrader of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI as described herein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof;

[0176] (b) a degron of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof;

[0177] (c) a degrader of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof for treating a disease 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;

[0178] (d) use of an effective amount of a degrader of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI in treating a patient (typically a human) suffering from any of the diseases described herein mediated by the target protein, including abnormal cell proliferation such as a tumor or cancer, an immune or autoimmune disease or inflammatory disease, a heart disease, an infectious disease, or other disease responsive to such treatment;

[0179] (e) use of an effective amount of a compound of Formula XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII for treating a patient (typically a human) having a disease responsive to such treatment, including by reducing cereblon-based ubiquitination of proteins, such as abnormal cell proliferation such as a tumor or cancer, an immune or autoimmune disease or an inflammatory disease, a cardiac disease, an infectious disease or other disease responsive to such treatment;

[0180] (f) use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, in the preparation of a medicament for treating a medical disease as further described herein;

[0181] (g) a method for preparing a medicament intended for therapeutic treatment of a disease in a host, characterized in that a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII is used in the preparation;

[0182] (h) a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, which can be used to treat abnormal cell proliferation in a host, such as cancer, including any cancer described herein;

[0183] (i) Use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof in the preparation of a medicament for treating abnormal cell proliferation (e.g., cancer, including any cancer described herein);

[0184] (j) a method of preparing a medicament intended for therapeutic use in treating abnormal cell proliferation in a host, such as cancer, including any cancer described herein, comprising using a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII in the preparation;

[0185] (k) a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, for treating a tumor in a host, including any tumor described herein;

[0186] (1) Use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof for treating a tumor in a host, including any tumor described herein;

[0187] (m) a method of preparing a medicament intended for therapeutic treatment of a tumor in a host, including any tumor described herein, comprising using a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII as described herein;

[0188] (n) a 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, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI or Formula XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, for the preparation of a medicament for treating an immune disease, autoimmune disease or inflammatory disease in a host;

[0189] (o) Use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof in the preparation of a medicament for treating an immune disease, autoimmune disease or inflammatory disease in a host;

[0190] (p) a method for preparing a medicament intended for the therapeutic treatment of an immune disease, an autoimmune disease or an inflammatory disease in a host, characterized in that a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII is used in the preparation;

[0191] (q) compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, and pharmaceutically acceptable salts, isotopic derivatives and prodrugs thereof, which can be used to treat infections in a host, including viral infections such as HIV, HBV, HCV and RSV;

[0192] (r) use of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative), or prodrug thereof, in the preparation of a medicament for treating an infection in a host, including a viral infection, such as HIV, HBV, HCV and RSV;

[0193] (s) a method for preparing a medicament intended for the therapeutic treatment of an infection in a host, said infection including a viral infection such as HIV, HBV, HCV and RSV, said method being characterized by using in the preparation a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII;

[0194] (t) a pharmaceutical formulation comprising a host-therapeutically effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

[0195] (u) compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII as described herein as mixtures of enantiomers or diastereomers (where relevant), including racemates;

[0196] (v) enantiomerically or diastereomerically (where relevant) enriched forms of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII as described herein, including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97% or 99% pure); and

[0197] (w) a method of preparing a therapeutic product comprising an effective amount of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII. BRIEF DESCRIPTION OF THE DRAWINGS

[0198] Figures 1A-1C Examples of Retinoid X Receptor (RXR) Targeting Ligands are shown, where R is the point of attachment of the Linker.

[0199] Figures 1D-1F An example of a general dihydrofolate reductase (DHFR) targeting ligand is shown, where R is the point of attachment of a linker.

[0200] Figure 1G An example of a Bacillus anthracis dihydrofolate reductase (BaDHFR) Targeting Ligand is shown, where R is the point of attachment of the linker.

[0201] Figures 1H-1J An example of a heat shock protein 90 (HSP90) targeting ligand is shown, where R is the point of attachment of the linker.

[0202] Figures 1K-1Q Examples of general kinase and phosphatase targeting ligands are shown, where R is the point of attachment of the linker.

[0203] Figure 1R-1S Examples of tyrosine kinase targeting ligands are shown, where R is the point of attachment of the linker.

[0204] Figure 1T Examples of Aurora Kinase Targeting Ligands are shown, where R is the point of attachment of the linker.

[0205] Figure 1U Examples of protein tyrosine phosphatase targeting ligands are shown, where R is the point of attachment of the linker.

[0206] Figure 1V Examples of ALK Targeting Ligands are shown, where R is the point of attachment of the linker.

[0207] Figure 1W Examples of ABL Targeting Ligands are shown, where R is the point of attachment of the linker.

[0208] Figure 1X Examples of JAK2 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0209] Figure 1Y-1Z Examples of MET Targeting Ligands are shown, where R is the point of attachment of the linker.

[0210] Figure 1AA Examples of mTORC1 and / or mTORC2 Targeting Ligands are shown, where R is the point of attachment of a linker.

[0211] Figure 1BB-1CC Examples of mast cell / stem cell growth factor receptor (SCFR) (also known as c-KIT receptor) targeting ligands are shown, where R is the point of attachment of the linker.

[0212] Figure 1DD Examples of IGF1R and / or IR Targeting Ligands are shown, where R is the point of attachment of the linker.

[0213] Figures 1EE-1FF Examples of HDM2 and / or MDM2 Targeting Ligands are shown, where R is the point of attachment of a linker.

[0214] Figure 1GG-1MM Examples of BET bromodomain-containing protein targeting ligands are shown, where R is the point of attachment of the linker.

[0215] Figure 1NN Examples of HDAC Targeting Ligands are shown, where R is the point of attachment of the linker.

[0216] Figure 1OO Examples of RAF receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0217] Figure 1PP Examples of FKBP receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0218] Figure 1QQ-1TTExamples of androgen receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0219] Figure 1UU Examples of estrogen receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0220] Figure 1VV-1WW Examples of thyroid hormone receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0221] Figure 1XX Examples of HIV protease targeting ligands are shown, where R is the point of attachment of the linker.

[0222] Figure 1YY Examples of HIV integrase targeting ligands are shown, where R is the point of attachment of the linker.

[0223] Figure 1ZZ Examples of HCV protease targeting ligands are shown, where R is the point of attachment of a linker.

[0224] Figure 1AAA Examples of AP1 and / or AP2 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0225] Figure 1BBB-1CCC Examples of MCL-1 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0226] Figure 1 DDD Examples of IDH1 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0227] Figure 1EEE-1FFF Examples of RAS or RASK Targeting Ligands are shown, where R is the point of attachment of the linker.

[0228] Figure 1GGG Examples of MERTK or MER targeting ligands are shown, where R is the point of attachment of the linker.

[0229] Figure 1HHH-1III Examples of EGFR Targeting Ligands are shown, where R is the point of attachment of the linker.

[0230] Figure 1JJJ-1KKK Examples of FLT3 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0231] Figure 1LLL Examples of SMRCA2 targeting ligands are shown, where R is the point of attachment of the linker.

[0232] Figure 2A An example of the kinase inhibitor targeting ligand U09-CX-5279 (derivatized) is shown, where R is the point of attachment of the linker.

[0233] Figures 2B-2C Examples of kinase inhibitor targeting ligands are shown, including kinase inhibitor compounds Y1W and Y1X (derivatized), where R is the point of attachment of the linker. 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).

[0234] Figure 2D Examples of kinase inhibitor targeting ligands are shown, including the kinase inhibitor compounds 6TP and OTP (derivatized), where R is the point of attachment of the linker. 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).

[0235] Figure 2E Examples of kinase inhibitor targeting ligands are shown, including kinase inhibitor compound 07U, where R is the point of attachment of a linker. For additional examples and related ligands, see the kinase inhibitors identified in: Van Eis et al., "26-Naphthyridines as potent and selective inhibitors of the novel proteinkinase C isozymes" Biorg. Med. Chem. Lett., 21(24):7367-72 (2011).

[0236] Figure 2F Examples of kinase inhibitor targeting ligands are shown, including the kinase inhibitor compound YCF, where R is the point of attachment of the linker. 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).

[0237] Figures 2G-2H Examples of kinase inhibitor targeting ligands are shown, including the kinase inhibitors XK9 and NXP (derivatized), where R is the point of attachment of the linker. 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).

[0238] Figures 2I-2J Examples of kinase inhibitor targeting ligands are shown, where R is the point of attachment for the linker r.

[0239] Figures 2K-2MExamples of cyclin-dependent kinase 9 (CDK9) targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Baumli et al., “The structure of P-TEFb(CDK9 / cyclin T1)its complex with flavopiridol and regulation by phosphorylation.” Embo J., 27:1907-1918 (2008); Bettayeb et al., “CDK Inhibitors Roscovitine and CR8Trigger Mcl-1 Down-Regulation and Apoptotic Cell 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 Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity." J. Med. Chem. 56:660 (2013); Lücking et al., "Identification of thepotent and highly selective PTEFb inhibitor 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.

[0240] Figure 2N-2PExamples of cyclin-dependent kinase 4 / 6 (CDK4 / 6) targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Lu H.; Schulze-Gahmen U.; “Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition.” J. Med. Chem., 49:3826-3831 (2006); 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4 / 6. Cho et al., (2010) J. Med. Chem. 53:7938-7957; Cho YS et al., “Fragment-Based Discovery of 7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4 / 6 Inhibitors.” ACS Med Chem Lett 3:445-449 (2012); Li Z. et al., “Discovery of AMG 925a 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).

[0241] Figure 2Q Examples of cyclin-dependent kinase 12 and / or cyclin-dependent kinase 13 targeting ligands are shown, where R is the point of attachment of a linker. 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).

[0242] Figure 2R-2S Examples of glucocorticoid receptor targeting ligands are shown, where R is the point of attachment of the linker.

[0243] Figure 2T-2U Examples of RasG12C Targeting Ligands are shown, where R is the point of attachment of the linker.

[0244] Figure 2V An example of a Her3 targeting ligand is shown, where R is the point of attachment of the linker, and R' is

[0245] Figure 2W Examples of Bcl-2 or Bcl-XL Targeting Ligands are shown, where R is the point of attachment of the linker.

[0246] Figure 2X-2NNExamples of BCL2 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Toure BB et al., “The role of the acidity of N-heteroarylsulfonamides as inhibitors of bcl-2family protein-protein interactions.” ACSMed Chem Lett, 4:186-190 (2013); Porter J. et al., “Tetrahydroisoquinoline AmideSubstituted Phenyl Pyrazoles as Selective Bcl-2 Inhibitors” Bioorg. Med. Chem. Lett. 19:230 (2009); Souers AJ et al., “ABT-199a potent and selective BCL-2 inhibitor achieves antitumor activity while sparing platelets.” Nature Med. 19:202-208 (2013); Angelo Aguilar et al., “A Potent and Highly Efficacious Bcl-2 / Bcl-xL Inhibitor” J Med Chem.56(7):3048–3067(2013); Longchuan Bai et al., "BM-1197: A Novel and Specific Bcl-2 / Bcl-xL Inhibitor Inducing Complete and Long-Lasting Tumor Regression In Vivo" PLoS ONE 9(6):e99404; Fariba Ne'mati1 et al., "Targeting Bcl-2 / Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts" PLoS ONE 9(1):e80836; WO2015011396, titled "Novel derivatives of indole and pyrrole method for the production thereof and pharmaceutical compositions containing same"; WO2008060569A1, titled "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., "Tetrahydroisoquinolineamide substituted phenyl pyrazoles as selective Bcl-2 inhibitors" Bioorg Med Chem Lett., 19(1):230-3(2009).

[0247] Figure 2OO-2UUExamples of BCL-XL targeting ligands are shown, where R is the point of attachment of the linker. 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 cells 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)).

[0248] Figure 2VV Examples of PPAR-γ targeting ligands are shown, where R is the point of attachment of the linker.

[0249] Figure 2WW-2YY Examples of EGFR targeting ligands that target the EGFR L858R mutant, including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, are shown, where R is the point of attachment of the linker.

[0250] Figure 2ZZ-2FFF Examples of EGFR targeting ligands that target the EGFR T790M mutant are shown, including osimertinib, rociletinib, omotinib, naquotinib, nazartinib, PF-06747775, icotinib, neratinib, Avitinib, Tarloxotinib, PF-0645998, Tesevatinib, Transtinib, WZ-3146, WZ8040 and CNX-2006, where R is the point of attachment of the linker.

[0251] Figure 2GGG Examples of EGFR targeting ligands targeting the EGFR C797S mutant are shown, including EAI045, where R is the point of attachment of a linker.

[0252] Figure 2HHH Examples of BCR-ABL targeting ligands targeting the BCR-ABL T315I mutant, including nilotinib and dasatinib, are shown, where R is the point of attachment of the linker. See, for example, crystal structure PDB 3CS9.

[0253] Figure 2III Examples of targeting ligands that target BCR-ABL, including nilotinib, dasatinib, ponatinib, and bosutinib, are shown, where R is the point of attachment of the linker.

[0254] Figure 2JJJ-2KKK Examples of ALK targeting ligands targeting the ALK L1196M mutant, including ceritinib, are shown, where R is the point of attachment of the linker. See, e.g., crystal structure PDB 4MKC.

[0255] Figure 2LLL Examples of JAK2 targeting ligands that target the JAK2V617F mutant, including ruxolitinib, are shown, where R is the point of attachment of the linker.

[0256] Figure 2MMM Examples of BRAF targeting ligands targeting the BRAF V600E mutant are shown, including vemurafenib, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PBD 3OG7.

[0257] Figure 2NNN Examples of BRAF targeting ligands, including dabrafenib, are shown, where R is the point of attachment of the linker.

[0258] Figure 2OOO An example of an LRRK2 Targeting Ligand that targets the LRRK2 R1441C mutant is shown, where R is the point of attachment of the linker.

[0259] Figure 2PPP Examples of LRRK2 Targeting Ligands that target the LRRK2 G2019S mutant are shown, where R is the point of attachment of the linker.

[0260] Figure 2 QQQ Examples of LRRK2 Targeting Ligands that target the LRRK2 I2020T mutant are shown, where R is the point of attachment of the linker.

[0261] Figure 2RRR-2TTTExamples of PDGFRα targeting ligands targeting the PDGFRα T674I mutant are shown, including AG-1478, CHEMBL94431, dovitinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, sorafenib, sunitinib and WHI-P180, where R is the point of attachment of the linker.

[0262] Figure 2UUU Examples of RET targeting ligands targeting the RET G691S mutant are shown, including tauzerti, where R is the point of attachment of the linker.

[0263] Figure 2VVV Examples of RET targeting ligands targeting the RET R749T mutant are shown, including tauzerti, where R is the point of attachment of the linker.

[0264] Figure 2WWW Examples of RET targeting ligands targeting the RET E762Q mutant are shown, including tauzertin, where R is the point of attachment of the linker.

[0265] Figure 2XXX Examples of RET targeting ligands that target the RET Y791F mutant are shown, including tauzerti, where R is the point of attachment of the linker.

[0266] Figure 2YYY Examples of RET targeting ligands targeting the RET V804M mutant are shown, including tauzerti, where R is the point of attachment of the linker.

[0267] Figure 2ZZZ Examples of RET targeting ligands targeting the RET M918T mutant are shown, including tauzerti, where R is the point of attachment of the linker.

[0268] Figure 2AAAA Examples of fatty acid binding protein targeting ligands are shown, where R is the point of attachment of the linker.

[0269] Figure 2BBBB An example of a 5-lipoxygenase activating protein (FLAP) targeting ligand is shown, where R is the point of attachment of the linker.

[0270] Figure 2CCCC An example of a Kringle domain V 4BVV Targeting Ligand is shown, where R is the point of attachment of the linker.

[0271] Figure 2DDDD Examples of lactoylglutathione lyase targeting ligands are shown, where R is the point of attachment of the linker.

[0272] Figure 2EEEE-2FFFFExamples of mPGES-1 targeting ligands are shown, where R is the point of attachment of the linker.

[0273] Figure 2GGGG-2JJJJ Examples of factor Xa targeting ligands are shown, where R is the point of attachment of the linker. 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 Nonamidine Inhibitors Bound to Factor Xa." Biochemistry 41:15514-15523 (2002); Roehrig S. et al., "Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-Oxo-3-[4-(3-Oxomorpholin-4-Yl)Phenyl]-1

[0274] 3-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An OralDirect Factor Xa Inhibitor." J. Med. Chem. 48: 5900 (2005); Anselm L. et al., "Discovery of a Factor 4R)-1-(22-Difluoro-Ethyl)-Pyrrolidine-3 4-Dicarboxylic Acid3-[(5-Chloro-Pyridin-2-Yl)-Amide]

[0275] and Pinto DJ et al., "Discovery" of1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 5 67-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).

[0276] Figure 2KKKK Examples of kallikrein 7 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Maibaum J. et al., "Small-molecule factor D inhibitors targeting the alternative complement pathway." Nat. Chem. Biol. 12: 1105-1110 (2016).

[0277] Figure 2LLLL-2MMMM Examples of cathepsin K targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Rankovic Z. et al., "Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors" Bioorg. Med. Chem. Lett. 20: 1524-1527 (2010); and Cai J. et al., "Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors." Bioorg. Med. Chem. Lett. 20: 6890-6894 (2010).

[0278] Figure 2NNNNExamples of cathepsin L targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Kuhn B. et al., "Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors." J. Med. Chem. 60: 2485-2497 (2017).

[0279] Figure 2OOOO Examples of cathepsin S targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Jadhav PK et al., "Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm" ACS Med. Chem. Lett. 5: 1138-1142. (2014).

[0280] Figure 2PPPP-2SSSSExamples of MTH1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Kettle JG et al., “Potent and Selective Inhibitors of Mth1 Probe its Role in Cancer Cell Survival.” J. Med. Chem. 59:2346 (2016); Huber KVM et al., “Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.” Nature 508:222 (2014); Gad H. et al., “MTH1 inhibition eradicates cancer bypreventing sanitation of the dNTP pool.” Nature 508:215-221 (2014); Nissink J. WM et al., “Mth1 Substrate Recognition—an Example of Specific Promiscuity.” Plos One 11:51154 (2016); and Manuel Ellermann et al., “Novel class of potent and selective inhibitors efface MTH1 as broad-spectrum cancer target." AACR National Meeting Abstract 5226, 2017.

[0281] Figure 2TTTT-2ZZZZExamples of MDM2 and / or MDM4 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Popowicz GM et al., “Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX / MDM2 antagonist drug discovery.” Cell Cycle, 9 (2010); Miyazaki M. et al., “Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors.” Bioorg. Med. Chem. 21:4319-4331 (2013); Miyazaki M. et al., “Discovery of DS-5272 as apromising candidate: A potent and orally active p53-MDM2 interaction inhibitor.” Bioorg Med Chem. 23:2360-7 (2015); Holzer P. et al., “Discovery of aDihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1Clinical Trials in p53wt Tumors." J.Med.Chem.58:6348-6358(2015); Gonzalez-Lopez de Turiso F. et al., "Rational Design and Binding Mode Duality ofMDM2-p53 Inhibitors." J.Med.Chem.56:4053-4070(2013); Gessier F. et al., "Discovery of dihydroisoquinolinone derivatives as novelinhibitors of the p53-MDM2 interaction with adistinct binding mode." Bioorg.Med.Chem.Lett.25:3621-3625(2015); Fry DCet al., “Deconstruction of anutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.” ACS Med Chem Lett 4:660-665 (2013); Ding Q. 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-7209 a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.” J. Med. Chem. 57:10499-10511 (2014); Bogen S.L. et al., “Discovery of Novel 3 3-Disubstituted Piperidines as Orally Bioavailable Potent and Efficacious HDM2-p53 Inhibitors.” ACS Med. Chem. Lett. 7:324-329 (2016); and Sun D. et al., “Discovery of AMG 232 a Potent Selective and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development.” J. Med. Chem. 57:1454-1472 (2014).

[0282] Figure 2AAAAA-2EEEEEExamples of PARP1, PARP2 and / or PARP3 targeting ligands are shown, where R is the point of attachment of a linker. 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 / 2inhibitors." Febs Lett. 579: 1389-1393 (2005); crystal structure PDB 2RCW (PARP in complex with A861695, Park C H); crystal structure PDB 2RD6 (PARP in complex with A861696, Park C.H.); crystal structure PDB 3GN7; Miyashiro J. et al., "Synthesis and SAR of novel tricyclicquinoxalinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)" Bioorg. Med. Chem. Lett. 19: 4050-4054 ​​(2009); Gandhi VB et al., "Discovery and SAR ofsubstituted3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose)polymerase(PARP) for the treatment of cancer." Bioorg.Med.Chem.Lett.20:1023-1026(2010); Penning TD et al., "Optimization of phenyl-substitutedbenzimidazole carboxamide poly(ADP-ribose)polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxa mide(A-966492) a highly potent and efficacious inhibitor." J. Med. Chem. 53: 3142-3153 (2010); Ye N.et al., "Design, Synthesis, and Biological Evaluation of a Series of Benzo[de]

[17] naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors." J. Med. Chem. 56:2885-2903 (2013); Patel M.R. et al., "Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors." J. Med. Chem. 57:5579-5601 (2014); 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 inhibitor Rucaparib", Karlberg T. et al.); Papeo G.M.E. 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-1 Inhibitor 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 ofnovel benzo[b][1 4]oxazin-3(4H)-ones as poly(ADP-ribose)polymeraseinhibitors." Bioorg. Med. Chem. Lett. 23:4501-4505 (2013). .

[0283] Figure 2FFFFF-2GGGGG Examples of PARP14 targeting ligands are shown, where R is the point of attachment of the linker.

[0284] Figure 2HHHHH Examples of PARP15 targeting ligands are shown, where R is the point of attachment of the linker.

[0285] Figure 2IIIII Examples of PDZ domain targeting ligands are shown, where R is the point of attachment of one or more linkers.

[0286] Figure 2JJJJJ Examples of phospholipase A2 domain targeting ligands are shown, where R is the point of attachment of the linker.

[0287] Figure 2KKKKK An example of a protein S100-A7 2WOS targeting ligand is shown, where R is the point of attachment of the linker.

[0288] Figure 2LLLLL-2MMMMM An example of a Saposin-B Targeting Ligand is shown, where R is the point of attachment of the linker.

[0289] Figure 2NNNNN-2OOOOO Examples of Sec7 targeting ligands are shown, where R is the point of attachment of the linker.

[0290] Figure 2PPPPP-2QQQQQ Examples of SH2 domain targeting ligands for pp60 Src are shown, where R is the point of attachment of the linker.

[0291] Figure 2RRRRR Examples of Tank1 targeting ligands are shown, where R is the point of attachment of the linker.

[0292] Figure 2SSSSS An example of a targeting ligand for the Ubc9 SUMO E2 ligase SF6D is shown, where R is the point of attachment of the linker.

[0293] Figure 2TTTTT Examples of Src targeting ligands are shown, including AP23464, where R is the point of attachment of the linker.

[0294] Figure 2UUUUU-2XXXXX Examples of Src-AS1 and / or Src AS2 targeting ligands are shown, where R is the point of attachment of the linker.

[0295] Figure 2YYYYY Examples of JAK3 targeting ligands, including tofacitinib, are shown, where R is the point of attachment of the linker.

[0296] Figure 2ZZZZZ Examples of ABL targeting ligands are shown, including tofacitinib and ponatinib, where R is the point of attachment of the linker.

[0297] Figures 3A-3B Examples of MEK1 targeting ligands are shown, including PD318088, trametinib, and G-573, where R is the point of attachment of the linker.

[0298] Figure 3C Examples of KIT targeting ligands, including regorafenib, are shown, where R is the point of attachment of the linker.

[0299] Figures 3D-3E Examples of HIV reverse transcriptase targeting ligands are shown, including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir, where R is the point of attachment of the linker.

[0300] Figures 3F-3G Examples of HIV protease targeting ligands are shown, including ritonavir, raltegravir, and atazanavir, where R is the point of attachment of the linker.

[0301] Figures 3H-3I Examples of KSR1 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0302] Figures 3J-3L Examples of CNNTB1 targeting ligands are shown, where R is the point of attachment of the linker.

[0303] Figure 3M Examples of BCL6 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0304] Figure 3N-3O Examples of PAK1 targeting ligands are shown, where R is the point of attachment of the linker.

[0305] Figure 3P-3R Examples of PAK4 targeting ligands are shown, where R is the point of attachment of the linker.

[0306] Figures 3S-3TExamples of TNIK Targeting Ligands are shown, where R is the point of attachment of the linker.

[0307] Figure 3U Examples of MEN1 targeting ligands are shown, where R is the point of attachment of the linker.

[0308] Figure 3V-3W Examples of ERK1 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0309] Figure 3X Examples of IDO1 Targeting Ligands are shown, where R is the point of attachment of the linker.

[0310] Figure 3Y Examples of CBP Targeting Ligands are shown, where R is the point of attachment of the linker.

[0311] Figure 3Z-3SSExamples of MCL1 Targeting Ligands are shown, where R is the point of attachment of the linker. 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 analysis of target proteins." J. Med. Chem. 56:9635-9645 (2013); Friberg A. et al., "Discovery of potentmyeloid structural cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods." andstructure-based design." J.Med.Chem.56:15-30(2013); Petros AM et al., "Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1protein." Bioorg.Med.Chem.Lett.24:1484-1488(2014); Burke JP et al., "Discovery of tricyclicindoles that potently inhibit mcl-1using fragment-based methods andstructure-based design." J. Med. Chem. 58: 3794-3805 (2015); Pelz NF 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 MC et al., “AMaltose-Binding Protein Fusion Construct Yields a Robust CrystallographyPlatform for MCL1.”Plos One 10:e0125010-e0125010(2015); Kotschy A et al., “The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538:477-482(2016); EP 2886545A1 titled “New thienopyrimidine derivatives a process for their preparation and pharmaceutical compositions containing them”; Jeffrey W. Johannes et al., “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors” ACS Med.Chem.Lett. (2017); DOI:10.1021 / acsmedchemlett.6b00464; Bruncko M. et al., “Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity.” J.Med.Chem. 58:2180-2194(2015); Taekyu Lee et al., “Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.” 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 that inhibit mcl-1 protein”; WO 2016207217A1, entitled “Preparation of new bicyclic derivatives as pro-apoptotic agents”; Gizem. et al., “Inhibition of Mcl-1 through covalentmodification of a noncatalytic lysine side chain” Nature Chemical Biology 12:931–936 (2016).

[0312] Figure 3TT Examples of ASH1L targeting ligands are shown, where R is the point of attachment of the linker. See, for example, crystal structure PDB 4YNM ("Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)" Rogawski DS et al.).

[0313] Figure 3UU-3WWExamples of ATAD2 targeting ligands are shown, where R is the point of attachment of a linker. For additional examples and related ligands, see Chaikuad A. et al., "Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain" MedChem Comm 5:1843-1848 (2014); Poncet-Montange G. et al., "Observed bromodomain flexibility reveals histone peptide-and small molecule ligand-compatible forms of ATAD2." Biochem. J. 466:337-346 (2015); Harner MJ et al., "Fragment-Based Screening of the Bromodomain of ATAD2." J. Med. Chem. 57:9687-9692 (2014); Demont E. H. et al., "Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors." J. Med. Chem. 58: 5649 (2015); and Bamborough P. et al., "Structure-BasedOptimization of Naphthyridones into Potent Atad2 Bromodomain Inhibitors." J. Med. Chem. 58: 6151 (2015).

[0314] Figure 3XX-3AAAExamples of BAZ2A and BAZ2B Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 4CUU ("Human Baz2B in Complex with Fragment-6N09645" Bradley A. et al.); crystal structure PDB 5CUA ("Second Bromodomain of Bromodomain Adjacent to Zinc Finger Domain Protein 2B (BAZ2B) in complex with 1-Acetyl-4-(4-hydroxyphenyl)piperazine". Bradley A. et al.); Ferguson, FM et al., "Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain." J. Med. Chem. 56:10183-10187 (2013); Marchand JR et al., "Derivatives of 3-Amino-2-methylpyridine as BAZ2BBromodomain 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." J. Med. Chem. 59:1410-1424 (2016).

[0315] Figure 3BBBExamples of BRD1 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 5AME ("the Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment4-Acetyl-Piperazin-2-One Pearce", N.M. et al.); crystal structure PDB 5AMF ("Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment Ethyl 4 56 7-Tetrahydro-1H-Indazole-5-Carboxylate", Pearce N.M. 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).

[0316] Figure 3CCC-3EEE Examples of BRD2 bromodomain 1 targeting ligands are shown, where R is the point of attachment of the linker. 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.

[0317] Figure 3FFF-3HHHExamples of BRD2 bromodomain 2 targeting ligands are shown, where R is the point of attachment of the linker. 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 KG et al., "RVX-208:an Inducer of ApoA-I in Humans is a BET Bromodomain Antagonist." PLoS One 8:e83190-e83190 (2013); Baud MG et al., "Chemical biology. Abump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes" Science 346:638-641 (2014); Baud MG 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); Gosmini R. et al., "The Discovery of I-Bet726 (Gsk1324726A) a Potent Tetrahydroquinoline Apoa1 Up-Regulator and Selective Bet Bromodomain Inhibitor" J. Med. Chem. 57: 8111 (2014); Crystal structure PDB 5EK9 ("Crystal structure of the second bromodomain of human BRD2 in complex with ahydroquinolinone inhibitor", Tallant C. et al.); Crystal structure PDB 5BT5; Crystal structure PDB 5dfd; Baud MGet 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). .

[0318] Figure 3III-3JJJ Examples of BRD4 bromodomain 1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 5WUU and crystal structure PDB 5F5Z.

[0319] Figure 3KKK-3LLL Examples of BRD4 bromodomain 2 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0320] Figure 3MMM Examples of BRDT targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 4flp and crystal structure PDB 4kcx.

[0321] Figure 3NNN-3QQQ Examples of BRD9 targeting ligands are shown, where R is the point of attachment of the linker. 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; and crystal structure PDB 5fp2.

[0322] Figure 3RRR Examples of SMARCA4 PB1 and / or SMARCA2 Targeting Ligands are shown, wherein R is the point of attachment of the linker, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0323] Figure 3SSS-3XXX Examples of other bromodomain targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Hewings et al., "35-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands." J. Med. Chem. 54, 6761-6770 (2011); Dawson et al., "Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia." Nature, 478, 529-533 (2011); US 2015 / 0256700; US 2015 / 0148342; WO 2015 / 074064; WO 2015 / 067770; WO 2015 / 022332; WO 2015 / 015318; and WO 2015 / 011084.

[0324] Figure 3YYY Examples of PB1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 3mb4; crystal structure PDB 4q0n; and, crystal structure PDB 5fh6.

[0325] Figure 3ZZZ Examples of SMARCA4 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure 3uvd and crystal structure 5dkd.

[0326] Figure 3AAAA Examples of SMARCA2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure 5dkc and crystal structure 5dkh.

[0327] Figure 3BBBB Examples of TRIM24 (TIF1a) and / or BRPF1 Targeting Ligands are shown, where R is the point of attachment of the linker and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0328] Figure 3CCCCAn example of a TRIM24 (TIF1a) targeting ligand is shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Palmer WS et al., "Structure-Guided Design of IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor." J. Med. Chem. 59: 1440-1454 (2016).

[0329] Figure 3DDDD-3FFFF Examples of BRPF1 targeting ligands are shown, wherein R is the point of attachment of the linker. 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.

[0330] Figure 3GGGG Examples of CECR2 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0331] Figure 3HHHH-3OOOOExamples of CREBBP Targeting Ligands are shown, wherein R is the point of attachment of the linker, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For additional examples and related ligands, see crystal structure PDB 3pld; crystal structure PDB 3svh; crystal structure PDB 4nr4; crystal structure PDB 4nr5; crystal structure PDB 4ts8; crystal structure PDB 4nr6; crystal structure PDB 4nr7; crystal structure PDB 4nyw; crystal structure PDB 4nyx; crystal structure PDB 4tqn; crystal structure PDB 5cgp; crystal structure PDB 5dbm; crystal structure PDB 5ep7; crystal structure PDB 5i83; crystal structure PDB 5i86; crystal structure PDB 5i89; crystal structure PDB 5i8g; crystal structure PDB 5j0d; crystal structure PDB 5ktu; crystal structure PDB 5ktw; crystal structure PDB 5ktx; crystal structure PDB 5tb6.

[0332] Figure 3 PPPP Examples of EP300 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 5BT3.

[0333] Figure 3QQQQ An example of a PCAF targeting ligand is shown, where R is the point of attachment of the linker. See, e.g., M. Ghizzoni et al., Bioorg. Med. Chem. 18:5826-5834 (2010).

[0334] Figure 3RRRR Examples of PHIP targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Mol Cancer Ther. 7(9):2621-2632 (2008).

[0335] Figure 3SSSS Examples of TAF1 and TAF1L targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Picaud S. et al., Sci Adv 2:e1600760-e1600760 (2016).

[0336] Figure 3TTTTShown are examples of histone deacetylase 2 (HDAC2) targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see Lauffer BEJ Biol. Chem. 288: 26926-26943 (2013); Wagner FF Bioorg. Med. Chem. 24: 4008-4015 (2016); Bressi J. C. Bioorg. Med. Chem. Lett. 20: 3142-3145 (2010); and Lauffer BEJ Biol. Chem. 288: 26926-26943 (2013).

[0337] Figure 3UUUU-3VVVV Shown are examples of histone deacetylase 4 (HDAC4) targeting ligands, where R is the point of attachment of a linker. For additional examples and related ligands, see Burli RWJ Med.Chem.56:9934 (2013); Luckhurst CAACS Med.Chem.Lett.7:34 (2016); Bottomley MJJ Biol.Chem.283:26694-26704 (2008).

[0338] Figure 3WWWW Examples of histone deacetylase 6 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Harding RJ (to be published); Hai Y. Nat. Chem. Biol. 12: 741-747, (2016); and Miyake Y. Nat. Chem. Biol. 12: 748 (2016).

[0339] Figure 3XXXX-3YYYY Examples of histone deacetylase 7 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0340] Figure 3ZZZZ-3DDDDDExamples of histone deacetylase 8 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Whitehead L. Biol. Med. Chem. 19: 4626-4634 (2011); Tabackman AA J Struct. Biol. 195: 373-378 (2016); Dowling DP Biochemistry 47, 13554-13563 (2008); Somoza JRB 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.ACSChem.Biol.9:2157-2164(2014);Somoza JRBiochemistry 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).

[0341] Figure 3EEEEE Shown are examples of histone acetyltransferase (KAT2B) targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see Chaikuad AJ Med. Chem. 59: 1648-1653 (2016); crystal structure PDB 1ZS5; and Zeng LJ Am. Chem. Soc. 127: 2376-2377 (2005).

[0342] Figure 3FFFFF-3GGGGG Shown are examples of histone acetyltransferase (KAT2A) targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see Ringel AE Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016).

[0343] Figure 3HHHHHShown are examples of histone acetyltransferase catalytic unit (HAT1) targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 2POW.

[0344] Figure 3IIIII An example of a cyclic AMP-dependent transcription factor (ATF2) targeting ligand is shown, where R is the point of attachment of the linker.

[0345] Figure 3JJJJJ An example of a Histone Acetyltransferase (KAT5) Targeting Ligand is shown, where R is the point of attachment of the linker.

[0346] Figure 3KKKKK-3MMMMM Examples of lysine-specific histone demethylase 1A (KDM1A) targeting ligands are shown, where R is the point of attachment of a linker. For additional examples and related ligands, see Mimasu S. Biochemistry 49: 6494-6503 (2010); Sartori LJ Med. Chem. 60: 1673-1693 (2017); and Vianello P. J. Med. Chem. 60: 1693-1715 (2017).

[0347] Figure 3NNNNN Examples of HDAC6 Zn finger domain targeting ligands are shown, where R is the point of attachment of the linker.

[0348] Figure 3OOOOO-3PPPPP An example of a general lysine methyltransferase targeting ligand is shown, where R is the point of attachment of the linker.

[0349] Figure 3QQQQQ-3TTTTT Examples of DOT1L targeting ligands are shown, wherein R is the point of attachment of the linker, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For additional examples and related ligands, see crystal structure PDB 5MVS ("Dot1Lin complex with adenosine and inhibitor CPD1" Be C. et al.); crystal structure PDB 5MW4 ("Dot1Lin complex inhibitor CPD7" Be C. et al.); crystal structure PDB 5DRT ("Dot1L in complex inhibitor CPD2" Be C. et al.); Be C. et al., ACS Med. Lett. 8:338-343 (2017); crystal structure PDB 5JUW "(Dot1L in complex with SS148" Yu W. et al., Structural Genomics Consortium).

[0350] Figure 3UUUUU Examples of EHMT1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 5TUZ ("EHMT1 in complex with inhibitor MS0124", Babault N. et al.).

[0351] Figure 3VVVVV Examples of EHMT2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 5TUY ("EHMT2 in complex with inhibitor MS0124", Babault N. et al.); PDB crystal structure 5TTF ("EHMT2 in complex with inhibitor MS012", Dong A. et al.); PDB crystal structure 3RJW (Dong A. et al., Structural Genomics Consortium); PDB crystal structure 3K5K; Liu F. et al., J. Med. Chem. 52:7950-7953 (2009); and, PDB crystal structure 4NVQ ("EHMT2 in complex with inhibitor A-366" Sweis RF et al.).

[0352] Figure 3WWWWW Examples of SETD2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5LSY ("SETD2 in complex with cyproheptadine", 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).

[0353] Figure 3XXXXX-3YYYYYExamples of SETD7 targeting ligands are shown, where R is the point of attachment of the linker. 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 J.R. et al., Structural Genomics Consortium); PDB crystal structure 3VUZ ("SETD7 in complex with AAM-1." Niwa H. et al.); PDB crystal structure 3VVO; and, Niwa H et al., Acta Crystallogr. Sect. D 69:595-602 (2013).

[0354] Figure 3ZZZZZ Examples of SETD8 targeting ligands are shown, where R is the point of attachment of the linker. 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.; to be published).

[0355] Figures 4A-4B Examples of SETDB1 targeting ligands are shown, where R is the point of attachment of a linker. For additional examples and related ligands, see PDB crystal structures 5KE2 ("SETDB1 in complex with inhibitor XST06472A", Iqbal A. et al.); PDB crystal structures 5KE3 ("SETDB1 in complex with fragment MRT0181a", Iqbal A. et al.); PDB crystal structures 5KH6 ("SETDB1 in complex with fragment methyl 3-(methylsulfonylamino)benzoate", Walker JR et al., Structural Genomics Consortium); and PDB crystal structures 5KCO ("SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide", Walker JR et al.).

[0356] Figures 4C-4P Examples of SMYD2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5KJK ("SMYD2 in complex with inhibitor AZ13450370", Cowen SD, etc.); PDB crystal structure 5KJM ("SMYD2 in complex with AZ931", Cowen SD, etc.); PDB crystal structure 5KJN ("SMYD2 in complex with AZ506", Cowen SD, etc.); PDB crystal structure 5ARF ("SMYD2 in complex with N-[3-(4-chlorophenyl)-1-{N'-cyano-N-[3-(difluoromethoxy)phenyl]carbamidoyl}-4 ...

[0357] 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-14-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide”, Ferguson AD et al.).

[0358] Figure 4Q-4RExamples of SMYD3 targeting ligands are shown, where R is the point of attachment of the linker. 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 with oxindole compound", Mitchell LH, et al.); and crystal structure 5CCM ("Crystal structure of SMYD3 with SAM and EPZ030456").

[0359] Figure 4S Examples of SUV4-20H1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5CPR ("SUV4-20H1 in complex with inhibitor A-196", Bromberg KD et al.).

[0360] Figure 4T-4AAExamples of wild-type androgen receptor targeting ligands are shown, where R is the point of attachment of the linker. 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-[[(1R2R)-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 SARMS-22”, Bohl CE 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 C.E. et al.); Bohl C.E. et al., Bioorg. Med. Chem. Lett. 18:5567-5570 (2008); PDB crystal structure 2PIP ("Androgen Receptor ligand binding domain in complex with small molecule", Estebanez-Perpina E. et al.); Estebanez-Perpina.E. Proc. Natl. Acad. Sci. 104:16074-16079 (2007); PDB crystal structure 2PNU ("Androgen Receptor ligand binding domain incomplex 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 MutantHuman Androgen Receptor(Ar(Ccr))Derived from an Androgen-Independent ProstateCancer." J. Med. Chem. 45:1439 (2002); Sack JS et al., "Crystallographic Structures of the ligand-binding domains of the androgen receptor and its T877Amutant complexed with the natural agonist dihydrotestosterone." Proc.Natl.Acad.Sci.98:4904-4909(2001); He B.et al., "Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance." Mol. Cell 16:425-438 (2004); Pereira de Jesus-Tran K. "Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity." Protein Sci. 15:987-999 (2006); Bohl C.E. et al., "Structural Basis for Accommodation of Nonsteroidal Ligands in the Androgen Receptor." Mol Pharmacol. 63(1):211-23 (2003); Sun C. et al., "Discovery of potent orally-active and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold." J. Med. Chem. 49:7596-7599 (2006); Nirschl A.A. et al., "N-aryl-oxazolidin-2-imines muscle selective androgen receptor modulators enhance potency through pharmacophore reorientation." J. Med. Chem. 52:2794-2798 (2009); Bohl C.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).

[0361] Figure 4BBAn example of a mutant T877A androgen receptor targeting ligand is shown, where R is the point of attachment of the linker. 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.).

[0362] Figure 4CC An example of a mutant W741L androgen receptor targeting ligand is shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4OJB ("Androgen Receptor T877A-AR-LBD", Hsu CL et al.).

[0363] Figure 4DD-4EE Examples of estrogen and / or androgen targeting ligands are shown, where R is the point of attachment of a linker.

[0364] Figure 5A The example of afatinib, a targeting ligand for EGFR and ErbB2 / 4 receptors, is shown. R is the point of attachment of the linker.

[0365] Figure 5B An example of axitinib (a targeting ligand for VEGFR1 / 2 / 3, PDGFRβ and Kit receptors) is shown. R is the point of attachment of the linker.

[0366] Figures 5C-5D An example is shown for Bosutinib, a targeting ligand for BCR-Abl, Src, Lyn and Hck receptors. R is the point of attachment of the linker.

[0367] Figure 5E An example of cabozantinib (a targeting ligand for RET, c-Met, VEGFR1 / 2 / 3, Kit, TrkB, Flt3, Axl and Tie2 receptors) is shown. R is the point of attachment of the linker.

[0368] Figure 5F An example is shown for Ceritinib, a targeting ligand for ALK, IGF-1R, InsR, and ROS1 receptors. R is the point of attachment of the linker.

[0369] Figure 5G The example of crizotinib, a targeting ligand for ALK, c-Met, HGFR, ROS1 and MST1R receptors is shown. R is the point of attachment of the linker.

[0370] Figure 5HAn example of dabrafenib, a targeting ligand for the B-Raf receptor, is shown. R is the point of attachment of the linker.

[0371] Figure 5I The example of dasatinib, a targeting ligand for BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2 and PDGFRβ receptors is shown. R is the point of attachment of the linker.

[0372] Figure 5J The example of Erlotinib, a targeting ligand for the EGFR receptor, is shown. R is the point of attachment of the linker.

[0373] Figures 5K-5M The example of everolimus (a targeting ligand for the HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor) is shown. R is the point of attachment of the linker.

[0374] Figure 5N The example of gefitinib, a targeting ligand for EGFR and PDGFR receptors, is shown. R is the point of attachment of the linker.

[0375] Figure 5O The example of ibrutinib, a targeting ligand for the BTK receptor, is shown. R is the point of attachment of the linker.

[0376] Figure 5P-5Q The example of imatinib, a targeting ligand for BCR-Abl, Kit and PDGFR receptors, is shown. R is the point of attachment of the linker.

[0377] Figure 5R-5S The example of lapatinib, a targeting ligand for EGFR and ErbB2 receptors, is shown. R is the point of attachment of the linker.

[0378] Figure 5T An example is shown for Lenvatinib, a targeting ligand for VEGFR1 / 2 / 3, FGFR1 / 2 / 3 / 4, PDGFRα, Kit, and RET receptors. R is the point of attachment of the linker.

[0379] Figure 5U-5V An example is shown for nilotinib, a targeting ligand for BCR-Abl, PDGRF and DDR1 receptors. R is the point of attachment of the linker.

[0380] Figure 5W-5X An example is shown for nintedanib, a targeting ligand for FGFR1 / 2 / 3, Flt3, Lck, PDGFRα / β, and VEGFR1 / 2 / 3 receptors. R is the point of attachment for the linker.

[0381] Figure 5Y-5ZAn example of palbociclib, a targeting ligand for the CDK4 / 6 receptor, is shown. R is the point of attachment of the linker.

[0382] Figure 5AA An example is shown for pazopanib, a targeting ligand for VEGFR1 / 2 / 3, PDGFRα / β, FGFR1 / 3, Kit, Lck, Fms, and Itk receptors. R is the point of attachment of the linker.

[0383] Figure 5BB-5CC The example of Ponatinib (a targeting ligand for BCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2 and Flt3 receptors) is shown. R is the point of attachment of the linker.

[0384] Figure 5DD An example is shown for regorafenib (a targeting ligand for VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα / β, RET, FGFR1 / 2, Tie2, and Eph2A). R is the point of attachment for the linker.

[0385] Figure 5EE An example of ruxolitinib, a targeting ligand for JAK1 / 2 receptors, is shown. R is the point of attachment of the linker.

[0386] Figures 5FF-5GG The example of sirolimus, a targeting ligand for the FKBP12 / mTOR receptor, is shown. R is the point of attachment of the linker.

[0387] Figure 5HH An example is shown for Sorafenib, a targeting ligand for B-Raf, CDK8, Kit, Flt3, RET, VEGFR1 / 2 / 3, and PDGFR receptors. R is the point of attachment for the linker.

[0388] Figures 5II-5JJ An example is shown for sunitinib (a targeting ligand for PDGFRα / β, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, RET). R is the point of attachment of the linker.

[0389] Figure 5KK-5LL An example of temsirolimus, a targeting ligand for FKBP12 / mTOR, is shown. R is the point of attachment of the linker.

[0390] Figure 5MM An example of tofacitinib, a targeting ligand for the JAK3 receptor, is shown. R is the point of attachment of the linker.

[0391] Figure 5NNAn example is shown for trametinib, a targeting ligand for the MEK1 / 2 receptor. R is the point of attachment of the linker.

[0392] Figure 5OO-5PP An example is shown for vandetanib, a targeting ligand for EGFR, VEGFR, RET, Tie2, Brk, and EphR. R is the point of attachment for the linker.

[0393] Figure 5QQ An example is shown for vemurafenib, a targeting ligand for A / B / C-Raf, KSR1 and B-Raf (V600E) receptors. R is the point of attachment of the linker.

[0394] Figure 5RR An example of Idelasib, a targeting ligand for the PI3Ka receptor, is shown. R is the point of attachment of the linker.

[0395] Figure 5SS An example of Buparlisib, a targeting ligand for the PI3Ka receptor, is shown. R is the point of attachment of the linker.

[0396] Figure 5TT An example of Taselisib, a targeting ligand for the PI3Ka receptor, is shown. R is the point of attachment of the linker.

[0397] Figure 5UU An example of Copanlisib, a targeting ligand for PI3Ka, is shown. R is the point of attachment of the linker.

[0398] Figure 5VV An example of Alpelisib (a targeting ligand for PI3Ka) is shown. R is the point of attachment of the linker.

[0399] Figure 5WW An example of niclosamide, a targeting ligand for CNNTB1, is shown. R is the point of attachment of the linker.

[0400] Figures 6A-6BExamples of targeting ligands for the BRD4 bromodomain of PCAF and GCN5 receptor 1 are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5tpx ("Discovery of a PCAF Bromodomain Chemical Probe"); Moustakim, M., et al., Angew. Chem. Int. Ed. Engl. 56:827 (2017); PDB crystal structure 5mlj ("Discovery of a Potent, Cell Penetrant, and Selective p300 / CBP-Associated Factor (PCAF) / General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe"); and, Humphreys, PG et al., J. Med. Chem. 60:695 (2017).

[0401] Figures 6C-6D Examples of G9a (EHMT2) targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structures 3k5k; ("Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysinemethyltransferase 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).

[0402] Figures 6E-6GExamples of EZH2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5ij8 ("Polycomb repressive complex 2 structure within inhibitor reveals a mechanism of activation and drug resistance"); Brooun, A. et al., Nat Commun 7:11384 (2016); PDB crystal structure 5ls6 ("Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas"); Vaswani, RG et al., J. Med. Chem. 59:9928 (2016); and, the PDB crystal structures 5ij8 and 5ls6.

[0403] Figures 6H-6I Examples of EED targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structures 5h15 and 5h19 ("Discovery and Molecular Basis of a DiverseSet of Polycomb Repressive Complex 2 Inhibitors Recognition by EED"); Li, L. et al., PLoS ONE 12:e0169855 (2017); and, PDB crystal structure 5h19.

[0404] Figure 6J An example of a KMT5A (SETD8) targeting ligand is shown, where R is the point of attachment of the linker. See, e.g., PDB crystal structure 5t5g.

[0405] Figures 6K-6LExamples of DOT1L targeting ligands are shown, where R is the point of attachment of the linker. 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., ACSMed. Chem. Lett. 7:735 (2016); PDB crystal structure 5dt2 (“Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach”) Approach"); and, Chen, C. et al., ACS Med. Chem. Lett. 7:735 (2016).

[0406] Figures 6M-6N Examples of PRMT3 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 3smq ("An allosteric inhibitor of protein argininemethyltransferase 3"); Siarheyeva, A. et al., Structure 20:1425 (2012); PDB crystal structure 4ryl ("A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein ArginineMethyltransferase 3 (PRMT3)"); and, Kaniskan, HU et al., Angew. Chem. Int. Ed. Engl. 54:5166 (2015).

[0407] Figure 6O Examples of CARM1 (PRMT4) targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0408] Figure 6P Examples of PRMT5 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4x61 and related ligands, described in "A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models". Chan-Penebre, E. Nat. Chem. Biol. 11: 432 (2015).

[0409] Figure 6Q Examples of PRMT6 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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).

[0410] Figure 6RExamples of LSD1 (KDM1A) targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0411] Figures 6S-6T Examples of KDM4 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0412] Figure 6UExamples of KDM5 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 3fun and related ligands, described in "Structural Analysis of Human Kdm5B Guides Histone Demethylase Inhibitor Development". Johansson, C. et al., Nat. Chem. Biol. 12: 539 (2016), and PDB crystal structure 5ceh and related ligands, described in "An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells". Vinogradova, M. et al., Nat. Chem. Biol. 12: 531 (2016).

[0413] Figure 6V-6W Examples of KDM6 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4ask and related ligands, described in "A Selective Jumonji H3K27Demethylase Inhibitor Modulates the Proinflammatory Macrophage Response". Kruidenier, L. et al., Nature 488:404 (2012).

[0414] Figure 6X An example of an L3MBTL3 targeting ligand is shown, where R is the point of attachment of the linker. See, e.g., PDB crystal structure 4f16.

[0415] Figure 6YExamples of Menin targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 4x5y and related ligands, described in "Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo" Borkin, D. et al., Cancer Cell 27:589 (2015), and PDB crystal structure 4og8 and related ligands, described in "High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction" He, S. et al., J. Med. Chem. 57:1543 (2014).

[0416] Figure 6Z-6AA Examples of HDAC6 targeting ligands are shown, where R is the point of attachment of the linker. See, for example, PDB crystal structures 5kh3 and 5eei.

[0417] Figure 6BB The example of HDAC7 targeting ligand is shown, wherein R is the connection point of joint.For other examples and related ligands, see PDB crystal structure 3c10 and related ligands, described in " Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. " Schuetz, A. et al., J.Biol.Chem.283:11355 (2008), and PDB crystal structure PDB 3zns and related ligands, described in " Selective Class Ia Histone Deacetylase Inhibition Via aNon-Chelating Zinc Binding Group ". Lobera, M. et al., Nat.Chem.Biol.9:319 (2013).

[0418] Figures 7A-7CExamples of protein tyrosine phosphatase, non-receptor type 1, PTP1B targeting ligands are shown, where R is the point of attachment of the linker. 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 structures 2azr and 2b07, described in "Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitor". inhibitors." Moretto, AF et al., Bioorg. Med. Chem. 14: 2162-2177 (2006); PDB crystal structures PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cmb, 2cmc, described 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); PDB crystal structures 2f6t and 2f6w, described in "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1Binhibitors".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 structures 2nt7, 2nta, described in "Probing acid replacements of thiophenePTP1B inhibitors." Wan, ZK et al., Bioorg. Med. Chem. Lett. 17:2913-2920 (2007); and, WO2008148744 A1 assigned to Novartis AG, entitled "Thiadiazole derivatives as antidiabeticagents." See also, PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 118g, 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). .

[0419] Figure 7D Examples of tyrosine protein phosphatase non-receptor type 11, SHP2 targeting ligands are shown, where R is the point of attachment of a linker. For additional examples and related ligands, see crystal structures PDB 4pvg and 305x, described in "Salicylicacid based small molecule inhibitor for the oncogenic Src homology-2domaincontaining protein tyrosine phosphatase-2 (SHP2)." Zhang, X. et al., J. Med. Chem. 53: 2482-2493 (2010); and, crystal structure PDB 5ehr and related ligands, described in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." Garcia Fortanet, J. et al., J. Med. Chem. 59: 7773-7782 (2016). See also, crystal structure PDB 5ehr, described in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." GarciaFortanet, 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).

[0420] Figure 7E Examples of non-receptor type 22 targeting ligands for tyrosine protein phosphatases are shown, where R is the point of attachment of the linker. 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).

[0421] Figure 7F Examples of targeting ligands for the scavenger mRNA decapping enzyme DcpS are shown, where R is the point of attachment of the linker. 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 spinal muscular atrophy." Singh, J. et al., ACS Chem. Biol. 3:711-722 (2008).

[0422] Figures 8A-8SExamples of BRD4 bromodomain 1 targeting ligands are shown, where R is the point of attachment of the linker. 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 3u51; crystal structure PDB 3zyu and related ligands, described in Dawson, MA et al., “Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for M11-Fusion Leukaemia.” Nature 478: 529 (2011); crystal structure PDB 4bw1 and related ligands, 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, described in Fish, PV et al., “Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of afragment-derived hit.” J. Med. Chem. 55:9831-9837 (2012); crystal structure PDB 4clb and related ligands, described in Atkinson, SJ 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, described in Zhang, G. et al., “Down-regulation of NF-{kappa}B Transcriptional Activityin HIV-associated Kidney Disease by BRD4 Inhibition.” J.Biol.Chem.287:28840-28851 (2012); crystal structure PDB 4hxl and related ligands, described in Zhao, L. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4Bromodomain.” J.Med.Chem.56:3833-3851 (2013); crystal structure PDB 4hxs and related ligands, described in Zhao, L. et al., “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitorsof the Histone Reader BRD4 Bromodomain." J. Med. Chem. 56: 3833-3851 (2013); crystal structure PDB 4lrg and related ligands, 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, 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); crystal structures PDB 4nr8 and PDB 4c77 and related ligands, described in Ember, SW et al., "Acetyl-lysine Binding Site of Bromodomain-Containing Protein4(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." 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 Protein 9 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); crystal structure PDB 4wiv and related ligands are described in McKeown, MRet al., “Biased multicomponent reactions to develop novel bromodomain inhibitors.” J. Med. Chem. 57: 9019-9027 (2014); crystal structure PDB 4x2i and related ligands, described in Taylor, AM et al., “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.” ACS Med. Chem. Lett. 7: 145-150 (2016); 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, 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 4z1q and related ligands, described in Taylor, AM "Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains." ACS Med. 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, described in Bamborough, P."Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain 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, EL 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, 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, 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, described in Kharenko, O.A. et al., "RVX-297-anovel 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, described in Albrecht, BK et al., "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, 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-terminal domain (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 the treatment of cancer", assigned to Boehringer Ingelheim International GmbH, Germany; and WO 2011143669 A2, entitled "Azolodiazepine derivatives and their preparation, compositions and methods for treating neoplasia, inflammatory disease and other disorders” and transferred it to Dana-Farber Cancer Institute, Inc, USA.

[0423] Figure 8T-8VExamples of ALK targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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); crystal structures PDB 2yfx, 4ccb, 4ccu and 4cd0snd 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, described in Johnson, TW et al., "Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetra hydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetra decine-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 PDB4fny and related ligands, 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, described in Bryan, MC et al., "Rapid development ofpiperidine carboxamides as potent and selective anaplastic lymphoma kinaseinhibitors." J. Med. Chem. 55:1698-1705 (2012); crystal structure PDB 4joa and related ligands, described in Gummadi, VR et al., "Discovery of 7-azaindole based anaplastic lymphoma kinase(ALK)inhibitors:wild type and mutant(L1196M)active compounds with uniquebinding mode." (2013) Bioorg. Med. Chem. Lett. 23:4911-4918; and, crystal structure PDB 5iui and related ligands, described in Tu, CH et al., "Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes ofAnaplastic Lymphoma Kinase(ALK)." J.Med.Chem.59:3906-3919(2016).

[0424] Figures 8W-8XExamples of BTK Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see, 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); 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, 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, described in Kuglstatter, A. et al., "Insights into the conformational flexibility of Bruton's tyrosinekinase from multiple ligand complex structures." Protein Sci.20:428-436 (2011); and, crystal structure PDB 3pij and related ligands, described in Bujacz, A. et al., "Crystal structures of theapo form of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose." Febs J. 278:1728-1744 (2011). .

[0425] Figure 8Y Examples of FLT3 targeting ligands are shown, where R is the point of attachment of a linker. 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).

[0426] Figure 8Z-8AA Examples of TNIK targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0427] Figure 8BB-8CCExamples of NTRK1, NTRK2, and NTRK3 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 4aoj and related ligands, described in Wang, T. et al., "Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as PotentTrk Inhibitors." ACS Med. Chem. Lett. 3:705 (2012); 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); 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, described in Bertrand, T. et al., “The Crystal Structures of Trka and Trkb Suggest Key Regions for Achieving Selective Inhibition.” J. Mol. Biol. 423: 439 (2012); and, crystal structures PDB 3v5q and 4ymj and related ligands, described in Albaugh, P. et al., “Discovery of GNF-5837, a selective TRK Inhibitor with efficacy in rodent cancer tumor models.” ACS Med. Chem. Lett. 3: 140–145 (2012) and Choi, HSetc., “(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med Chem Lett 6:562-567 (2015).

[0428] Figure 8DD-8EEThe example of FGFR1 targeting ligand is shown, wherein R is the connection point of joint.For other example and related ligand, referring to crystal structure PDB 3tto and 2fgi and related ligand, be described in Brison, Y. etc., " Functional and structural characterization of alpha-(1-2) branching sucrase derived from DSR-Eglucansucrase. " J.Biol.Chem.287:7915-7924 ​​(2012) and Mohammadi, M. etc., " Crystal structure of an angiogenesis inhibitor bound to the FGFreceptor tyrosine kinase domain. " EMBO J.17:5896-5904 (1998);Crystal structure PDB 4fb3;Crystal structure PDB 4rwk and related ligand, be described in Harrison, C. etc., " Polyomavirus large Tantigen binds symmetrical repeats at the viral origin in an asymmetrical manner." J. Virol. 87: 13751-13759 (2013); crystal structure PDB 4rwl and related ligands, 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, 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 PDB5ew8 and related ligands, described in Patani, H. et al., “Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.” Oncotarget 7:24252-24268 (2016). .

[0429] Figure 8FF Examples of FGFR2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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).

[0430] Figure 8GG The example of FGFR4 targeting ligand is shown, wherein R is the connection point of joint.For other examples and related ligands, see crystal structure PDB 4tyi and related ligands, described in Lesca, E. et al., " Structural analysis of the human fibroblast growth factor receptor 4 kinase." J.Mol.Biol.426:3744-3756 (2014).

[0431] Figure 8HH-8IIExamples of MET Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 3qti and 3zcl; crystal structures PDB 4xmo, 4xyf and 3zcl and related ligands, 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-ray crystallographic analysis,and biological activities." J. Med. Chem. 51:5330-5341 (2008); crystal structure PDB 2rfn and related ligands, described in Bellon, SF et al., "c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations." J. Biol. Chem. 283:2675-2683 (2008); and, crystal structure PDB 5dg5 and related ligands, 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). .

[0432] Figure 8JJExamples of JAK1 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 4ivd and related ligands, described in Zak, M. et al., "Identification of C-2Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2." J. Med. Chem. 56:4764-4785 (2013); crystal structure PDB 5e1e and related ligands, described in Vasbinder, MM et al., "Identification of azabenzimidazoles as potent JAK1 selective inhibitors." Bioorg. Med. Chem. Lett. 26:60-67 (2016); crystal structure PDB 5hx8 and related ligands, described in Simov, V., et al., "Structure-based design and development of (benz)imidazolepyridones as JAK1-selective kinase inhibitors." Bioorg. Med. Chem. Lett. 26: 1803-1808 (2016); crystal structure PDB 5hx8 and related ligands, 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 JAK1 selective kinase inhibitor AZD4205", AACR National Meeting, April 2017.

[0433] Figure 8KK-8LLExamples of JAK2 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 3ugc and related ligands, described in Andraos, R. et al., "Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent." Cancer Discov 2:512-523 (2012); 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); 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 structures PDB 4ytf, 4yth and 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 structures 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 JAK2 inhibitors." Bioorg.Med.Chem. Lett. 23: 5014-5021 (2013); and, crystal structures PDB 3io7 and 3iok and related ligands, described in Schenkel, LB et al., "Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors." J. Med. Chem. 54: 8440-8450 (2011).

[0434] Figure 8MM Examples of JAK3 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 3zc6 and related ligands, described in Lynch, SM et al., "Strategic Use ofConformational Bias and Structure Based Design to Identify Potent Jak3Inhibitors 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 VivoModels." J. Med. Chem. 56:345-356 (2013) and Jaime-Figueroa, S. et al., "Discovery of aseries of novel5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers,as potent JAK3kinase inhibitors." Bioorg. Med. Chem. Lett. 23:2522-2526 (2013).

[0435] Figures 8NN-8OOExamples of KIT targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 1t46 and related ligands, described in Mol, CD et al., "Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase." J. Biol. Chem. 279: 31655-31663 (2004); and, 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).

[0436] Figure 8PP-8VVExamples of EGFR Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 5hcy, 4rj4, and 5cav; Heald, R., “Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study”, J. Med. Chem. 58, 8877–8895 (2015); Hanano, 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" Nature 534,129(2016); Ward, RA "Structure-and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factorreceptor(EGFR)"J.Med.Chem.56,7025-7048(2013); crystal structure PDB 4zau and related ligands, 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, 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, described in Zhou, W. et al., “Novel mutant-selective EGFR kinase inhibitors against EGFR T790M” Nature 462(7276), 1070–1074(2009); crystal structure see PDB5feq 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, 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, 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 PDB 5hg7 and related ligands, described in Cheng, H." Discovery of1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyr rolo[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, 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 the related 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).

[0437] Figure 8WW-8XXExamples of PAK1 targeting ligands are shown, where R is the point of attachment of the linker. 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 ChemLett. 22; 6(7): 776-81 (2015).

[0438] Figure 8YY Examples of PAK4 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0439] Figure 8ZZ-8AAAExamples of IDO targeting ligands are shown, where R is the point of attachment of the linker. 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, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy" Abstract 491, AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC; and, WO2012142237, entitled “Fusedimidazole derivatives useful as IDO inhibitors”.

[0440] Figure 8BBB-8EEEExamples of ERK1 and ERK2 targeting ligands are shown, where R is the point of attachment of a linker. For further examples and related ligands, see crystal structures PDB 5K4I and 5K4J and 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); 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, 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, 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, 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, described by 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 potent antitumor activities in cancer models with MAPK pathway alterations.” AACR National Meeting 2017; Crystal structures PDB 3FHR and 3FXH and related ligands, described in Cheng, R. et al., “High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand” Protein Sci. 19:168-173 (2010); crystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and 5NHV, and related ligands, described in Ward, RA et al., “Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1 / 2 from a Modestly Active and Promiscuous Chemical Start Point.” J. Med. Chem. 60, 3438–3450 (2017); and, crystal structures PDB 3SHE and 3R1N, and related ligands, 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)。

[0441] Figure 8FFF-8IIIExamples of ABL1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 1fpu and 2e2b and related ligands, described in Schindler, T. et al., "Structural mechanism for STI-571 inhibition of abelson tyrosine kinase", Science 289:1938-1942 (2000); and Horio, T. et al., "Structural factors contributing to the Abl / Lyn dual inhibitory activity of 3-substituted benzamide derivatives", Bioorg. Med. Chem. Lett. 17:2712-2717 (2007); crystal structures PDB 2hzn and 2hiw and related ligands, described in Cowan-Jacob, SW et al., "Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia", Acta Crystallog. Sect. D 63:80-93 (2007) and Okram, B. et al., “A general strategy for creating”, Chem. Biol. 13:779-786 (2006); 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); 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 kinase agonists 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 structures PDB 3qri and 3qrk and related ligands are described in Chan, WW et al., “Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”, Cancer Cell 19:556-568 (2011); crystal structures PDB 5hu9 and 2f4j and related ligands, described in Liu, F. et al., “Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”, Oncotarget 7:45562-45574 (2016) and 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 structures PDB 2gqg and 2qoh and related ligands, 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); 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); 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); crystal structures PDB 3dk3 and 3dk8 and related ligands, described in Berkholz, DSet al., “Catalytic cycle of human glutathione reductase near 1A resolution” J. Mol. Biol. 382: 371-384 (2008); crystal structure PDB 3ue4 and related ligands, described in Levinson, NM et al., “Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain”, PLoS One 7: e29828-e29828 (2012); crystal structure PDB 4cy8 and related ligands, described in Jensen, CN et al. “Structures of the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl3-Monooxygenase (Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution”, Chembiochem 16: 968 (2015); crystal structure PDB 2hz0 and related ligands, described in Cowan-Jacob, SW et al., "Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia", Acta Crystallogr D Biol Crystallogr.63(Pt 1):80-93(2007); crystal structure PDB 3pyy and related ligands, described in Yang, J. et al., "Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl KinaseActivator that Binds to the Myristoyl Binding Site", Chem.Biol.18:177-186(2011); and, crystal structure PDB 5k5v and related ligands, described in Kim, MK, et al., "Structural basis for dual specificity of yeast N-terminal amidase in the N-end rule pathway", Proc.Natl.Acad.Sci.USA113:12438-12443 (2016). .

[0442] Figure 8JJJ Examples of ABL2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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); 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 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.

[0443] Figure 8KKK-8MMMExamples of AKT1 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Lippa, B. et al., “Synthesis and structure based optimization of novel Akt inhibitors Bioorg. Med. Chem. Lett. 18:3359-3363 (2008); Freeman-Cook, 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 That Restricts Phosphatase Accessibility of Akt", Sci.Signal.5:ra37-ra37(2012); Addie, M. et al., "Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide(AZD5363),an Orally Bioavailable,Potent Inhibitor of AktKinases", J. Med. Chem. 56: 2059-2073 (2013); Wu, WI, et al., "Crystal structure of humanAKT1 with an allosteric inhibitor reveals a new mode of kinaseinhibition. 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).

[0444] Figure 8NNN-8OOOExamples of AKT2 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structures PDB 2jdo and 2jdr and related ligands described in Davies, TG et al., “AStructural 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-Carboxamidase B”. Selective, Orally Active Inhibitors of Protein Kinase B (Akt)", J. Med. Chem. 53: 2239d (2010); crystal structure PDB 3d03 and related ligands, described in Hadler, KS et al., "Substrate-promoted formation of a catalytically competent binuclear center and regulation of reactivity in a glycerophosphodiesterase from Enterobacter aerogenes', J. Am. Chem. Soc. 130: 14129-14138 (2008); and, crystal structures PDB 3e87, 3e8d and 3e88 and related ligands, described in Rouse, MB et al., "Aminofurazans as potent inhibitors of AKT kinase" Bioorg. Med. Chem. Lett. 19: 1508-1511 (2009).

[0445] Figure 8 PPPExamples of BMX targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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 x chromosome: a Tec family kinase", Chem. Biol. Drug Des. 78: 739-748 (2011).

[0446] Figure 8QQQ-8SSSExamples of CSF1R Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 2i0v and 2i1m and related ligands, described in Schubert, C. et al., "Crystal structure of the tyrosine kinase domain of colony-stimulatingfactor-1 receptor (cFMS) in complex with two inhibitors", J. Biol. Chem. 282: 4094-4101 (2007); 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); crystal structure PDB 3dpk and related ligands, described in MT, McKay, DB Overgaard, "Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon", to be published; 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-pipe ridinyl]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); 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); 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, crystal structure PDB4r7i and related ligands, described in Tap, WD et al., “Structure-Guided Blockade of CSF1R Kinasein Tenosynovial Giant-Cell Tumor”, N Engl J Med 373:428-437 (2015).

[0447] Figure 8TTT Examples of CSK targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Levinson, NM et al., "Structural basis for the recognition of c-Src bys inactivator Csk", Cell 134: 124-134 (2008).

[0448] Figure 8UUU-8YYYExamples of DDR1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structures PDB 3zos and 4bkj and related ligands, described in Canning, P. et al., "Structural Mechanisms Determining Inhibition of the Collagen Receptor Ddr1by Selective and Multi-Targeted Type II Kinase Inhibitors", J. Mol. Biol. 426: 2457 (2014); 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); crystal structures PDB 5bvk, 5bvn and 5bvw and related ligands, described in Murray, CW et al., "Fragment-Based Discovery of Potent and Selective DDR1 / 2Inhibitors", ACSMed.Chem.Lett.6:798-803 (2015); crystal structure PDB 5fdp and related ligands, described in Wang, Z. et al., "Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors", J. Med. Chem. 59:5911-5916 (2016); and, crystal structure PDB 5fdx and related ligands, described in Bartual, SG et al., "Structure of DDR1 receptor tyrosine kinase in complex with D2164 inhibitor at 2.65 Angstroms resolution", to be published.

[0449] Figure 8ZZZ-8CCCCExamples of EPHA2 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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); 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, 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).

[0450] Figure 8DDDD-8FFFFExamples of EPHA3 Targeting Ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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); 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); crystal structure PDB 4gk3 and related ligands, described in Lafleur, K. et al., “Optimization of Inhibitors of the Tyrosine Kinase EphB4.2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography”, J. Med. Chem. 56:84-96 (2013). Binding 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 / 2andII Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and inVivo Validation”, J. Med. Chem. 57: 6834-6844 (2014); Crystal structure PDB 4p5z and related ligands are described in Unzue, A.et al., “Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2and IIEph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation”, J. Med. Chem. 57: 6834-6844 (2014); 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 III inhibitors to Eph Tyrosine Kinases”, ACS Med. Chem. Lett. 6: 79-83 (2015); 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.

[0451] Figure 8GGGG Examples of EPHA4 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 2y60 and related ligands described in Clifton, IJ et al., "The Crystal Struture of Isopenicillin NSynthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals Thioether Coordination to Iron", Arch. Biochem. Biophys. 516: 103 (2011) and crystal structure PDB 2xyu and related ligands described in Van Linden, OP et al., "Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase", Eur. J. Med. Chem. 47: 493 (2012).

[0452] Figure 8HHHHExamples of EPHA7 targeting ligands are shown, where R is the point of attachment of the linker. 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-areceptor 7 (epha7) in complex with ALW-II-49-7," to be published.

[0453] Figure 8III-8LLLLExamples of EPHB4 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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 Optimisation of 3,5-Bis Substituted Anilinopyrimidines", Bioorg. Med. Chem. Lett. 18: 5717 (2008); 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); 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 EphbTyrosine 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 V600E Selective 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 Optimisation of 3,5-Bis Substituted Anilinopyrimidines”, Bioorg. Med. Chem. Lett. 18:5717 (2008); and, crystal structure PDB 2vxo and related ligands, described in Welin, M. et al., “Substrate Specificity and Oligomerization of Human Gmp Synthetas”, J. Mol. Biol. 425:4323 (2013).

[0454] Figure 8MMMMExamples of ERBB2 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0455] Figure 8NNNN Examples of ERBB3 targeting ligands are shown, where R is the point of attachment of the linker. 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).

[0456] Figure 8OOOOExamples of ERBB4 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Qiu, C. et al., "Mechanism of Activation and Inhibition of the HER4 / ErbB4 Kinase", Structure 16:460-467 (2008), and Wood, E.R. et al., "6-Ethynylthieno[3,2-d]- and 6-Ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases", Proc. Natl. Acad. Sci. Usa 105:2773-2778 (2008).

[0457] Figure 8PPPP-8QQQQ Examples of FES targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Filippakopoulos, P. et al., "Structural Coupling of SH2-KinaseDomains 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-FesProtein-Tyrosine Kinase", Chem. Biol. 19:529-540 (2012).

[0458] Figure 8RRRR Examples of FYN targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Kinoshita, T. et al., “Structure of human Fyn kinase domain complexed with staurosporine”, Biochem. Biophys. Res. Commun. 346:840-844 (2006).

[0459] Figure 8SSSS-8VVVVAn example of a GSG2 (Haspin) Targeting Ligand is shown, where R is the point of attachment of the linker. 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 a pyrazolo-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 in ERK1 / 2 is associated with slow binding kinetics,” Nat. Chem. Biol. 10:853-860 (2014).

[0460] Figure 8WWWW-8AAAAAExamples of HCK targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see 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); crystal structures PDB 2c0i and 2c0t and related ligands, described in Burchat, A. et al., "Discovery of A-770041, a Src-Family Selective Orally Active LckInhibitor that Prevents Organ Allograft Rejection", Bioorg. Med. Chem. Lett. 16:118 (2006); 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 inhibitor screening using the fluorescent ligand SKF86002", Acta Crystallogr., Sect. D 70: 392-404 (2014).

[0461] Figure 8BBBBB-8FFFFFThe example of IGF1R targeting ligand is shown, wherein R is the connection point of joint.For other 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, described in Sampognaro, AJ et al., “Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase”, Bioorg. Med. Chem. Lett. 20: 5027-5030 (2010); crystal structure PDB 3qqu and related ligands, 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 Kinase Inhibitors to Explore a Mek Resistance Hypothesis”. J. Med. Chem. 58: 2834 (2015); Crystal structure PDB 3fxq and related ligands, described in Monferrer, D. et al., “Structural studies on the full-length LysR-type regulator TsaR from Comamonas testosteroni T-2 reveal a novel open conformation of the tetrameric LTTR fold”, Mol. Microbiol. 75: 1199-1214 (2010); Crystal structure PDB 5fxs and related ligands, described in Degorce, S. et al., “Discovery of Azd9362, a Potent Selective Orally Bioavailable and Efficacious Novel Inhibitor 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, 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, 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, described in Stauffer, F. et al., “Identification of a5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimid ine series of IGF-1R inhibitors”, Bioorg.Med.Chem.Lett.26:2065-2067(2016).

[0462] Figure 8GGGGG-8JJJJJExamples of INSR Targeting Ligands are shown, where R is the point of attachment of the linker. 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 kinase inhibitors towards JNK selectivity", Bioorg. Med. Chem. Lett. 19: 360-364 (2009); crystal structure PDB 5e1s and related ligands, 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, 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); 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]pyrimid ineseries of IGF-1R inhibitors”, Bioorg. Med. Chem. Lett. 26:2065-2067 (2016); and, crystal structure PDB 4ibm and related ligands are described in Anastassiadis, T. et al., “A highly selective dualinsulin receptor(IR) / insulin-like growth factor 1receptor(IGF-1R)inhibitorderived from an extracellular signal-regulated kinase(ERK)inhibitor”, J.Biol.Chem.288:28068-28077(2013).

[0463] Figure 8KKKKK-8PPPPPExamples of HBV targeting ligands are shown, where R is the point of attachment of the linker, 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, SJ; Zlotnick, A. “BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly.” J. Mol. Recognit. 19, 542-548 (2006); Stray, SJ et al., “Heteroaryl dihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly." Proc. Natl. Acad. Sci. USA, 102, 8138-8143 (2005); Guan, H. et al., "Thenovel 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 aryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors.” J. Med. Chem. 59, 7651 - 7666(2016); Zhu, X. et al., “2,4 - Diaryl - 4,6,7,8 - tetrahydroquinazolin - 5(1H) - one derivatives as anti - HBV agents targeting at capsid assembly.” Bioorg. Med. Chem. Lett. 20, 299 - 301(2010); Campagna, M. R. et al., “Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J. Virol. 87, 6931 - 6942(2013); Campagna, M. R.; et al., “Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J. Virol. 87, 6931 - 6942(2013); WO 2013096744A1, titled “Hepatitis B antiviral agents”; WO 2015138895, titled “Hepatitis B core protein allosteric modulators”; Wang, Y. J. et al., “A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome - free capsid formation.” Antimicrob. Agents Chemother. 59, 7061 - 7072(2015); WO 2014033167, titled “Fused bicyclic sulfamoyl derivatives for the treatment of hepatitis”; U.S.20150132258, titled "Azepanederivatives and methods of treating hepatitis B infections"; and, WO 2015057945, "Hepatitis B viral assembly effector". .

[0464] Figure 9 A dendrogram of the human bromodomain family of proteins, divided into eight subfamilies, involved in epigenetic signaling and chromatin biology. Figure 9 Any protein of the bromodomain family in the genus Br can be selected as a target protein according to the present invention.

[0465] Figure 10 Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI. DETAILED DESCRIPTION

[0466] I. Definition

[0467] 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.

[0468] 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 (e.g., rotamers); as if each were specifically described unless the context clearly excludes it.

[0469] The terms "a" and "an" do not represent a limitation on quantity, but rather represent the presence of at least one of the referenced items. The term "or" means "and / or". Unless otherwise stated herein, the recording of a numerical range is intended only to serve as a shorthand method of referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually stated herein. The endpoints of all ranges are included within the range and can be independently combined. Unless otherwise expressly stated herein or clearly contradicted by the context, all methods described herein can be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is intended only to better illustrate the present invention, rather than to limit the scope of the present invention.

[0470] The present invention includes compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII having at least one desired isotopic substitution of an atom and an isotopic content greater than the natural abundance of that 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.

[0471] Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 In one non-limiting embodiment, isotope-labeled compounds can be used for metabolic studies (e.g., 14 C), reaction kinetic studies (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 determinations, or radiation therapy for patients. In particular, for PET or SPECT studies, 18 F-labeled compounds may be particularly desirable. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or the procedures disclosed in the Examples and Preparations described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0472] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope at any target position is enriched at 90%, 95% or 99% or more. In a non-limiting embodiment, at the desired position, deuterium is enriched at 90%, 95% or 99%.

[0473] In a non-limiting embodiment, deuterium atom substitution for a hydrogen atom can be provided in any compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII.

[0474] In one non-limiting embodiment, the replacement of a hydrogen atom by a deuterium atom occurs in one or more groups selected from any R or variable, linker, and targeting ligand described herein. For example, when any group is, or comprises, for example, by substitution, a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon atom may be deuterated.

[0475] 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 in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. The solvate can be in liquid or solid form.

[0476] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the carbonyl (C=O) group.

[0477] "Alkyl" is a saturated aliphatic hydrocarbon group that is branched or straight. 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 C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, a specified range means that the alkyl group with each member within the range is described as an independent species. For example, the term C1-C6 alkyl as used herein means a straight or branched alkyl group with 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that each of these is described as an independent species, and therefore, each subset is considered to be disclosed separately. For example, the term C1-C4 alkyl as used herein means a straight or branched alkyl group with 1, 2, 3, or 4 carbon atoms, and is intended to mean that each of them is described as an independent species. Examples of alkyl groups 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. In another embodiment, the alkyl group is optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when the term used includes "alk", then "cycloalkyl" or "carbocycle" may be considered part of the definition unless the context clearly excludes it. For example, but not limited to, the terms alkyl, alkoxy, haloalkyl, etc. may all be considered to include cyclic forms of alkyl groups unless the context clearly excludes it.

[0478] In one embodiment, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

[0479] In one embodiment, an "alkyl" group has one carbon.

[0480] In one embodiment, an "alkyl" group has two carbons.

[0481] In one embodiment, an "alkyl" group has three carbons.

[0482] In one embodiment, an "alkyl" group has four carbons.

[0483] In one embodiment, an "alkyl" group has five carbons.

[0484] In one embodiment, an "alkyl" group has six carbons.

[0485] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0486] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0487] Other non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0488] Other non-limiting examples of "alkyl" include tert-butyl, tert-amyl, and tert-hexyl.

[0489] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0490] In another embodiment, the "alkyl" group is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0491] In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0492] In one embodiment, a "cycloalkyl" group has three carbons.

[0493] In one embodiment, a "cycloalkyl" group has four carbons.

[0494] In one embodiment, a "cycloalkyl" group has five carbons.

[0495] In one embodiment, a "cycloalkyl" group has six carbons.

[0496] In one embodiment, a "cycloalkyl" group has seven carbons.

[0497] In one embodiment, a "cycloalkyl" group has eight carbons.

[0498] In one embodiment, a "cycloalkyl" group has nine carbons.

[0499] In one embodiment, a "cycloalkyl" group has ten carbons.

[0500] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0501] Other non-limiting examples of "cycloalkyl" include indane and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0502] For example: is a "cycloalkyl" group.

[0503] However, is an "aryl" group.

[0504] In another embodiment, "cycloalkyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0505] "Alkenyl" is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at stable points along the chain. As used herein, a specified range means that the alkenyl group with each member within the range is described as an independent species, as described above for the alkyl portion. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. In another embodiment, alkenyl is optionally substituted. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation. In another embodiment, "alkenyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0506] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group with one or more carbon-carbon triple bonds, which can occur at any stable point along the chain. As used herein, a specified range represents an alkynyl group with each member within the range described as an independent substance, 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. In another embodiment, alkynyl is optionally substituted. The term "alkynyl" also encompasses cycloalkyl or carbocyclic groups with at least one triple bond. In another embodiment, "alkynyl" is "optionally substituted" by 1, 2, 3, or 4 substituents.

[0507] "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 C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, or C1-C6 alkylene.

[0508] "Alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylene can be, for example, a 2 to 8 carbon moiety, a 2 to 6 carbon moiety, or a specified number of carbon atoms, such as C2-C4 alkenylene.

[0509] "Alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylene can be, for example, 2 to 8 carbon moieties, 2 to 6 carbon moieties, or a specified number of carbon atoms, such as C2-C4 alkynylene.

[0510] "Halo" and "halogen" refer to fluoro, chloro, bromo or iodo.

[0511] "Haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the above-mentioned halogen atoms, up to the maximum permissible 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 with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0512] In one embodiment, "haloalkyl" is C1-C 10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

[0513] In one embodiment, a "haloalkyl" group has one carbon.

[0514] In one embodiment, a "haloalkyl" group has one carbon and one halogen.

[0515] In one embodiment, a "haloalkyl" group has one carbon and two halogens.

[0516] In one embodiment, a "haloalkyl" group has one carbon and three halogens.

[0517] In one embodiment, a "haloalkyl" group has two carbons.

[0518] In one embodiment, a "haloalkyl" group has three carbons.

[0519] In one embodiment, a "haloalkyl" group has four carbons.

[0520] In one embodiment, a "haloalkyl" group has five carbons.

[0521] In one embodiment, a "haloalkyl" group has six carbons.

[0522] Non-limiting examples of "haloalkyl" include:

[0523] Other non-limiting examples of "haloalkyl" include:

[0524] Other non-limiting examples of "haloalkyl" include:

[0525] Other non-limiting examples of "haloalkyl" include:

[0526] "Chain" refers to a linear chain, and all other chains (long or short or both) can be considered as side chains of the linear chain. In the case where two or more chains can be equivalently considered as the main chain, "chain" refers to the chain that makes the simplest representation of the molecule.

[0527] "Haloalkoxy" means a haloalkyl group as defined herein attached through an oxygen bridge (the oxygen of the alcohol group).

[0528] "Heterocycloalkyl" is an alkyl group, as defined herein, substituted with a heterocyclyl group, as defined herein.

[0529] "Arylalkyl" is an alkyl group, as defined herein, substituted with an aryl group, as defined herein.

[0530] Non-limiting examples of "arylalkyl" include:

[0531]

[0532] In one embodiment, "arylalkyl" is

[0533] In one embodiment, "arylalkyl" refers to an alkyl group of 2 carbons substituted with an aryl group.

[0534] Non-limiting examples of "arylalkyl" include:

[0535]

[0536] In one embodiment, "arylalkyl" refers to a 3-carbon alkyl group substituted with an aryl group.

[0537] "Heteroarylalkyl" is an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

[0538] 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) having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). 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 aromatic ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aromatic ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. The one or more fused carbocyclyl or heterocyclyl groups may be 4 to 7 membered or 5 to 7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron to form, for example, 3,4-methylenedioxyphenyl. In one non-limiting embodiment, the aryl group is pendant. An example of a pendant ring is phenyl substituted with phenyl. In alternative embodiments, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl. The aryl group may be optionally substituted with one or more functional groups including, but not limited to, halogen, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocycle.

[0539] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0540] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0541] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aromatic 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.

[0542] For example is an "aryl" group.

[0543] However, is a "heterocyclyl" group.

[0544] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include dihydroindane and tetrahydronaphthalene, wherein the point of attachment of each group is on the aromatic ring.

[0545] For example is an "aryl" group.

[0546] However, is a "cycloalkyl" group.

[0547] In another embodiment, the "aryl" group is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0548] The terms "heterocyclyl," "heterocycle," and "heterocyclo" include saturated and partially saturated heteroatom-containing cyclic radicals, wherein the heteroatoms can be selected from nitrogen, sulfur, and oxygen. Heterocycles include 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered monocyclic 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. The "heterocyclyl" group can be optionally substituted, for example, with 1, 2, 3, 4, or more substituents, including, but not limited to, hydroxy, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.

[0549] 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.

[0550] 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-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 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.

[0551] The terms "heterocyclyl", "heterocycle" and "heterocyclo" groups also include moieties in which a heterocyclic group is fused / fused to an aryl or heteroaryl group: for example, unsaturated fused heterocyclic groups containing 1, 2, 3, 4 or 5 nitrogen atoms, e.g., indoline, isoindoline, unsaturated fused heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms, unsaturated fused heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated fused heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0552] In one embodiment, "heterocycle" refers to a ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0553] In one embodiment, "heterocycle" refers to a ring having one nitrogen and one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0554] In one embodiment, "heterocycle" refers to a ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0555] In one embodiment, "heterocycle" refers to a ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0556] In one embodiment, "heterocycle" refers to a ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0557] Non-limiting examples of "heterocycle" include aziridine, oxirane, thioethane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0558] Other non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0559] Other non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0560] Other non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0561] Other non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0562] For example, is a "heterocyclyl" group.

[0563] However, is an "aryl" group.

[0564] Non-limiting examples of "heterocyclyl" also include:

[0565]

[0566] Other non-limiting examples of "heterocyclyl" include:

[0567]

[0568] Other non-limiting examples of "heterocyclyl" include:

[0569]

[0570] Non-limiting examples of "heterocyclyl" also include:

[0571]

[0572] Non-limiting examples of "heterocyclyl" also include:

[0573]

[0574] Other non-limiting examples of "heterocyclyl" include:

[0575]

[0576] Other non-limiting examples of "heterocyclyl" include:

[0577]

[0578] In another embodiment, the "heterocyclyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0579] 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) with 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. 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 [such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl, thiadiazolyl [such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazole]. Other examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothiphenyl, indolinazinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl.

[0580] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0581] 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.

[0582] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0583]

[0584] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0585] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0586]

[0587] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0588] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0589] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0590]

[0591] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0592]

[0593] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0594]

[0595] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0596] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0597] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0598]

[0599] In another embodiment, the "heteroaryl" group is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0600] The term "optionally substituted" means that the groups herein are substituted with moieties including but not limited to: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C1-C 12 Heterocycloalkyl, C3-C 12 Heterocycloalkenyl, C1-C 10Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1-C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonylamino, arylsulfonylamino, C1-C 10 Alkyl imino, aryl imino, C1-C 10 Alkylsulfonyl imide, arylsulfonyl imide, hydroxyl, halogen, thio, C1-C 10 Alkylthio, arylthio, C1-C 10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylate.

[0601] In another embodiment, any suitable group may be present at a "substituted" or "optionally substituted" position if it indicates the formation of a stable molecule and meets the desired purpose of the present invention, including but not limited to, for example, halogen (which can independently be F, Cl, Br or I); cyano; hydroxy; nitro; azido; alkanoyl (e.g., C2-C6 alkanoyl); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those with one or more thioether bonds; alkylsulfinyl; alkylsulfonyl, including those with one or more sulfonyl bonds; aminoalkyl, including groups with more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring being substituted or unsubstituted); having, for example, 1 to 3 separate or fused rings; and aralkyl groups of 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy groups, for example, having 1 to 3 separate or fused rings, with benzyloxy being an exemplary arylalkoxy group; or heteroaryl groups having 1 to 3 saturated or partially unsaturated heterocyclic rings having one or more separate or fused rings containing N, O or S atoms, or having 1 to 3 separate or fused rings containing one or more N, O or S atoms, for example, coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen, and amino groups.

[0602] In certain embodiments, "optionally substituted" includes one or more substituents independently selected from the group consisting of halogen, hydroxy, amino, cyano, -CHO, -COOH, -CONH2, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alkenyl, alkynyl including C2-C6 alkynyl, -C1-C6 alkoxy, alkanoyl including C2-C6 alkanoyl, C1-C6 alkyl ester, (mono- and di-C1-C6 alkylamino)C0-C2 alkyl, haloalkyl including C1-C6 haloalkyl, hydroxy C1-C6 alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl(heterocyclic), C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(C3-C7 cycloalkyl), O-C1-C6 alkyl(C3-C7 cycloalkyl), B(OH)2, phosphate, phosphonate, and haloalkoxy including C1-C6 haloalkoxy. In some embodiments, suitable groups present on "substituted" or "optionally substituted" positions are divalent, including but not limited to oxo (=O), =S, =CH2, etc. Suitable groups on "substituted" or "optionally substituted" positions can be monovalent, divalent, or trivalent, so that they form stable molecules and meet the desired purposes of the present invention.

[0603] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0604] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0605] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0606] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0607] "Aliphatic" refers to a saturated or unsaturated straight chain, branched or cyclic hydrocarbon. "Aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties in this article, and therefore incorporates 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, the aliphatic group comprises 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms.

[0608] In one embodiment, aliphatic groups include 1 to about 8 carbon atoms. In certain embodiments, aliphatic groups are C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specified range represents that the aliphatic group with each member within the range is described as a separate substance. For example, the term C1-C6 aliphatic group used herein represents a straight or branched alkyl, alkenyl or alkynyl group with 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to represent that each of these is described as a separate substance. For example, the term C1-C4 aliphatic group used herein represents a straight or branched alkyl, alkenyl or alkynyl group with 1, 2, 3 or 4 carbon atoms, and is intended to represent that each of these is described as a separate substance. In one embodiment, aliphatic groups are substituted with one or more functional groups that result in the formation of a stable moiety.

[0609] The term "heteroaliphatic" refers to an aliphatic group that contains 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.

[0610] "Heteroaliphatic" is intended to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl in this article. In one embodiment, "heteroaliphatic" is used to represent a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or straight chain) having 1 to 20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable portion. Non-limiting examples of heteroaliphatic groups are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0611] "Dosage form" refers to a unit for administering an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. "Dosage form" may also include implants, such as ophthalmic implants.

[0612] As used herein, an "effective amount" refers to an amount that provides a therapeutic or prophylactic benefit.

[0613] As used herein, "endogenous" refers to any material that originates or originates from within an organism, cell, tissue, or system.

[0614] As used herein, the term "exogenous" refers to any material that is introduced from outside of an organism, cell, tissue, or system or that is generated outside of an organism, cell, tissue, or system.

[0615] As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of a response in a subject compared to the level of the response in the absence of the treatment or compound and / or compared to the level of response in 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.

[0616] "Parenteral" administration of the pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection or infusion techniques.

[0617] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present in a protein or peptide sequence is generally comparable to the number of amino acids found in nature. A polypeptide includes any peptide or protein comprising two or more amino acids linked to each other by peptide bonds. As used herein, the term also refers to both short chains, which are also commonly referred to in the art as peptides, oligopeptides, and oligomers, and long chains, 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, and the like. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0618] As used herein, the term "treating" a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject (i.e., palliative treatment) or reducing the cause or effects of the disease or condition (i.e., disease-modifying treatment).

[0619] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience only and should not be construed as limiting the scope of the invention. The description of a range should be considered to have explicitly disclosed all possible subranges and individual values ​​within that range. For example, a description of a range such as from 1 to 6 should be considered to have explicitly disclosed subranges such as 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., as well as individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This has nothing to do with the breadth of the range.

[0620] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents with instructions for using the active agents together to treat any of the conditions described herein, the active agents being combined in a single dosage form or provided together in separate dosage forms.

[0621] As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by preparing its inorganic and organic, non-toxic, acid or base addition salts. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of the two. Typically, non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, are used where feasible. Salts of the compounds of the present invention further include solvates of the compounds and salts of the compounds.

[0622] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts and quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. 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; salts derived 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, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, HOOC-(CH2) n -COOH (wherein n is 0-4), etc., or salts prepared using different acids that produce the same counterion. Lists of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0623] The term "carrier" as applied to the pharmaceutical composition / drug combination of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

[0624] "Pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition / drug combination, which is generally safe, non-toxic, and biologically or otherwise suitable for administration to a host, typically a human. In one embodiment, a veterinary acceptable excipient is used.

[0625] A "patient" or "host" or "individual" is a human or non-human animal in need of treatment or prevention of any of the diseases specifically described herein, e.g., according to the present invention, the disease is modulated by a native (wild-type) or modified (non-wild-type) protein that can be degraded to produce a therapeutic effect. Typically, the host is a human. "Host" alternatively refers to, for example, a mammal, a primate (e.g., a human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, etc.

[0626] A "therapeutically effective amount" of the pharmaceutical composition / drug combination of the present invention refers to an amount effective to provide a therapeutic benefit when administered to a host, such as relief of symptoms or alleviation or reduction of the disease itself.

[0627] II. Compounds of the Invention

[0628] In one aspect, compounds of Formula I or Formula II are provided:

[0629]

[0630] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0631] where all variables are as defined above.

[0632] In another aspect, provided are compounds of Formula III:

[0633]

[0634] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0635] where all variables are as defined above.

[0636] In another aspect, provided are compounds of formula IV:

[0637]

[0638] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0639] where all variables are as defined above.

[0640] In another aspect, a compound of Formula V is provided:

[0641]

[0642] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0643] where all variables are as defined above.

[0644] In another aspect, compounds of Formula VI or Formula VII are provided:

[0645]

[0646] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0647] where all variables are as defined above.

[0648] In another aspect, provided is a compound of Formula VIII:

[0649]

[0650] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0651] where all variables are as defined above.

[0652] In another aspect, provided are compounds of Formula IX:

[0653]

[0654] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0655] where all variables are as defined above.

[0656] In another aspect, compounds of Formula X or Formula XI are provided:

[0657]

[0658] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0659] where all variables are as defined above.

[0660] In one aspect, compounds of Formula XII or XIII are provided:

[0661]

[0662] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0663] where all variables are as defined above.

[0664] In one aspect, compounds of Formula XII or XIII are provided:

[0665]

[0666] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0667] where all variables are as defined above.

[0668] In another aspect, provided is a compound of Formula XIV:

[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 as defined above.

[0672] In another aspect, provided is a compound of Formula XV:

[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 as defined above.

[0676] In another aspect, provided is a compound of Formula XVI:

[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 as defined above.

[0680] In another aspect, provided are compounds of Formula XVII or XVIII:

[0681]

[0682] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0683] where all variables are as defined above.

[0684] In another aspect, provided is a compound of Formula XIX:

[0685]

[0686] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0687] where all variables are as defined above.

[0688] In another aspect, a compound of formula XX is provided:

[0689]

[0690] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0691] where all variables are as defined above.

[0692] In another aspect, provided are compounds of Formula XXI or XXII:

[0693]

[0694] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0695] where all variables are as defined above.

[0696] In any of the embodiments of Formulas I-VIII or XII-XIX, R 1 In any of the embodiments of Formulas I-VIII or XII-XOX, R 1 It's fluorine.

[0697] In any of the embodiments of Formulas I-VIII or XII-XIX, R 2 In any of the embodiments of Formulas I-VIII or XII-XOX, R 2 It's fluorine.

[0698] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formula XII-XXII, R 3a It's hydrogen.

[0699] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a In any one of the embodiments of formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a It is tert-butyl.

[0700] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of formula XII-XXII, R 3a It is trifluoroethyl.

[0701] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a It is ethynyl.

[0702] In any of the embodiments of Formulas I-XI, R3 In any one embodiment of Formulas I-XI, R 3 In any one embodiment of Formulas I-XI, R 3 In any one embodiment of Formulas I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a It is cyclohexyl.

[0703] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formulas I-XI, R 3 In any one embodiment of Formulas I-XI, R 3 is naphthyl, in any one of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a In any one of the embodiments of formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a Is an imidazolinyl group. In any one embodiment of Formula XII-XXII, R 3a It is a pyrimidinyl group.

[0704] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formulas I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of formula XII-XXII, formula R3a It is ethoxy.

[0705] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one embodiment of Formula XII-XXII, R 3a It's methylamino.

[0706] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a It is thio.

[0707] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a It is methylcarboxyl.

[0708] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formula XII-XXII, R 3a It is methylsulfonyl.

[0709] In any of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formula XII-XXII, R 3a In any one of the embodiments of formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3 In any one of the embodiments of Formula XII-XXII, R 3a It's iodine.

[0710] In any of the embodiments of Formulas I-XI, R 3 In any one embodiment of Formula I-XI, R 3In any one of the embodiments of Formulas I-XI, R 3 In any one of the embodiments of Formulas I-XI, R 3 It is R 5 In any one of the embodiments of Formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a In any one of the embodiments of Formula XII-XXII, R 3a It's nitro.

[0711] In any embodiment of Formula I-II, VIII-XIV or XIX-XXII, m is 1. In any embodiment of Formula I-II, VIII-XIV or XIX-XXII, m is 2. In any embodiment of Formula I-II, VIII-XIV or XIX-XXII, m is 3. In any embodiment of Formula I-II, VIII-XIV or XIX-XXII, m is 4.

[0712] In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 1. In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 2. In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 3. In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 4. In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 5. In any embodiment of Formula I, II, IV-XIII, or XV-XXII, n is 6.

[0713] In any embodiment of Formula I, II, XII, or XIII, o is 1. In any embodiment of Formula I, II, XII, or XIII, o is 2. In any embodiment of Formula I, II, XII, or XIII, o is 3.

[0714] In any embodiment of Formula V or XVI, p is 1. In any embodiment of Formula V or XVI, p is 2. In any embodiment of Formula V or XVI, p is 3. In any embodiment of Formula V or XVI, p is 4. In any embodiment of Formula V or XVI, p is 5.

[0715] In any of the embodiments of formula VI, VII, XVII or XVIII, q is 1. In any of the embodiments of formula VI, VII, XVII or XVIII, q is 2.

[0716] In any of the embodiments of Formulas I, II, or VI-XI, X A In any of the embodiments of Formulas I, II, or VI-XI, X A Is N. In any of the embodiments of Formulas I, II, or VI-XI, X A It's CR 3 .

[0717] In any of the embodiments of Formulas I, II, IV, or VI-XI, X B Is CH2. In any of the embodiments of Formulas I, II, IV, or VI-XI, X B It is CH R 3 In any of the embodiments of Formulas I, II, IV, or VI-XI, X B In any of the embodiments of Formulas I, II, IV, or VI-XI, X B It is NR 3 .

[0718] In any of the embodiments of Formula III, VI or VII, R 8 In any embodiment of formula III, VI or VII, R 8 In any embodiment of formula III, VI or VII, R 8 It is R 5 .

[0719] In any one of the embodiments of Formulas I-VIII or XII-XIX, Can be selected from:

[0720]

[0721] In any one of the embodiments of Formulas I and VIII-XI, Can be selected from:

[0722]

[0723] In any one of the embodiments of Formulae XII and XIX-XXII, Can be selected from:

[0724]

[0725]

[0726] In any one embodiment of Formula I, X or XI, Can be selected from:

[0727]

[0728]

[0729] In any one embodiment of Formula I, X or XI, Can be selected from:

[0730]

[0731]

[0732] In any one embodiment of Formula II, Can be selected from:

[0733]

[0734] In any one embodiment of Formula II, Can be selected from:

[0735]

[0736] In any one embodiment of Formula III, Can be selected from:

[0737]

[0738]

[0739] In any one embodiment of Formula III, Can be selected from:

[0740]

[0741]

[0742] In one embodiment of Formula V, Can be selected from:

[0743]

[0744]

[0745] In one embodiment of Formula XVI, Can be selected from:

[0746]

[0747] In any one of the embodiments of Formula V, Can be selected from:

[0748]

[0749] In any one embodiment of Formula VI, Selected from:

[0750]

[0751] In any one embodiment of Formula VI, Can be selected from:

[0752]

[0753] In any one embodiment of Formula VII, Selected from:

[0754]

[0755]

[0756] In any one embodiment of Formula VII, Can be selected from:

[0757]

[0758]

[0759] In any one of the embodiments of Formula VIII, Can be selected from:

[0760]

[0761] In any one of the embodiments of Formula VIII, Can be selected from:

[0762]

[0763] In any one embodiment of Formula IX, Can be selected from:

[0764]

[0765]

[0766] In any one embodiment of Formula IX, Can be selected from:

[0767]

[0768]

[0769] In any one of the embodiments of Formula XII, Can be selected from:

[0770]

[0771] In any one of the embodiments of Formula XII, Can be selected from:

[0772]

[0773] In any one of the embodiments of Formula XIII, Can be selected from:

[0774]

[0775]

[0776] In any one of the embodiments of Formula XIII, Can be selected from:

[0777]

[0778]

[0779] In any one of the embodiments of Formula XIV, Can be selected from:

[0780]

[0781] In any one of the embodiments of Formula XV, Can be selected from:

[0782]

[0783] In any one of the embodiments of Formula XVI, Can be selected from:

[0784]

[0785] In any one of the embodiments of Formula XVII, Selected from:

[0786]

[0787] In any one of the embodiments of Formula XVII, Can be selected from:

[0788]

[0789] In any one of the embodiments of Formula XVIII, Selected from:

[0790]

[0791]

[0792] In any one of the embodiments of Formula XVIII, Can be selected from:

[0793]

[0794] In any one of the embodiments of Formula XIX, Can be selected from:

[0795]

[0796] In any one of the embodiments of Formula XIX, Can be selected from:

[0797]

[0798]

[0799] In any one embodiment of Formula XX, Can be selected from:

[0800]

[0801] In any one embodiment of Formula XX, Can be selected from:

[0802]

[0803] In any one of the embodiments of Formula XXI, Can be selected from:

[0804]

[0805]

[0806] In any one of the embodiments of Formula XXI, Can be selected from:

[0807]

[0808] In any one of the embodiments of Formula XXII, Can be selected from:

[0809]

[0810] In any one of the embodiments of Formula XII, Can be selected from:

[0811]

[0812] In certain embodiments of Formula I, X or XI, yes

[0813] In certain embodiments of Formula II, yes

[0814] In certain embodiments of Formula VI, yes

[0815] In certain embodiments of Formula XII, yes

[0816] In certain embodiments of Formula XIII, yes

[0817] In certain embodiments of Formula XVIII, yes

[0818] In certain embodiments of Formula XXI, yes

[0819] Representative examples of compounds of Formula I include:

[0820]

[0821]

[0822]

[0823]

[0824] Representative examples of compounds of Formula II include:

[0825]

[0826] Representative examples of compounds of formula III include:

[0827]

[0828] Representative examples of compounds of formula IV include:

[0829]

[0830] Representative examples of compounds of Formula V include:

[0831]

[0832]

[0833] Representative examples of compounds of Formula VI include:

[0834]

[0835] Representative examples of compounds of Formula VII include:

[0836]

[0837] Representative examples of compounds of Formula VIII include:

[0838]

[0839]

[0840] Representative examples of compounds of Formula IX include:

[0841]

[0842]

[0843]

[0844] Representative examples of compounds of formula X include:

[0845]

[0846] Representative examples of compounds of formula XI include:

[0847]

[0848]

[0849] Representative examples of compounds of Formula XII include:

[0850]

[0851]

[0852]

[0853]

[0854] Representative examples of compounds of Formula XIII include:

[0855]

[0856] Representative examples of compounds of Formula XIV include:

[0857]

[0858]

[0859] Representative examples of compounds of Formula XV include:

[0860]

[0861] Representative examples of compounds of Formula XVI include:

[0862]

[0863]

[0864] Representative examples of compounds of Formula XVII include:

[0865]

[0866]

[0867] Representative examples of compounds of Formula XVIII include:

[0868]

[0869] Representative examples of compounds of Formula XIX include:

[0870]

[0871]

[0872] Representative examples of compounds of formula XX include:

[0873]

[0874]

[0875] Representative examples of compounds of formula XXI include:

[0876]

[0877]

[0878] Representative examples of compounds of formula XXII include:

[0879]

[0880] In one aspect, a compound of one of the following formulae is provided:

[0881]

[0882] where all variables are as defined above.

[0883] In another aspect, a compound of one of the following formulae is provided:

[0884]

[0885]

[0886] where all variables are as defined above.

[0887] In another aspect, a compound of one of the following formulae is provided:

[0888]

[0889] where all variables are as defined above.

[0890] In another aspect, a compound of one of the following formulae is provided:

[0891]

[0892] where all variables are as defined above.

[0893] In one aspect, a compound of one of the following formulae is provided:

[0894]

[0895]

[0896] where all variables are as defined above.

[0897] In one aspect, a compound of one of the following formulae is provided:

[0898]

[0899]

[0900] where all variables are as defined above.

[0901] In one embodiment, a compound of one of the following formulae is provided:

[0902]

[0903]

[0904] where all variables are as defined above.

[0905] In one embodiment, a compound of one of the following formulae is provided:

[0906] where all variables are as defined above.

[0907] In one embodiment, a compound of one of the following formulae is provided:

[0908]

[0909]

[0910] where all variables are as defined above.

[0911] In one embodiment, a compound of one of the following formulae is provided:

[0912]

[0913] where all variables are as defined above.

[0914] In one embodiment, a compound of one of the following formulae is provided:

[0915]

[0916] where all variables are as defined above.

[0917] In one aspect, a compound of one of the following formulae is provided:

[0918]

[0919] where all variables are as defined above.

[0920] In one aspect, provided are compounds of Formula IA, Formula IIA, Formula IIIA, or Formula IVA:

[0921]

[0922]

[0923] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0924] in:

[0925] W 200 is O or S;

[0926] R 201ais selected from the group consisting of: -(C0-C2 alkyl)(cycloalkyl), -(C1-C2 alkyl)(monocyclic heterocyclyl), -(C1-C2 alkyl)(aryl), and -(C1-C2 alkyl)(heteroaryl), wherein R 201a R 208 and optionally substituted by one or more selected from R 205 substituted with a group (e.g., 1, 2, 3, or 4 groups) of , wherein the point of attachment of the monocyclic heterocyclyl is a carbon atom; or

[0927] R 201a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 and –(CS)R 208 ;

[0928] R 202a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 202a R 208 and optionally substituted by one or more selected from R 205 or

[0929] R 202a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 or –(CS)R 208 ;

[0930] R 203a is selected from -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(monocyclic heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 203a R 208 and optionally substituted by one or more selected from R 205 or

[0931] R 203a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ;

[0932] R 204a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 204a R 208 and optionally substituted by one or more selected from R 205 or

[0933] R 204a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ;

[0934] R 201 and R 202 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocycloalkyl), -(C0-C2 alkyl)(aryl), -(C0-C2 alkyl)(heteroaryl), and acyl, wherein each R except hydrogen is 201 and R 202 may optionally be one or more selected from R 205 or

[0935] R 201 yes

[0936] R 203 and R 204 are independently selected from hydrogen, halogen (eg, fluorine, chlorine, bromine or iodine), -OR 207 、-SR 207 、-NR 207 R 207’ , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CO)R 206 、-CH=CH(CO)R 206 and nitro, where each R except hydrogen and halogen 203 and R 204 may optionally be one or more selected from R 205 substituted with a group (e.g., 1, 2, 3 or 4 groups);

[0937] R 205 independently selected at each occurrence from C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 Heterocyclyl, aryl, heteroaryl, -OR 207 、-N(R 207 )(R 207’ )、-S(R 207 ),-(CO)R 206 、-(CS)R 206 、-(C=NH)R 206 、-(SO)R 206 、-(SO2)R 206 , halogen, cyano, azido, R 208 and nitro; in one embodiment, R 205 It can't be R 208 ;

[0938] R 206 independently selected at each occurrence from hydrogen, C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl) and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2;

[0939] R 207 and R 207’ independently selected at each occurrence from hydrogen, C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C1-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 Heterocyclyl, aryl, heteroaryl, -(CO)R 206 、-(CS)R206 、-(C=NH)R 206 、-(SO)R 206 and -(SO2)R 206 ;

[0940] Y 200 O, S, -CH2-, -CHR 205 -or–C(R 205 )2-;

[0941] Z 201 Selected from hydroxyl or amino;

[0942] Z 202 Selected from O, S or CR 212 R 213 ;

[0943] R 209 and R 210 Independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0944] R 211 is selected from hydrogen, halogen, azido, cyano and heteroaryl;

[0945] R 212 、R 213 、R 214 and R 215 are independently selected from hydrogen, -OR 207 , cyano, azido, halogen, -NHR 207 、-NR 207 R 207’ , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkyl and C1-C4 haloalkyl, or

[0946] R 212 and R 214 can form a carbon-carbon double bond together with the carbon to which it is attached; or

[0947] R 212 and R 214 can form a 3- to 6-membered carbocyclic ring together with the carbon to which it is attached;

[0948] If R 212 is a hydroxyl group, then R 213 、R 214 and R 215 At least one of them is not hydrogen;

[0949] If R 213 is a hydroxyl group, then R 212 、R 214 and R 215 At least one of them is not hydrogen;

[0950] R 216 is selected from hydrogen, methyl, hydroxymethyl and fluoromethyl;

[0951] is selected at each occurrence from a single bond or a double bond;

[0952] Each R 208 independently are – linker-targeting ligand;

[0953] A linker is a divalent chemical group that connects R 208 attached to a targeting ligand; and

[0954] Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of a host disease.

[0955] In one embodiment, the linker is a divalent chemical group that attaches the degron to the targeting ligand.

[0956] In one embodiment, the linker is selected from

[0957] X 1 and X 2 are independently selected from a bond, NR 4 , CH2, CHR 4 、C(R 4 )2, O and S;

[0958] R 20 、R 21 、R 22 、R 23 and R 24 independently selected from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-、-CH(-NR 4 R 4’ )-、-C(-OR 26 )alkyl-, -C(-NR 4 R 4’ )alkyl-, -C(R 40 R 40 )-、-alkyl(R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26)O-、-P(O)(OR 26 )-、-NR 4 C(O)NR 4’ -, alkene, haloalkyl, alkoxy, alkynyl, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -、-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH- and -NH-(CH2) 1-12 -S-, wherein 1-6 can independently be 1, 2, 3, 4, 5 or 6, wherein 1-2 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more CH2 or NH groups can be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc. as described herein, and optionally inserting a heteroatom, heteroalkyl, aryl, heteroaryl or cycloaliphatic group in the chain.

[0959] Some non-limiting examples include -O-CH(CH3)-CH(CH3)CH-O-, -O-CH2-CH(CH3)CH-O-, -O-CH(CH3)-CH2CH-O-, etc.;

[0960] Each R 20 、R 21 、R 22 、R 23 and R 24 Optionally one or more selected from R 101 or substituted with a substituent as described in the definition section;

[0961] R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic;

[0962] R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclyl, aliphatic, and heteroaliphatic;

[0963] R 27 and R 28 are independently selected from hydrogen, alkyl and amine; or together with the carbon atom to which they are attached form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings; and

[0964] R 40 and wherein each occurrence is independently selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl, or heterocyclyl), -N(alkyl)SO2(aryl, heteroaryl, or heterocyclyl), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclyl, and carbocyclyl; and wherein all other variables are as described herein.

[0965] In one embodiment, the targeting ligand is a small molecule that binds to the targeted protein.

[0966] In one embodiment, the targeted protein is a mediator of abnormal cell proliferation in a host in need of such treatment.

[0967] In another aspect, a compound of Formula VA, Formula VIA, or Formula VIIA is provided;

[0968] or

[0969]

[0970] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0971] in:

[0972] Z 200A Selected from –OR 207 and –N(R 207 )(R 207’ );

[0973] Z 200B Selected from –O(CO)R 208 ,–N(R 207 )(CO)R 208 、-O(SO)R 208 、-N(R 207 )(SO)R 208 、-O(SO2)R 208 、-N(R 207 )(SO2)R 208 ,–O(CS)R 208 ,–N(R 207 )(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ;

[0974] R 213a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 213a R 208 and optionally substituted by one or more selected from R 205 or

[0975] R 213a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 , where if R 213a Yes–OR 208 , then R 212 、R 214 and R 215 At least one of them cannot be hydrogen;

[0976] R 215a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl); wherein R 215a R 208 and optionally substituted by one or more selected from R 205 substituted with a group (e.g., 1, 2, 3 or 4 groups);

[0977] or R215a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ;and

[0978] All other variables are as defined above.

[0979] In another aspect, provided is a compound of Formula VIIIA:

[0980]

[0981] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0982] in:

[0983] R 250 and R 251 independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, azido, cyano, -OR 207 、-N(R 207 )(R 207’ ) and –SR 207 ;

[0984] R 253 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl and cyano;

[0985] R 252 Selected from –N(R 207 )(R 208 ) and –OR 208 ;or

[0986] R 252 is at least one R 208 and optionally substituted with one or more selected from R 205 a heterocyclyl or heteroaryl group substituted with a group (e.g., 1, 2, 3, or 4 groups) of , said heterocyclyl or heteroaryl group containing at least one nitrogen atom through which it is attached;

[0987] and wherein all other variables are as defined above.

[0988] In another aspect, provided is a compound of Formula IXA:

[0989]

[0990] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0991] in:

[0992] R 254 Selected from:

[0993] in

[0994] Q 201 Each example is independently selected from N, CH, CR 205 and CR 255a , where at least one Q 201 It's CR 255a ;

[0995] Q 202 Each example is independently selected from N, CH, CR 205 and CR 255b , where at least one Q 202 It's CR 255b ;

[0996] R 255a is a heterocyclyl moiety containing at least one nitrogen atom and attached via a carbon atom, wherein the heterocyclyl moiety may be substituted by one or more (e.g., 1, 2, 3, or 4) R 205 wherein the heterocyclyl moiety may be substituted with one or more oxo groups where valence permits;

[0997] R 255b is a heterocyclyl moiety containing at least one nitrogen atom, wherein the heterocyclyl moiety may be substituted by one or more (e.g., 1, 2, 3, or 4) R 205 wherein the heterocyclyl moiety may be substituted with one or more oxo groups where valence permits;

[0998] and wherein all other variables are as defined above.

[0999] Non-limiting examples of compounds of the present invention include:

[1000]

[1001]

[1002]

[1003]

[1004]

[1005] Non-limiting examples of compounds of the present invention include:

[1006]

[1007]

[1008] In another aspect, compounds of Formula IB or Formula IC are provided:

[1009]

[1010] wherein the linker is a bond or a divalent or multivalent chemical group that attaches the degron to the targeting ligand as described herein;

[1011] connector B Selected from -(linker) as defined herein B In one embodiment, the linker B covalently attached to at least one degron and not attached to a targeting ligand;

[1012] Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of host disease;

[1013] The degron is selected from the group consisting of:

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026] wherein the degron can be optionally replaced by one or more selected from R 101 substituted with 1, 2, 3 or 4 substituents;

[1027] wherein the linker is covalently attached to the degron where valency permits; and

[1028] All other variables are as defined above.

[1029] In another embodiment, a degron is provided that is selected from the group consisting of:

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043] In one embodiment, a compound of Formula A is provided:

[1044]

[1045] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[1046] in:

[1047] Q A Selected from NR 8 , O, S, C=O, S=O and SO2;

[1048] Q B It's CR 3 or N; and

[1049] All other variables are as defined above.

[1050] In another embodiment, a compound of Formula B is provided:

[1051]

[1052] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[1053] in:

[1054] Q A1 Selected from NR 8a , O, S, C=O, S=O and SO2;

[1055] Q B1 It's CR 3a or N; and

[1056] All other variables are as defined above.

[1057] III. Connectors

[1058] The degraders of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, and XI include a linker. A linker is a bond or a chemically stable divalent group that connects the degradant to the targeting ligand. In some embodiments, the linker may have closed valencies and thus will contain one or more covalent bonds to ensure full valency, which may be one or more hydrogen atoms, or in the case of carboxyl, sulfonyl, thiol, thiol, alcohol, or phenol groups, deprotonated species and their salts, or in the case of amines, ammonium species and their salts.

[1059] The linkers described herein can be used in either orientation, i.e., either the left end is linked to the degron and the right end is linked to the target linker, or the left end is linked to the target linker and the right end is linked to the degron. In one embodiment, the linker is a divalent chemical group. According to the present invention, any desired linker can be used, so long as the resulting compound as part of a pharmaceutically acceptable dosage form has a stable shelf life of at least 2 months, 3 months, 6 months, or 1 year, and the compound itself is pharmaceutically acceptable.

[1060] In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms, wherein one or more carbons may be replaced by heteroatoms such as O, N, S or P. In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 consecutive atoms in the chain. For example, the chain may comprise one or more ethylene glycol units (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units) that may be continuous, partially continuous or discontinuous. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7 or 8 consecutive chains that may have branches that may independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocyclic substituents.

[1061] In other embodiments, the joint can include or be made up of one or more of the following: ethylene glycol, propylene glycol, lactic acid and / or glycolic acid. Typically, propylene glycol increases hydrophobicity, while propylene glycol increases hydrophilicity. Lactic acid fragments tend to have a longer half-life than glycolic acid fragments. Block and random lactic acid-to-glycolic acid moieties and ethylene glycol and propylene glycol are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain required half-life and hydrophilicity. In some aspects, as needed, the two sides of these units have other parts or are interspersed with other parts to achieve suitable pharmaceutical properties, such as aliphatic (including alkyl), heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc.

[1062] In one embodiment, the linker is a moiety selected from Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, and Formula LVII:

[1063]

[1064] where all variables are as defined above.

[1065] In other embodiments, the linker is a moiety selected from Formula LVIII, LIX, and LX:

[1066]

[1067] where all variables are as defined above.

[1068] In other embodiments of LVIII, LIX, and LX, a carbocycle is used in place of a heterocycle.

[1069] The following are non-limiting examples of linkers that can be used in the present invention.Based on this detailed description, those skilled in the art will understand how to use the full-length linker to achieve the purposes of the present invention.

[1070] As some non-limiting examples, Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, or Formula LVII include:

[1071]

[1072]

[1073]

[1074] In other embodiments, the linker is selected from:

[1075]

[1076] In other embodiments, the linker is selected from:

[1077]

[1078] In one embodiment, X 1 In another embodiment, X 2 Attached to a targeting ligand.

[1079] R 20 、R 21 、R 22 、R 23 and R 24 Non-limiting examples of parts include:

[1080] R 20 、R 21 、R 22 、R 23 and R 24 Other non-limiting examples of parts include:

[1081]

[1082] R 20 、R 21 、R 22 、R 23 and R 24 Other non-limiting examples of parts include:

[1083]

[1084] In other embodiments, the linker moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P or Si atoms. In certain embodiments, the linker is flanked by, substituted with or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclyl groups. In certain embodiments, the linker can be asymmetric or symmetric. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to about 6 ethylene glycol units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units. In any embodiment of the compounds described herein, the linker group can be any suitable moiety described herein.

[1085] In other embodiments, the linker is selected from:

[1086] -NR 61 (CH2) n1 -(lower alkyl)-, -NR 61 (CH2) n1 -(lower alkoxy)-, -NR 61 (CH2) n1 -(lower alkoxy)-OCH2-, -NR 61 (CH2) n1 -(lower alkoxy)-(lower alkyl)-OCH2-, -NR 61 (CH2) n1 -(cycloalkyl)-(lower alkyl)-OCH2-, -NR 61 (CH2) n1 -(heterocycloalkyl)-, -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-CH2-, -NR 61 (CH2CH2O) n1 -(Heterocycloalkyl)-O-CH2-, -NR 61 (CH2CH2O) n1 -Aryl-O-CH2-, -NR 61 (CH2CH2O) n1 -(heteroaryl)-O-CH2-, -NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-aryl-O-CH2-, -NR61 (CH2CH2O) n1 -(lower alkyl)-NH-aryl-O-CH2-, -NR 61 (CH2CH2O) n1 -(lower alkyl)-O-aryl-CH2, -NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-, -NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-, -NR 61 (CH2CH2) n1 -(cycloalkyl)-O-(heterocyclyl)-CH2, -NR 61 (CH2CH2) n1 -(heterocyclyl)-(heterocyclyl)-CH2 and -NR 61 -(heterocyclyl)-CH2;

[1087] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1088] R 61 It is H, methyl or ethyl.

[1089] In other embodiments, the linker is selected from:

[1090] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-, -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-, -O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -O-;-N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2)p1 -O(CH2) q1 -O(CH2) r1 -O-; -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -O-; -(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-; -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-; -O(CH2) m1 O(CH2) n2 O(CH2) p1 O(CH2) q1 OCH2-;

[1091] m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and

[1092] R 61 It is H, methyl or ethyl.

[1093] In other embodiments, the linker is selected from:

[1094]

[1095]

[1096] in

[1097] m1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5.

[1098] In other embodiments, the linker is selected from:

[1099]

[1100]

[1101] In other embodiments, the linker is selected from:

[1102]

[1103] In other embodiments, the linker is selected from:

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110] where R 71 It is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic or -Nme.

[1111] In other embodiments, the linker is selected from:

[1112]

[1113]

[1114] In other embodiments, the linker is selected from:

[1115]

[1116]

[1117]

[1118]

[1119] In other embodiments, the linker is selected from:

[1120]

[1121]

[1122] In other embodiments, the linker is selected from:

[1123]

[1124] In other embodiments, the linker is selected from:

[1125]

[1126]

[1127] In other embodiments, the linker is selected from:

[1128]

[1129] In other embodiments, the linker is selected from:

[1130]

[1131] In certain embodiments, the linker is selected from:

[1132]

[1133] In certain embodiments, the linker is selected from:

[1134]

[1135]

[1136] In the above structure, represent

[1137] In certain embodiments, the linker can be a linear chain of 4 to 24 carbon atoms, wherein one or more carbon atoms in the linear chain can be replaced or substituted by oxygen, nitrogen, amide, fluorinated carbon, etc., for example, as follows:

[1138]

[1139]

[1140]

[1141] In certain embodiments, the linker may be non-linear and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[1142] In certain embodiments, the linker may comprise continuous, partially continuous, or discontinuous groups of ethylene glycol units ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units, such as 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units.

[1143] In certain embodiments, the linker can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment, the linker is perfluorinated. In another embodiment, the linker is a partially or fully fluorinated polyether. Non-limiting examples of fluorinated linker moieties include:

[1144]

[1145]

[1146] In certain embodiments, selectivity can be enhanced by varying the length of the linker when the target ligand binds to more than one protein (i.e., not completely selective), where the ligand binds to some of its targets in different binding pockets (e.g., deeper or shallower than other pockets). Thus, the length can be adjusted as needed.

[1147] In another embodiment, the -Linker-Targeting Ligand is -(Linker) B , where -(connector) B Is a monovalent group. In one embodiment, -(linker) B is covalently attached to at least one degron and is not attached to a targeting ligand. In another embodiment, the -linker-targeting ligand is -(linker) C , where –(connector) C Covalently attached to a Targeting Ligand and one or more other Targeting Ligands and / or Degrons.

[1148] In one embodiment, -(linker) B Selected from

[1149] where all variables are as defined above.

[1150] In one embodiment, -(linker) B is a moiety selected from Formula LBI, Formula LBII, Formula LBIII, Formula LBIV, Formula LBV, Formula LBVI, and Formula LBVII:

[1151]

[1152] where all variables are as defined above.

[1153] In other embodiments, -(linker) B is a moiety selected from the group consisting of formulae LBVIII, LBIX and LBX:

[1154]

[1155] Wherein all variables are as defined above. B VIII.L B IX and L B In other embodiments of X, a carbocycle is used in place of a heterocycle.

[1156] The following are useful in the present invention: BBased on this detailed description, a person skilled in the art will understand how to use the full-length-(linker) that will achieve the goals of the present invention. B part.

[1157] As some non-limiting examples, Formula L B I. Formula L B II. Formula L B III. Formula L B IV. Formula L B V, Type L B VI or Formula L B VII includes:

[1158]

[1159]

[1160]

[1161] In other embodiments, –(linker) B Selected from:

[1162]

[1163] In other embodiments, –(linker) B Selected from:

[1164]

[1165]

[1166] R 20 、R 21 、R 22 、R 23 and R 24 Non-limiting examples of parts include:

[1167]

[1168] R 20 、R 21 、R 22 、R 23 and R 24 Other non-limiting examples of parts include:

[1169]

[1170]

[1171] R 20 、R 21 、R22 、R 23 and R 24 Other non-limiting examples of parts include:

[1172]

[1173] In other embodiments, -(linker) B is an optionally substituted ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, -(linker) B On both sides of the -(linker) are substituted or interspersed with aryl, phenyl, benzyl, alkyl, alkylene or heterocyclic groups. In certain embodiments, -(linker) B Can be asymmetric or symmetric. In some embodiments, -(linker) B is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units. In any embodiment of the compounds described herein, -(linker) B The group can be any suitable moiety described herein.

[1174] In other embodiments, –(linker) B Selected from:

[1175] -NR 61 (CH2) n1 -(lower alkyl)-X 22 、-NR 61 (CH2) n1 -(lower alkoxy)-X 22 、-NR 61 (CH2) n1 -(lower alkoxy)-OCH2-X 22 、-NR 61 (CH2) n1 -(lower alkoxy)-(lower alkyl)-OCH2-X 22 、-NR 61 (CH2) n1 -(cycloalkyl)-(lower alkyl)-OCH2-X 22 、-NR 61 (CH2) n1 -(Heterocycloalkyl)-X 22 、-NR 61 (CH2CH2O) n1-(lower alkyl)-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(Heterocycloalkyl)-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -Aryl-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(Heteroaryl)-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-(heteroaryl)-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(cycloalkyl)-O-aryl-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(lower alkyl)-NH-aryl-O-CH2-X 22 、-NR 61 (CH2CH2O) n1 -(lower alkyl)-O-aryl-CH2-X 22 、-NR 61 (CH2CH2O) n1 -cycloalkyl-O-aryl-X 22 、-NR 61 (CH2CH2O) n1 -cycloalkyl-O-heteroaryl-X 22 、-NR 61 (CH2CH2) n1 -(cycloalkyl)-O-(heterocyclyl)-CH2-X 22 、-NR 61 (CH2CH2) n1 -(Heterocyclyl)-(Heterocyclyl)-CH2-X 22 and -NR 61 -(Heterocyclyl)-CH2-X 22 ;

[1176] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1177] R 61 It is H, methyl or ethyl.

[1178] In other embodiments, –(linker) B Selected from:

[1179] -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 、-O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OCH2-X 22 、-O-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;-N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2)r1-OH;-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH2) r1 -OH;-(CH​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​q1 OCH2-X 22 ;in

[1180] m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and

[1181] R 61 It is H, methyl or ethyl.

[1182] In other embodiments, –(linker) B Selected from:

[1183]

[1184]

[1185] wherein m1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5. In other embodiments, –(linker) B Selected from:

[1186]

[1187]

[1188] In other embodiments, –(linker) B Selected from:

[1189]

[1190] In other embodiments, –(linker) B Selected from:

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197] where R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic, or -NMe. In other embodiments, -(linker) B Selected from:

[1198]

[1199]

[1200]

[1201]

[1202]

[1203] In other embodiments, –(linker) B Selected from:

[1204]

[1205]

[1206] In other embodiments, –(linker) B Selected from:

[1207]

[1208] In other embodiments, –(linker) B Selected from:

[1209]

[1210]

[1211]

[1212] In other embodiments, –(linker) B Selected from:

[1213]

[1214] In the above embodiment, select X 22 To make the compound sufficiently stable or for its intended use.

[1215] In other embodiments, –(linker) B Selected from:

[1216]

[1217] In certain embodiments, –(linker) B Selected from:

[1218]

[1219] In certain embodiments, –(linker) B Selected from:

[1220]

[1221]

[1222] In the above structure, represent

[1223] In certain embodiments, -(linker) B It can be a straight chain of 4-24 carbon atoms, wherein one or more carbon atoms in the straight chain can be replaced or substituted by oxygen, nitrogen, amide, fluorinated carbon, etc., for example, as follows:

[1224]

[1225]

[1226]

[1227] In certain embodiments, -(linker) B It may be non-linear and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[1228] In certain embodiments, -(linker) B It can include continuous, partially continuous or discontinuous groups of ethylene glycol units ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, from about 2 to 4 ethylene glycol units, such as 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[1229] In certain embodiments, -(linker) B There may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 fluorine substituents. In another embodiment, -(linker) B - is perfluorinated. In another embodiment, -(linker) B It is a partially or fully fluorinated polyether. Fluorinated-(connector) B Some non-limiting examples include:

[1230]

[1231] In certain embodiments, the length may be adjusted as needed or found necessary for a desired application.

[1232] IV. Target Protein

[1233] Cellular homeostasis and normal cellular functions (e.g., proliferation, differentiation, and cell death) require cellular protein degradation. When this system malfunctions or fails to recognize and reduce abnormal protein behavior in vivo, a disease state can occur in a host (e.g., a human). As is well known to those skilled in the art, as disclosed in the literature and patent applications, and as suggested in scientific reports, a wide range of proteins can cause, modulate, or enhance disease in vivo.

[1234] Thus, in one embodiment, a selected degrader compound of the present invention can be administered to a host in need thereof in an effective amount to degrade a selected protein that mediates the disease to be treated. The selected protein target can modulate human disease through mechanisms of action such as altering biological pathways, pathogenic signaling, or modulating signaling cascades or cell entry.

[1235] In one embodiment, the target protein is a protein that is not druggable in the classical sense, because it does not have a binding pocket or active site that can be inhibited or otherwise bound, and is not easily amenable to allosteric control. In another embodiment, the target protein is a protein that is druggable in the classical sense, but for therapeutic purposes, the degradation of the protein is preferably inhibited.

[1236] The target protein is recruited with a targeting ligand (which is a ligand of the target protein). Typically, the targeting ligand binds to the target protein in a non-covalent manner. In another embodiment, the target protein is covalently bound to the degron in an irreversible or reversible manner.

[1237] In one embodiment, the selected target protein is expressed by a gene that has undergone an amplification, translocation, deletion, or inversion event, which causes a medical disease or is caused by a medical disease. In some aspects, the selected target protein is post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation, and polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylation, ubiquitination, ubiquitination-like, or sulfation, which causes a medical disease or is caused by a medical disease.

[1238] As contemplated herein, the present invention includes degraders having targeting ligands that bind to a target protein of interest. A target protein is any amino acid sequence to which a degrader can bind, causing a beneficial therapeutic effect in vivo through degradation of the target protein.

[1239] In one embodiment, the target protein is a non-endogenous peptide, such as a peptide from a pathogen or toxin. In another embodiment, the target protein may be an endogenous protein that mediates a disease. The endogenous protein may be a normal form of the protein or an abnormal form. For example, the target protein may be a mutant protein found in cancer cells, or a protein in which, for example, partial or complete gain-of-function or loss-of-function is encoded by a nucleotide polymorphism. In some embodiments, the degrader targets the abnormal form of the protein rather than the normal form of the protein.

[1240] In another embodiment, the target protein may mediate an inflammatory disease or an immune disease, including an autoimmune disease.

[1241] In one embodiment, the target protein is a non-endogenous protein from a virus, such as, by way of non-limiting example, HIV, HBV, HCV, RSV, HPV, CMV, flavivirus, pestivirus, coronavirus, norovirus, etc.

[1242] In one embodiment, the target protein is a non-endogenous protein from a bacterium, which can be, for example, a Gram-positive bacterium, a Gram-negative bacterium, or other bacterium, and can be a drug-resistant form of the bacterium.

[1243] In one embodiment, the target protein is a non-endogenous protein from a fungus. In one embodiment, the target protein is a non-endogenous protein from a prion. In one embodiment, the target protein is a protein from a eukaryotic pathogen such as a protist or a parasitic helminth.

[1244] In one aspect, target protein mediates chromatin structure and function.Target protein can mediate epigenetic effects, such as DNA methylation or the covalent modification of histones.An example is histone deacetylase (HDAC 1,2,3,4,5,6,7,8,9,10 or 11).Alternatively, target protein can be a bromodomain, which is a reader (e.g., BRD1,2,3,4,5,6,7,8,9 and T) of lysine acetylation. Figure 9 Proteins of the bromodomain family are shown, which, for example, can be used as target proteins according to the present invention.

[1245] Other non-limiting examples of target proteins are structural proteins, receptors, enzymes, cell surface proteins, proteins involved in apoptosis signaling, aromatases, helicases, mediators of metabolic processes (anabolism or catabolic), antioxidants, proteases, kinases, oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, enzyme modulators, signal transducers, structural molecules, binding activities (proteins, lipid carbohydrates), cell movement proteins, membrane fusion proteins, cell communication mediators, regulators of biological processes, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transporters, ion transporters, channel transporters, carrier activity, permeases, secretases or secretion mediators, electron transporters, molecular chaperone regulators, nucleic acid binding, transcriptional regulators, regulators of extracellular organization and biogenesis, and translational regulators).

[1246] In one embodiment, the target protein is a regulator of a signaling cascade associated with a known disease state. In another embodiment, the target protein mediates the disease by a mechanism other than regulating a signaling cascade. As further described herein, any protein in a eukaryotic or microbial system (including viruses, bacteria, or fungi) is a target for proteasomal degradation using the present invention. The target protein can be a eukaryotic protein, and in some embodiments, can be a human protein.

[1247] In one embodiment, the target protein is RXR, DHFR, Hsp90, kinase, HDM2, MDM2, BET bromodomain-containing protein, HDAC, IDH1, Mcl-1, human lysine methyltransferase, nuclear hormone receptor, aryl hydrocarbon receptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, BCL.

[1248] In one embodiment, the bromodomain-containing protein has histone acetyltransferase activity.

[1249] In one embodiment, the bromodomain-containing protein is BRD2, BRD3, BRD4, BRDT, or ASH1L.

[1250] In one embodiment, the bromodomain-containing protein is a non-BET protein.

[1251] In one embodiment, the non-BET protein is BRD7 or BRD9.

[1252] In one embodiment, FLT is not FLT3. In one embodiment, RAS is not RASK. In one embodiment, RAF is not RAF1. In one embodiment, SMARC is not SMARC2. In one embodiment, KSR is not KSR1. In one embodiment, NF2L is not NF2L2. In one embodiment, CTNB is not CTNB1. In one embodiment, BCL is not BCL6.

[1253] In one embodiment, the target protein is selected from the group consisting of: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[1254] In another embodiment, the target protein is not selected from the group consisting of: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[1255] In one embodiment, the targeting ligand is an EGFR ligand, a FLT3 ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, a CTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

[1256] In one embodiment, the Targeting Ligand is not an EGFR ligand, a FLT3 ligand, a RAF1 ligand, a SMRCA2 ligand, a KSR1 ligand, a NF2L2 ligand, a CTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

[1257] The present invention can be used to treat a wide range of disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and the patient would benefit from protein degradation.

[1258] For example, a target protein can be selected that is a target of a known human therapeutic agent, and when the therapeutic agent is incorporated into a degrader according to the invention, the therapeutic agent can serve as a targeting ligand. These include proteins that can be used to restore function in polygenic diseases, including, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl2 / Bax and other chaperones in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G proteins such as Gq, histamine receptor, 5-lipoxygenase, tryptase-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR, etc., HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MER / ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 (HSV-1), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neurotransmitterone receptor, Peptide Y and receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor of NGK, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptors, Her-2 / neu, telomerase inhibition, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[1259] In certain embodiments, the target protein is derived from a kinase to which a targeting ligand can bind or bind, including but not limited to tyrosine kinases (e.g., 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, IGF2, IGF3, IGF4, IGF6, IGF7, IGF8, IGF9, IGF10, IGF11, IGF2, IGF3, IGF4, IGF12, IGF13, IGF14, IGF15, IGF16, IGF17, IGF18, IGF19, IGF21, IGF22, IGF33, IGF4, IGF19, IGF23, IGF24, IGF25, IGF26, IGF27, IGF28, IGF29, IGF34, IGF35, IGF36, IGF37, IGF38, IGF39, IGF3A, IGF3A, IGF3B, IGF3C, IGF3C, IGF3A, IGF3B, IGF3C, IGF3C, IGF3 LK, INSR, 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, PDGF RB, 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 or ZAP70).

[1260] In certain embodiments, the target protein is derived from a kinase to which a targeting ligand can bind or bind, including but not limited to serine / threonine kinases (e.g., 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, NE K6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RS K1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-beta, TLK2, TSSK1, TSSK2, ULK1 or ULK2).

[1261] In certain embodiments, the target protein is derived from a kinase to which a targeting ligand can bind or binds, including but not limited to a cyclin-dependent kinase, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.

[1262] In certain embodiments, the target protein is derived from a kinase to which a targeting ligand is capable of binding or binds, including but not limited to a leucine-rich repeat kinase (eg, LRRK2).

[1263] In certain embodiments, the target protein is derived from a kinase to which the targeting ligand is capable of binding or binds, including but not limited to a lipid kinase (eg, PIK3CA, PIK3CB) or a sphingosine kinase (eg, S1P).

[1264] In certain embodiments, the target protein is derived from a BET-bromodomain-containing protein to which a targeting ligand can bind or bind, including but not limited to 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. In certain embodiments, the BET bromodomain-containing protein is BRD4.

[1265] In certain embodiments, the target protein is derived from a nuclear protein to which a targeting ligand can bind or bind, including but not limited to BRD2, BRD3, BRD4, Antennapedia homeodomain protein, BRCA1, BRCA2, CCAAT-enhanced binding protein, histone, polycomb-based protein, high-mobility group box 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.

[1266] In certain embodiments, the target protein is a member of the retinoid X receptor (RXR) family and the disease being treated is a neuropsychiatric or neurodegenerative disease. In certain embodiments, the target protein is a member of the retinoid X receptor (RXR) family and the disease being treated is schizophrenia.

[1267] In certain embodiments, the target protein is dihydrofolate reductase (DHFR) and the disease to be treated is cancer. In certain embodiments, the target protein is dihydrofolate reductase (DHFR) and the disease to be treated is caused by a microorganism.

[1268] In certain embodiments, the target protein is dihydrofolate reductase (BaDHFR) from Bacillus anthracis and the disease being treated is anthrax.

[1269] In certain embodiments, the target protein is heat shock protein 90 (HSP90) and the disease being treated is cancer.

[1270] In certain embodiments, the target protein is a kinase or phosphatase and the disease being treated is cancer.

[1271] In certain embodiments, the target protein is HDM2 and / or MDM2, and the disease being treated is cancer.

[1272] In certain embodiments, the target protein is a BET bromodomain-containing protein and the disease being treated is cancer.

[1273] In certain embodiments, the target protein is a lysine methyltransferase and the disease being treated is cancer.

[1274] In certain embodiments, the target protein belongs to the RAF family and the disease being treated is cancer.

[1275] In certain embodiments, the target protein belongs to the FKBP family and the disease being treated is an autoimmune disease. In certain embodiments, the target protein belongs to the FKBP family and the disease being treated is organ rejection. In certain embodiments, the target protein belongs to the FKBP family and the compound is administered prophylactically to prevent organ failure.

[1276] In certain embodiments, the target protein is the androgen receptor and the disease being treated is cancer.

[1277] In certain embodiments, the target protein is the estrogen receptor and the disease being treated is cancer.

[1278] In certain embodiments, the target protein is a viral protein and the disease being treated is a viral infection. In certain embodiments, the target protein is a viral protein and the disease being treated is HIV, HPV or HCV.

[1279] In certain embodiments, the target protein is the AP-1 or AP-2 transcription factor and the disease being treated is cancer.

[1280] In certain embodiments, the target protein is HIV protease and the disease being treated is HIV infection. In certain embodiments, the target protein is HIV integrase and the disease being treated is HIV infection. In certain embodiments, the target protein is HCV protease and the disease being treated is HCV infection. In certain embodiments, the treatment is prophylactic and the target protein is a viral protein.

[1281] In certain embodiments, the target protein is a member of the histone deacetylase (HDAC) family and the disease is a neurodegenerative disease. In certain embodiments, the target protein is a member of the histone deacetylase (HDAC) family and the disease is Huntington's disease, Parkinson's disease, Kennedy's disease, amyotrophic lateral sclerosis, Rubinstein-Taybi syndrome, or stroke.

[1282] In certain embodiments, the targeting ligand forms a covalent bond with the target protein. Non-limiting examples of target proteins and targeting ligands utilizing covalent bonds include those described in: “Covalent Inhibitors Design and Discovery” Eur J Med Chem. 2017 Sep 29; 138: 96-114. doi: 10.1016 / j.ejmech.2017.06.019; “Lysine-Targeting Covalent Inhibitors.” Angew Chem Int Ed Engl. 2017 Aug 29. doi: 10.1002 / anie.201707630; “Inhibition of Mcl-1 Through Covalent Modification of a Noncatalytic Lysine Side Chain.” Nat Chem Biol. 2016 Nov; 12(11): 931-936; “Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors” Cell Chem.Biol.2016Nov:24:1-13; “Global Profilingof Lysine Reactivity and Ligandability in the Human Proteome”Nat.Chem.2017Jul31,doi:10.1038 / nchem.2826; “The Resurgence of Covalent Drugs”Nat.Rev.DrugDisc.2011 10,307-217; U.S. Patent No. 8,008,309; and U.S. Patent No. 9,790,226.

[1283] In another embodiment, the target protein is selected from DOTL1, CBP, WDR5, BRAF, KRAS, MCL1, PTPN2, HER2, and SHOC2. In another embodiment, the target protein is selected from UCHL1, USP6, USP14, and USP30. In another embodiment, the target protein is selected from USP1, USP2, USP4, USP6, USP7, USP8, USP9x, USP10, USP11, USP13, USP14, USP17, and USP28.

[1284] In one embodiment, the target protein is selected from 4QL1, 3SMR, 5EAL, 6DAK, 6DAR and 6DAS.

[1285] In certain embodiments, the target protein referred to herein is named after the gene expressing it. Those skilled in the art will recognize that when a gene is referred to as a target protein, the protein encoded by the gene is the target protein. For example, a ligand of the protein SMCA2 encoded by SMRCA2 is referred to as a SMRCA2 targeting ligand.

[1286] V. Targeting Ligands

[1287] In certain aspects, a targeting ligand is a ligand that covalently or non-covalently binds to a target protein that has been selected for proteasomal degradation by a selected degrader. A targeting ligand is a molecule or moiety (e.g., a peptide, nucleotide, antibody, antibody fragment, aptamer, biomolecule, or other chemical structure) that binds to a target protein, and wherein the target protein is a disease mediator in a host, as described in detail below. Exemplary targeting ligands are provided in Figure 1A-8PPPPP .

[1288] In one embodiment, as a means of achieving a therapeutic effect on the host, the targeting ligand binds to an endogenous protein that has been selected for degradation. Exemplary targeting ligands include: RXR ligands, DHFR ligands, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, MerTK ligands, IDH1 ligands, Mcl-1 ligands, SMRCA2 ligands, EGFR ligands, RAF ligands, cRAF ligands, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptor (AHR), etc. Targeting ligands are also considered to include pharmaceutically acceptable salts, prodrugs, and isotopic derivatives thereof.

[1289] In certain aspects, the targeting ligand binds to a dehalogenase in a patient or individual or in a diagnostic assay and is a halogenated alkane (preferably a C1-C12 substituted with at least one halogen group). 10The alkyl, preferably halogen, group is distal to the alkyl (i.e., distal to the linker). In other embodiments, the targeting ligand is a haloalkyl, wherein the alkyl group typically ranges in size from about 1 or 2 carbons to about 12 carbons in length, typically from about 2 to 10 carbons, typically from about 3 to 8 carbons, and more typically from about 4 to 6 carbons in length. The haloalkyl is typically a straight chain alkyl (although branched alkyls may also be used) and is terminated by at least one halo group, preferably a halo group, typically a chloro group. The haloalkyl PT group used in the present invention is preferably represented by the chemical structure -(CH2)v-halogen, wherein v is any integer from 2 to about 12, typically from about 3 to about 8, more typically from about 4 to about 6. The halo can be any halogen, but is preferably Cl or Br, more typically Cl.

[1290] In certain embodiments, the targeting ligand is a retinoid X receptor (RXR) agonist or antagonist. Non-limiting examples include retinol, retinoic acid, bexarotene, docosahexaenoic acid, WO9929324, a publication by Canan Koch et al. entitled "Identification of the First Retinoid X Receptor Homodimer Antagonist" (J. Med. Chem. 1996, 39, 3229-3234), WO 9712853, EP 0947496A1, compounds disclosed in WO 2016002968, and analogs thereof.

[1291] In certain embodiments, the targeting ligand is a DHFR agonist or antagonist. Non-limiting examples include folic acid, methotrexate, 8,10-dideazatetrahydrofolate compounds disclosed in Tian et al. (Che...

Claims

1. The compound of the following formula or a pharmaceutically acceptable salt thereof; in: m is 1, 2, 3, or 4; n is 1, 2, 3, 4, 5 or 6; o is 1, 2 or 3; p is 1, 2, 3, 4, or 5; R 1 and R 2 independently selected from hydrogen and fluorine; Each are independently a single bond or a double bond; Y 1 is CH, N or CR 3 ; R 3 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azido, nitro and R 5 ; At least one of the R 3 Selected from R 5 ; X A is CH or N, where if X A is N, then yes and if X A is CH, then yes Or if the valence state allows, X A forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X A R 3 Replace, then X A It's CR 3 ; X B selected from NH and CH2; If X B R 3 Replace, then X B It is NR 3 or CHR 3 ; R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ; Each R 5 Independently selected from -Linker-Targeting Ligand and -(Linker) B ; R 6 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 9 and R 9’ independently selected from hydrogen, C1-C6 alkyl and C1-C3 haloalkyl; or R 9 and R 9’ can be combined with the carbon to which it is attached to form a cyclopropyl ring; A linker is a chemical group that 5 The attached atom is connected to the targeting ligand; -(Connector) B is a chemical group that is related to R 5 The attached atom is connected to, but not to, the targeting ligand; and Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of host disease.

2. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof; in: m is 1, 2, 3, or 4; n is 1, 2, 3, 4, 5, or 6; p is 1, 2, 3, 4, or 5; R 1 and R 2 independently selected from hydrogen and fluorine; Each are independently a single bond or a double bond; Y 1 is CH, N or CR 3 ; R 3 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azido, nitro and R 5 ; At least one of the R 3 Selected from R 5 ; X A is CH or N, where if X A is N, then yes and if X A is CH, then yes Or if the valence state allows, X A forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X A R 3 Replace, then X A It's CR 3 ; X B selected from NH and CH2; If X B R 3 Replace, then X B It is NR 3 or CHR 3 ; R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ; Each R 5 Independently selected from -Linker-Targeting Ligand and -(Linker) B ; R 6 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 9 and R 9’ independently selected from hydrogen, C1-C6 alkyl and C1-C3 haloalkyl; or R 9 and R 9’ can be combined with the carbon to which it is attached to form a cyclopropyl ring; A linker is a chemical group that 5 The attached atom is connected to the targeting ligand; -(Connector) B is a chemical group that is related to R 5 The attached atom is connected to, but not to, the targeting ligand; and Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of host disease.

3. The compound according to claim 1 or 2, wherein the linker is in X 1 and X 2 are independently selected from a bond, NR 4 , CH2, CHR 4 、C(R 4 )2, O and S; R 20 、R 21 、R 22 、R 23 and R 24 independently selected from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-、-CH(-NR 4 R 4’ )-、-C(-OR 26 )alkyl-, -C(-NR 4 R 4’ )alkyl-, -C(R 40 R 40 )-、-alkyl(R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-、-NR 4 C(O)NR 4’ -, alkene, haloalkyl, alkoxy, alkynyl, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -、-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH- and -NH-(CH2) 1-12 -S-; wherein 1-6 may independently be 1, 2, 3, 4, 5, or 6; wherein 1-12 may independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and wherein one or more CH2 or NH groups may be modified by replacing H with methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein, and optionally inserting a heteroatom, heteroalkyl, aryl, heteroaryl, or cycloaliphatic group in the chain; where R 20 、R 21 、R 22 、R 23 and R 24 Each of which is optionally replaced by one or more selected from R 101 Substituents substituted; R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic; R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclyl, aliphatic, and heteroaliphatic; R 27 and R 28 are independently selected from hydrogen, alkyl and amine; or together with the carbon atom to which they are attached form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings; and R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic), -NHSO(aliphatic), -N(aliphatic)SOalkyl, -NHSO(aryl, heteroaryl, or heterocyclyl), -N(alkyl)SO(aryl, heteroaryl, or heterocyclyl), -NHSOalkenyl, -N(alkyl)SOalkenyl, -NHSOalkynyl, -N(alkyl)SOalkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclyl, and carbocycle.

4. The composition of claim 3, wherein the linker is selected from the group consisting of:

5. The composition of claim 3, wherein the linker is selected from the group consisting of:

6. The compound of any one of claims 1-5, wherein the targeting ligand is selected from the structures of Figures 1A to 8PPPPP, and R is the point to which the linker is attached.

7. The compound according to claim 1 or 2, wherein (linker) B yes in X 22 It's X 22a or X 22b ; X 22a Selected from halogen, -NH2, -NHR 4 、-N(R 4 )2, hydroxyl, mercapto, -B(OH)2, -Sn(R 6 )3、-Si(R 6 )3, -OS(O)2 alkyl, -OS(O)2 haloalkyl, alkenyl, alkynyl, ethynyl, vinyl, -C(O)H, -NR 4 C(O)olefins, -NR 4 C(O)alkyne, cyano, -SC(O)alkynyl, OC(O)alkyl, heterocyclyl, and -C(O)OH; X 22b is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, aliphatic, heteroaliphatic, and carbocycle; R 20 、R 21 、R 22 、R 23 and R 24 independently selected from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR 26 )-、-CH(-NR 4 R 4’ )-、-C(-OR 26 )alkyl-, -C(-NR 4 R 4’ )alkyl-, -C(R 40 R 40 )-、-alkyl(R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-、-NR 4 C(O)NR 4’ -, alkene, haloalkyl, alkoxy, alkynyl, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, carbocycle, -(ethylene glycol) 1-6 -,-(lactic-co-glycolic acid) 1-6 -,-(propylene glycol) 1-6 -、-O-(CH2) 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, -O-(CH2) 1-12 -NH-, -S-(CH2) 1-12 -O-, -O-(CH2) 1-12 -S-, -S-(CH2) 1-12 -S-, -S-(CH2) 1-12 -NH- and -NH-(CH2) 1-12 -S-; wherein 1-6 can independently be 1, 2, 3, 4, 5 or 6; wherein 1-12 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Each R 20 、R 21 、R 22 、R 23 and R 24 Optionally, one or more selected from R 101 Substituents substituted; R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl), aliphatic, and heteroaliphatic; R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclyl, aliphatic, and heteroaliphatic; R 27 and R 28 are independently selected from hydrogen, alkyl and amine; or together with the carbon atom to which they are attached form C(O), C(S), C=CH2, C3-C6 spirocarbocycle, or a 4-, 5- or 6-membered spiroheterocycle containing 1 or 2 heteroatoms selected from N and O, or form 1 or 2 carbon bridged rings; and R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic), -N(aliphatic), -NHSO(aliphatic), -N(aliphatic)SOalkyl, -NHSO(aryl, heteroaryl, or heterocyclyl), -N(alkyl)SO(aryl, heteroaryl, or heterocyclyl), -NHSOalkenyl, -N(alkyl)SOalkenyl, -NHSOalkynyl, -N(alkyl)SOalkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl, heterocyclyl, and carbocycle.

8. The compound of claim 7, wherein (linker) B Selected from:

9. The compound of any one of claims 1 to 8, wherein Selected from:

10. Compounds of the following formula or a pharmaceutically acceptable salt thereof; in: m is 1, 2, 3, or 4; n is 1, 2, 3, 4, 5, or 6; q is 1 or 2; R 1 and R 2 independently selected from hydrogen and fluorine; Each are independently a single bond or a double bond; Y 1 is CH, N or CR 3 ; R 3 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azido, nitro and R 5 ; X A is CH or N, where if X A is N, then yes and if X A is CH, then yes Or if the valence state allows, X A forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X A R 3 Replace, then X A It's CR 3 ; X B selected from NH and CH2; If X B R 3 Replace, then X B It is NR 3 or CHR 3 ; R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ; Each R 5 Independently selected from -Linker-Targeting Ligand and -(Linker) B ; R 6 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 8 is hydrogen, C1-C6 alkyl or R 5 ; If R 8 Not R 5 , then at least one R 3 Selected from R 5 ; A linker is a chemical group that 5 The attached atom is connected to the targeting ligand; -(Connector) B is a chemical group that is related to R 5 The attached atom is connected to, but not to, the targeting ligand; and Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of host disease.

11. The compound of claim 10, wherein Selected from:

12. Compounds of the following formula or a pharmaceutically acceptable salt thereof; in: m is 1, 2, 3, or 4; n is 1, 2, 3, 4, 5, or 6; q is 1 or 2; Y 1a is N, CH or CR 3a ; R 1 and R 2 independently selected from hydrogen and fluorine; Each are independently a single bond or a double bond; If X A R 3 Replace, then X A It's CR 3 ; R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ; R 6 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 3a is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azide, and nitro groups; X 1a is CH or N, where if X 1a is N, then yes and if X 1a is CH, then yes or When the valence state allows, X 1a forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X 1a R 3a Replace, then X 1a It's CR 3a ; X 2a is CH2 or NH; If X 2a R 3a Replace, then X 2a It is NR 3a or CHR 3a ;and R 8a is hydrogen or C1-C6 alkyl; and X 1b is CH or N, where if X 1b is N, then yes and if X 1b is CH, then yes or When the valence state allows, X 1b forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X 1b R 3a Replace, then X 1b It's CR 3a ; X 2b is NH or CH2; If X 2b R 3a Replace, then X 2b It is NR 3a or CHR 3a ;and If X 1b is N, then X 2b It can't be CH2.

13. Compounds of the following formula or a pharmaceutically acceptable salt thereof; in: m is 1, 2, 3, or 4; n is 1, 2, 3, 4, 5, or 6; q is 1 or 2; Y 1a is N, CH or CR 3a ; R 1 and R 2 independently selected from hydrogen and fluorine; Each are independently a single bond or a double bond; If X A R 3 Replace, then X A It's CR 3 ; R 4 and R 4’ is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ; R 6 is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl), and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 3a is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, aryl, heteroaryl, -OR 4 、-N(R 4 )(R 4’ ),-SR 4 、-C(O)R 6 、-(SO)R 6 、-(SO2)R 6 , halogen, cyano, azide, and nitro groups; X 1a is CH or N, where if X 1a is N, then yes and if X 1a is CH, then yes or When the valence state allows, X 1a forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X 1a R 3a Replace, then X 1a It's CR 3a ; X 2a is CH2 or NH; If X 2a R 3a Replace, then X 2a It is NR 3a or CHR 3a ;and R 8a is hydrogen C1-C6 alkyl; and X 1c is CH or N, where if X 1c is N, then yes and if X 1c is CH, then yes or When the valence state allows, X 1c forms a carbon-carbon double bond with the adjacent carbon to which it is attached; If X 1c R 3a Replace, then X 1c It's CR 3a ; X 2c is NH or CH2; If X 2c R 3a Replace, then X 2c It is NR 3a or CHR 3a ;and If X 1c is N, then X 2c Cannot be NH or NR 3a .

14. The compound of any one of claims 1 to 11, wherein Selected from:

15. A compound selected from: or a pharmaceutically acceptable salt thereof.

16. Compounds of the formula: or a pharmaceutically acceptable salt thereof; in: W 200 is O or S; R 201a is selected from -(C0-C2 alkyl)(cycloalkyl), -(C1-C2 alkyl)(monocyclic heterocyclyl), -(C1-C2 alkyl)(aryl) and -(C1-C2 alkyl)(heteroaryl), wherein R 201a R 208 and optionally substituted by one or more selected from R 205 and wherein the point of attachment of the monocyclic heterocyclic group is a carbon atom; or R 201a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 and –(CS)R 208 ; R 202a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 202a R 208 and optionally substituted by one or more selected from R 205 or R 202a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 or –(CS)R 208 ; R 203a is selected from -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(monocyclic heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 203a R 208 and optionally substituted by one or more selected from R 205 or R 203a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ; R 204a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 204a R 208 and optionally substituted by one or more selected from R 205 or R 204a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ; R 201 and R 202 R is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocycloalkyl), -(C0-C2 alkyl)(aryl), -(C0-C2 alkyl)(heteroaryl), and acyl, wherein each R other than hydrogen is 201 and R 202 may optionally be one or more selected from R 205 or R 201 yes R 203 and R 204 are independently selected from hydrogen, -OR 207 、-SR 207 、-NR 207 R 207’ , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CO)R 206 、-CH=CH(CO)R 206 and nitro, where each R other than hydrogen and halogen 203 and R 204 Can be selected from one or more R 205 The group substitution; R 205 independently selected at each occurrence from C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 Heterocyclyl, aryl, heteroaryl, -OR 207 、-N(R 207 )(R 207’ )、-S(R 207 ),-(CO)R 206 、-(CS)R 206 、-(C=NH)R 206 、-(SO)R 206 、-(SO2)R 206 , halogen, cyano, azido, R 208 and nitro; R 206 independently selected at each occurrence from hydrogen, C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 heterocyclyl, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl) and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, aryl or heteroaryl)2; R 207 and R 207’ independently selected at each occurrence from hydrogen, C1-C 12 Alkyl, C1-C 12 Halogenated alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C3-C 12 Heterocyclyl, aryl, heteroaryl, -(CO)R 206 、-(CS)R 206 、-(C=NH)R 206 、-(SO)R 206 and -(SO2)R 206 ; Y 200 O, S, -CH2-, -CHR 205 -or–C(R 205 )2-; Z 201 Selected from hydroxyl or amino; Z 202 Selected from O, S or CR 212 R 213 ; R 209 and R 210 Independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl; R 211 is selected from hydrogen, halogen, azido, cyano and heteroaryl; R 212 、R 213 、R 214 and R 215 are independently selected from hydrogen, -OR 207 , cyano, azido, halogen, -NHR 207 、-NR 207 R 207’ , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkyl and C1-C4 haloalkyl; or R 212 and R 214 can form a carbon-carbon double bond together with the carbon to which it is attached; or R 212 and R 214 can form a 3- to 6-membered carbocyclic ring together with the carbon to which it is attached; If R 212 is a hydroxyl group, then R 213 、R 214 and R 215 At least one of them is not hydrogen; If R 213 is a hydroxyl group, then R 212 、R 214 and R 215 At least one of R is not hydrogen; 216 is selected from hydrogen, methyl, hydroxymethyl and fluoromethyl; is selected at each occurrence from a single bond or a double bond; Each R 208 independently are – linker-targeting ligand; A linker is a chemical group that 208 The attached atom is linked to the targeting ligand; and Targeting ligands are molecules that bind to a target protein, where the target protein is a mediator of host disease; Z 200A selected from –OR 207 and –N(R 207 )(R 207 ’); Z 200B selected from –O(CO)R 208 、–N(R 207 )(CO)R 208 、-O(SO)R 208 、-N(R 207 )(SO)R 208 、-O(SO2)R 208 、-N(R 207 )(SO2)R 208 、–O(CS)R 208 、–N(R 207 )(CS)R 208 、–N(R 207 )(R 208 ) and –OR 208 ; R 213a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), wherein R 213a R 208 substituted, and optionally substituted with one or more groups; or R 213a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 , where if R 213a Yes–OR 208 , then R 212 、R 214 and R 215 At least one of them cannot be hydrogen; R 215a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclyl), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl); wherein R 215a R 208 and optionally substituted by one or more selected from R 205 The group substitution; or R 215a Selected from –(CO)R 208 、-(SO)R 208 、-(SO2)R 208 、–(CS)R 208 ,–N(R 207 )(R 208 ) and –OR 208 ;and R 250 and R 251 independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, azido, cyano, -OR 207 、-N(R 207 )(R 207’ ) or –SR 207 ; R 253 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl, heteroaryl and cyano; R 252 Selected from –N(R 207 )(R 208 ) and –OR 208 ;or R 252 is at least one R 208 and optionally substituted with one or more selected from R 205 a heterocyclic or heteroaryl group substituted with a group containing at least one nitrogen atom through which it is attached; R 254 Selected from: Q 201 Each instance of is independently selected from N, CH, CR 205 and CR 255a , where at least one Q 201 It's CR 255a ; Q 202 Each instance of is independently selected from N, CH, CR 205 and CR 255b , where at least one Q 202 It's CR 255b ; R 255a is a heterocyclyl moiety containing at least one nitrogen atom and attached via a carbon atom, wherein the heterocyclyl moiety may be replaced by one or more R 205 and wherein the heterocyclyl moiety may be substituted with one or more oxo groups where valence permits; and R 255b is a heterocyclyl moiety containing at least one nitrogen atom, wherein the heterocyclyl moiety may be replaced by one or more R 205 The heterocyclyl group may be substituted with one or more oxo groups, where valence permits.

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, wherein the composition is suitable for delivery to humans.

19. A method of treating a medical condition comprising administering to a host in need thereof an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 or 18.

20. A method for treating abnormal cell proliferation, comprising administering to a host in need thereof an effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17 or 18.

21. The method of claim 20, wherein the abnormal cell proliferation is cancer.

22. The method of claim 20, wherein the abnormal cell proliferation is a tumor.

23. The method of claim 20, wherein the abnormal cell proliferation is multiple myeloma.

24. The method of claim 20, wherein the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, leukemia, lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, Kaposi's sarcoma, Liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, breast cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma.

25. A method for preparing a medicament for therapeutic use in treating a disease, characterized in that The compound or pharmaceutical composition thereof according to any one of claims 1 to 18 is used in the preparation.

26. Use of a compound according to any one of claims 1 to 18 or a pharmaceutical composition thereof for the preparation of a medicament for treating a disease.

27. A method for preparing a medicament for therapeutic use in treating abnormal cell proliferation, characterized in that: The compound or pharmaceutical composition thereof according to any one of claims 1 to 18 is used in the preparation.

28. Use of a compound according to any one of claims 1 to 18 or a pharmaceutical composition thereof for preparing a medicament for treating abnormal cell proliferation.

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