Targeted protein degradation

Abstract

The present invention provides drug protein degraders and E3 ubiquitin ligase binders for therapeutic applications as further described herein.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 783,004, filed on Dec. 20, 2018. For all purposes, the entire contents of that application are hereby incorporated by reference. TECHNICAL FIELD

[0003] The present invention provides drug degraders and E3 ubiquitin ligase binders (degrons) for therapeutic applications as further described herein. BACKGROUND ART

[0004] Protein degradation is a highly regulated process that is essential for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded, or excessive proteins are 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, response to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0005] Multiple ubiquitin molecules are covalently linked to the terminal lysine residues of a protein by an E3 ubiquitin ligase for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, which are used as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular diseases, and cancer, among others.

[0006] Thalidomide and its analogs, lenalidomide and pomalidomide, have attracted attention as immunomodulators and anti-tumor 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" 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 mechanisms of action of thalidomide, lenalidomide, and pomalidomide are not fully understood, these compounds exhibit 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, forms an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), where it acts as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon promotes 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;. et al., “Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells” Science, 2014, 343:301-305).

[0007] The disclosure of the binding of thalidomide to the cereblon E3 ubiquitin ligase has led to research on incorporating thalidomide and certain derivatives into compounds to target the destruction of proteins. Celgene has disclosed imides with similar uses, including those in the following US patents: 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,959,566; 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.

[0008] Patent applications submitted by C4 Therapeutics, Inc. that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein to be degraded include: WO / 2019 / 204354, titled "Spirocyclic Compounds"; WO / 2019 / 191112, titled "Cereblon Binders for the Degradation of Ikaros"; WO / 2019 / 099868, titled "Degraders snd Degrons for Targeted Protein Degradation"; WO / 2018 / 237026, titled "N / O-Linked Degrons snd Degronimers gor ProteinDegradation"; WO 2017 / 197051, titled "Amine-Linked C3-Glutarimide Degronimersfor Target Protein Degradation"; WO 2017 / 197055, titled "HeterocyclicDegronimers for Target Protein Degradation"; WO 2017 / 197036, titled "SpirocyclicDegronimers for Target Protein Degradation"; WO 2017 / 197046, titled "C3-CarbonLinked Glutarimide Degronimers for Target Protein Degradation"; and WO 2017 / 197056, titled "Bromodomain Targeting Degronimers for Target ProteinDegradation.".

[0009] 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; WO2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 2017 / 046036; WO 2017 / 176708; WO2017 / 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.

[0010] The object of the present invention is to provide new compounds, methods, compositions and preparation methods that can be used to degrade selected proteins in vivo. Summary of the Invention

[0011] Compounds that can cause the degradation of selected proteins through the ubiquitin proteasome pathway (UPP), their uses and preparations are provided. Degradation determinant 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 that bind to E3 ligases (usually the cereblon subunit) are described. Degraders of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X and formula XI are disclosed, which include a "targeting ligand" that binds to the selected target protein, a "degradation determinant" that binds to the E3 ligase (usually through the cereblon subunit), and optionally a linker that covalently connects the targeting ligand to the degradation determinant.

[0012] The degraders provided herein, or their pharmaceutically acceptable salts or their pharmaceutically acceptable compositions, can be used to treat diseases mediated by the selected target proteins that bind to the targeting ligand. Accordingly, in some embodiments, a method of treating a host suffering from a disease mediated by a target protein is provided, the method comprising administering to the host an effective amount of the degrader described herein or its pharmaceutically acceptable salt, optionally in the form of a pharmaceutically acceptable composition.

[0013] In one embodiment, the selected target protein is derived from a gene that has undergone an amplification, translocation, rearrangement, copy number variation, alteration, deletion, mutation, or inversion event, which causes or is caused by a medical disease. In certain aspects, the selected target protein has been post-translationally modified by phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylation, ubiquitination, ubiquitin-like modification, or sulfation, either alone or in combination, which causes or is caused by a medical disease. In another embodiment, the target protein can be covalently modified with a targeting ligand that has been functionalized to create a covalent bond with the target protein, and the covalent bond can be irreversible or reversible.

[0014] In one aspect, there is provided a compound of Formula I or Formula II:

[0015]

[0016] or a pharmaceutically acceptable salt, N-oxide, isotopically derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0017] Wherein:

[0018] R 1 and R 2 are independently selected from hydrogen and fluorine;

[0019] Each is independently a single bond or a double bond;

[0020] R 3 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, 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 ;

[0021] Wherein for the compounds of Formula I and Formula II, at least one R 3 is selected from R 5 ;

[0022] m is 1, 2, 3 or 4;

[0023] n is 1, 2, 3, 4, 5 or 6;

[0024] o is 1, 2 or 3;

[0025] X A is CH or N, where if X A is N, then is and if X A is CH, then is or

[0026] When the valence allows, X A forms a carbon-carbon double bond with the adjacent carbon to which it is attached, for example can be

[0027] where if X A is substituted by R 3 then X A is CR 3 ;

[0028] X B is selected from NH and CH2;

[0029] where if X B is substituted by R 3 then X B is NR 3 or CHR 3 ;

[0030] R 4 and R 4’ are each independently selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, cyclopropyl or C1-C3 alkyl), C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, -(CO)R 6 、-(CS)R 6 、-(C=NH)R 6 、-(SO)R 6 and -(SO2)R 6 ;

[0031] Each R 5 is independently selected from – linker - targeting ligand and –(linker) B ;

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

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

[0034] -(linker) B is a group that is covalently attached to at least one degron and not attached to the 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 wherein

[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 are 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(-O-R 26 )-, -CH(-NR 4 R 4’ )-, -C(-O-R 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 group, aliphatic group, heteroaliphatic group, heteroaryl, lactic acid, glycolic acid, carbocyclic ring, -(ethylene glycol) 1-6 -, -(lactic acid - 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 substituting H with methyl, ethyl, cyclopropyl, F (if on carbon), etc. as described herein, and optionally inserting heteroatoms, heteroalkyl groups, aryl groups, heteroaryl groups 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] wherein each R 20 、R 21 、R 22 、R 23 and R 24 is optionally substituted by one or more substituents selected from R 101 or the substituents as described in the definition section;

[0041] R 101Independently selected from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl)2, aliphatic and heteroaliphatic at each occurrence;

[0042] R 26 Selected from hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;

[0043] R 27 and R 28 Independently selected from hydrogen, alkyl and amine; or together with the carbon atom to which it is attached form C(O), C(S), C=CH2, a C3-C6 spirocarbocyclic ring, or a 4-, 5- or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O, or form a 1- or 2-carbon bridged ring; and

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

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

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

[0047] Wherein

[0048] X 22 Is X 22a Or X 22b ;

[0049] X 22a Is selected from the following: halogen, -NH2, -NHR 4 , -N(R 4 )2, hydroxy, 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) alkene, -NR 4 C(O) alkyne, cyano, OC(O) alkyl, heterocyclic group, and -C(O)OH; and

[0050] X 22b is selected from hydrogen, alkyl, aryl, heteroaryl, aliphatic group, heteroaliphatic group, and carbocyclic group; and all other variables are defined above.

[0051] A targeting ligand is a molecule that binds 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, there is provided a compound 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] wherein:

[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] where for the compound of formula III, if R 8 is not R 5 , then at least one R 3 is selected from R 5 ; and

[0061] All other variables are defined as above.

[0062] In another aspect, there is provided a compound of formula IV:

[0063]

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

[0065] wherein for a compound of formula IV, at least one R 3 is R 5 ; and

[0066] all variables are as defined above.

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

[0068]

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

[0070] wherein for a compound of formula V, at least one R 3 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, there is provided a compound of formula VI or formula VII:

[0074]

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

[0076] wherein if R 8 is not R 5 , then at least one R 3 is R 5 ;

[0077] q is 1 or 2; and

[0078] all other variables are as defined above.

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

[0080]

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

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

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

[0084] Or R 9 and R 9’ may combine 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’ is hydrogen.

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

[0088] In another aspect, a compound of formula IX is provided:

[0089]

[0090] or a pharmaceutically acceptable salt, N-oxide, isotope 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 is R 5 ; and

[0092] All other variables are as defined above.

[0093] In another aspect, a compound of formula X or formula XI is provided:

[0094]

[0095] or a pharmaceutically acceptable salt, N-oxide, isotope 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 is R 5 ; and

[0097] All other variables are as defined above.

[0098] The structure of the degrader is typically selected such that it is stable enough to maintain a shelf life of at least two, three, four, or five months under environmental conditions. To this end, each R group described herein must be stable enough to maintain the corresponding desired shelf life of at least two, three, four, or five months under environmental conditions. Those of ordinary skill in the art are well aware of the stability of chemical moieties and can avoid those that are unstable or too reactive under appropriate conditions.

[0099] If it is desired to achieve the target effect, the degrader (degradation determinant, linker, and targeting ligand) containing any "R" group defined herein may be optionally substituted as defined in Part I below, resulting in a stable R moiety and a final compound that is chemically meaningful to those skilled in the art, and if the final compound is for therapeutic use, the compound is pharmaceutically acceptable. Moreover, all R groups, whether with or without optional substituents, should be interpreted in a non-redundant manner (i.e., as is known in the art, an alkyl group substituted by an alkyl group is redundant; however, for example, an alkoxy group substituted by an alkoxy group is not redundant).

[0100] In one aspect, the degraders of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI are bifunctional compounds that have an E3 ubiquitin ligase targeting moiety (degradation determinant) linked to a protein targeting ligand (described in more detail below), the function of which is to generally recruit a target protein for degradation via the 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, where the target protein is an oncoprotein or signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0101] Based on this discovery, compounds and methods are provided for treating a patient suffering from a disease mediated by a protein targeted for selective degradation, the method comprising administering to a patient in need (typically a human) an effective amount of one or a combination of the degraders of Formula I, Formula II, Formula III, Formula IV, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI 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 proteinopathies, proteinopathies, or fibrotic diseases. In typical embodiments, the patient is a human.

[0103] In one embodiment, the present invention provides degrons 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 the disorders 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 of the linkers described in Section IV (Linkers). In exemplary embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms, where one or more of the carbon atoms can be replaced by a heteroatom (such as O, N, S, or P), provided that the resulting molecule has a 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 contiguous atoms in the chain. For example, the chain can contain 1 or more ethylene glycol units, and in some embodiments, in the linker, there can be at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguous, or non-contiguous ethylene glycol units. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches, which can independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, and in one embodiment, each branch has 10, 8, 6, 4, 3, 2, or 1 carbon.

[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 amenable 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 degrons 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 the uses known for the following cereblon binders: thalidomide, pomalidomide, and lenalidomide.

[0108] In certain embodiments, the degradative degrader described herein can be activated to reduce or alter the native activity of cereblon. Non-limiting examples of uses of cereblon binders are for the treatment of multiple myeloma, hematological diseases such as myelodysplastic syndromes, cancer, tumors, abnormal cell proliferation, HIV / AIDS, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behçet'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] wherein:

[0113] R 3a is independently selected, each time it appears, from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, -OR 4 , -N(R 4 )(R 4’ ), -SR 4 , -C(O)R 6 , -(SO)R 6 , -(SO2)R 6 , halogen, cyano, azido, and nitro;

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

[0115] Where valence permits, X 1a forms a carbon-carbon double bond with the adjacent carbon to which it is attached, e.g., can be

[0116] where if X 1a is substituted by R 3a , then X 1a is CR 3a ;

[0117] X 2a is CH2 or NH;

[0118] Wherein if X 2a is replaced by R 3a then X 2a is NR 3a or CHR 3a ; and

[0119] All other variables are as defined above.

[0120] In another aspect, there is provided 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] Wherein:

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

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

[0126] All other variables are as defined above.

[0127] In another aspect, there is provided 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, there is provided 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] Wherein all variables are as defined above.

[0134] In another aspect, there is provided a compound 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] wherein all variables are as defined above.

[0138] In another aspect, there is provided 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] wherein all variables are as defined above.

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

[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] wherein:

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

[0147] Where valence permits, X 1b forms a carbon-carbon double bond with the adjacent carbon to which it is attached, for example can be

[0148] wherein if X 1b is replaced by R 3a then X 1b is CR 3a ;

[0149] X 2b is NH or CH2;

[0150] wherein if X 2b is replaced by R 3a then X 2b is NR 3a or CHR 3a ;

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

[0152] all other variables are as defined above.

[0153] In another aspect, there is provided a compound of formula XXI or XXII:

[0154]

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

[0156] wherein

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

[0158] where valence permits, X 1c forms a carbon-carbon double bond with the adjacent carbon to which it is attached, for example can be

[0159] wherein if X 1c is substituted by R 3a then X 1c is CR 3a ;

[0160] X 2c is NH or CH2;

[0161] wherein if X 2c is substituted by R 3a then X 2c is NR 3a or CHR 3a ;

[0162] wherein 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, a compound of Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI or Formula XXII is capable of activating, reducing or altering the native activity of cereblon.

[0166] When administered to a host (typically a human) in an effective amount, these 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 for treating medical disorders treatable with thalidomide, pomalidomide or lenalidomide, and / or including but not limited to abnormal cell proliferation, including tumors or cancer, or myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, Wiskott-Aldrich syndrome or post-transplant lymphoproliferative disorder; immune disorders, including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, Hashimoto's thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus or type I diabetes; cardiac insufficiency disorders including hypercholesterolemia; infectious diseases including viral or bacterial infections; and inflammation including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease or hepatitis.

[0167] In certain embodiments, the present invention provides administering an effective amount of 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 and Formula XXII to 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 (Formulas I, II, III, IV, V, VI, VII, VIII, IX, X and XI), or acts by binding to cereblon or its E3 ubiquitin ligase (Formulas XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI and XXII), or acts by an independent mechanism, optionally in combination with another bioactive agent.

[0168] A disease state or disorder can be caused by a microbial agent or other exogenous factor, such as a virus (as non-limiting examples, 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.), fungi, protozoa, parasitic worms (helminth), worms (worm), prions, parasites or other microorganisms.

[0169] In certain embodiments, the compounds 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 have at least one isotope substitution of a desired atom and are present in an amount higher than the natural abundance of that isotope, i.e., are enriched.

[0170] In one embodiment, the compounds 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 include one deuterium atom or multiple deuterium atoms.

[0171] The compounds of the present invention can provide important clinical benefits to patients, particularly for treating disease states and disorders regulated by the target protein.

[0172] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In this specification, the singular forms also include the plural 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 to be regarded as prior art for the claimed application. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods and examples are illustrative only and not intended to be limiting.

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

[0174] Accordingly, 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 degradation determinant of formula XII, formula XIII, formula XIV, formula XV, formula XVI, formula XVII, formula XVIII, formula XIX, formula XX, formula XXI or formula XXII as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof;

[0177] (c) 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 for treating a disease mediated by a target protein, or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, wherein the compound comprises a targeting ligand for the target protein, and wherein the degradation determinant is optionally linked to the targeting ligand via a linker;

[0178] (d) Use of an effective amount of 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 in treating a patient (usually a human) suffering from any one of the diseases described herein mediated by a target protein, the diseases including abnormal cell proliferation such as tumor or cancer, immune disease or autoimmune disease or inflammatory disease, heart disease, infectious disease or other diseases responsive to such treatment;

[0179] (e) Use of an effective amount of a compound of formula XII, formula XIII, formula XIV, formula XV, formula XVI, formula XVII, formula XVIII, formula XIX, formula XX, formula XXI or formula XXII in treating a patient (usually a human) suffering from a disease responsive to such treatment (including by reducing cereblon-based ubiquitination of the protein), the disease such as abnormal cell proliferation such as tumor or cancer, immune disease or autoimmune disease or inflammatory disease, heart disease, infectious disease or other diseases responsive to such treatment;

[0180] (f) Use of 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, in the preparation of a medicament for the treatment of a medical disorder as further described herein;

[0181] (g) A method of preparing a medicament for the therapeutic treatment of a disease in a host, characterized in that 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 is used in the preparation;

[0182] (h) 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, which is useful for the treatment of abnormal cell proliferation in a host, such as cancer, including any cancer described herein;

[0183] (i) Use of 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, a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivative) or prodrug thereof, in the preparation of a medicament for the treatment of abnormal cell proliferation (such as cancer, including any cancer described herein);

[0184] (j) A method of preparing a medicament for the therapeutic use in the treatment of abnormal cell proliferation (such as cancer, including any cancer described herein) in a host, characterized in that 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 is used in the preparation;

[0185] A compound of formula (k) 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 derivatives) or prodrug thereof, for the treatment of tumors in a host, including any tumor described herein;

[0186] (l) 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 derivatives) or prodrug thereof, for the treatment of tumors in a host, including any tumor described herein;

[0187] (m) A method for preparing a medicament for the therapeutic treatment of tumors in a host (including any tumor described herein), 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 as described herein is used in the preparation;

[0188] (n) 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 derivatives) or prodrug thereof, for the preparation of a medicament for the treatment of immune diseases, autoimmune diseases or inflammatory diseases 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 derivatives) or prodrug thereof, in the preparation of a medicament for the treatment of immune diseases, autoimmune diseases or inflammatory diseases 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, 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 is used in the preparation;

[0191] (q) 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, its pharmaceutically acceptable salts, isotopic derivatives and prodrugs, can be used for treating an infection in a host, including viral infections such as HIV, HBV, HCV and RSV;

[0192] (r) Use of 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 its pharmaceutically acceptable salts, isotopic derivatives (including deuterated derivatives) or prodrugs in the preparation of a medicament for treating an infection in a host, said infection including viral infections 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 viral infections such as HIV, HBV, HCV and RSV, characterized in that 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 is used in the preparation;

[0194] (t) A pharmaceutical formulation comprising a therapeutically effective amount for a host of 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 its pharmaceutically acceptable salts, isotopic derivatives or prodrugs, and a pharmaceutically acceptable carrier or diluent;

[0195] (u) Compounds 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 as described herein, as a mixture of enantiomers or a mixture of diastereomers (where relevant), including racemates;

[0196] (v) Compounds 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 as described herein in an enantiomerically or diastereomerically (where relevant) enriched form, including isolated enantiomers or diastereomers (i.e., with a purity greater than 85%, 90%, 95%, 97% or 99%); and

[0197] (w) A method for preparing a therapeutic product comprising 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 in an effective amount. Description of the Drawings

[0198] Figures 1A - 1C Shows examples of retinoic acid X receptor (RXR) - targeting ligands, where R is the point of attachment of the linker.

[0199] Figures 1D - 1F Shows examples of general dihydrofolate reductase (DHFR) - targeting ligands, where R is the point of attachment of the linker.

[0200] Figure 1G Shows examples of Bacillus anthracis dihydrofolate reductase (BaDHFR) - targeting ligands, where R is the point of attachment of the linker.

[0201] Figures 1H - 1J Shows examples of heat shock protein 90 (HSP90) - targeting ligands, where R is the point of attachment of the linker.

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

[0203] Figures 1R - 1S Shows examples of tyrosine kinase - targeting ligands, 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] Figures 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 the linker.

[0211] Figures 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 the linker.

[0214] Figures 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] Figures 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] Figures 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 the 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] Figures 1BBB - 1CCC Examples of MCL-1 targeting ligands are shown, where R is the point of attachment of the linker.

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

[0227] Figures 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] Figures 1HHH - 1III Examples of EGFR targeting ligands are shown, where R is the point of attachment of the linker.

[0230] Figures 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 Examples of the kinase inhibitor targeting ligand U09-CX-5279 (derivatized) are 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 the following: 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 kinase inhibitor compounds 6TP and 0TP (derivatized), where R is the point of attachment of the linker. For additional examples and related ligands, see the kinase inhibitors identified in the following: 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 the linker. For additional examples and related ligands, see the kinase inhibitors identified in the following: Van Eis et al., “26 - Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes” Biorg. Med. Chem. Lett., 21(24):7367 - 72(2011).

[0236] Figure 2F Examples of kinase inhibitor targeting ligands are shown, including 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 the following: 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 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 the following: 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 of 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 CR8 Trigger 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 the potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer–From p.o. to i.v. application via scaffold hops.” Lücking et al., U. AACR Annual Meeting, April 1–5, 2017 Washington, D.C. USA。

[0240] Figures 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 Y.S. et al., “Fragment-Based Discovery of 7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4 / 6 Inhibitors.” ACS Med Chem Lett 3:445-449 (2012); Li Z. et al., “Discovery of AMG 925 a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.” J. Med. Chem. 57:3430-3449 (2014); Chen P. et al., “Spectrum and 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 the 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] Figures 2R - 2S Examples of glucocorticoid receptor-targeting ligands are shown, where R is the point of attachment of the linker.

[0243] Figures 2T - 2U Examples of RasG12C-targeting ligands are shown, where R is the point of attachment of the linker.

[0244] Figure 2V Examples of Her3-targeting ligands are shown, where R is the point of attachment of the linker and R' is or

[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] Figures 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 B.B. et al., “The role of the acidity of N-heteroarylsulfonamides as inhibitors of bcl-2 family protein-protein interactions.” ACS Med Chem Lett, 4:186-190 (2013); Porter J. et al., “Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as Selective Bcl-2 Inhibitors” Bioorg. Med. Chem. Lett. 19:230 (2009); Souers A.J. et al., “ABT-199 a 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, entitled "Novel derivatives of indole and pyrrole method for the production thereof and pharmaceutical compositions containing same"; WO2008060569A1, entitled "Compounds and methods for inhibiting the interaction of Bcl proteins with binding partners"; "Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review" Expert Opin. Ther. Patents 22(1):2008(2012); and Porter et al., "Tetrahydroisoquinolineamide substituted phenyl pyrazoles as selective Bcl-2 inhibitors" Bioorg Med Chem Lett.,19(1):230-3(2009).

[0247] Figures 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 cell survival dependencies and define improved strategies for cancer therapy” Science Translational Medicine, 7:279ra40 (2015); and the 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] Figures 2WW - 2YY Examples of EGFR targeting ligands are shown, which target the EGFR L858R mutant, including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, where R is the point of attachment of the linker.

[0250] Figures 2ZZ - 2FFF Examples of EGFR targeting ligands are shown, which target the EGFR T790M mutant, including osimertinib, rociletinib, omoertinib, 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 the linker.

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

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

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

[0255] Figure 2LLL Examples of JAK2 targeting ligands that target the JAK2 V617F mutant are shown, including ruxolitinib, where R is the point of attachment of the linker.

[0256] Figure 2MMM Examples of BRAF targeting ligands that target 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 are shown, including dabrafenib, where R is the point of attachment of the linker.

[0258] Figure 2OOO Examples of LRRK2 targeting ligands that target the LRRK2 R1441C mutant are 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 2QQQ Examples of LRRK2 targeting ligands that target the LRRK2 I2020T mutant are shown, where R is the point of attachment of the linker.

[0261] Figures 2RRR - 2TTTExamples of PDGFRα-targeted 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 attachment point of the linker.

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

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

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

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

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

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

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

[0269] Figure 2BBBB Examples of 5-lipoxygenase activating protein (FLAP)-targeted ligands are shown, where R is the attachment point of the linker.

[0270] Figure 2CCCC Examples of Kringle domain V 4BVV-targeted ligands are shown, where R is the attachment point of the linker.

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

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

[0273] Figures 2GGGG - 2JJJJExamples of Xa factor-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]-1,3-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An Oral Direct Factor Xa Inhibitor.” J. Med. Chem. 48:5900 (2005); Anselm L. et al., “Discovery of a Factor Xa Inhibitor (3R,4R)-1-(2,2-Difluoro-Ethyl)-Pyrrolidine-3,4-Dicarboxylic Acid 3-[(5-Chloro-Pyridin-2-Yl)-Amide]4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a Clinical Candidate.” Bioorg. Med. Chem. 20:5313 (2010); and Pinto D.J.et al., "Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 5 6 7-tetrahydro-1H-pyrazolo[3 4-c]pyridine-3-carboxamide (Apixaban BMS-562247), a Highly Potent Selective Efficacious and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa." J. Med. Chem. 50:5339-5356 (2007).

[0274] 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).

[0275] Figures 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).

[0276] 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).

[0277] 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 P.K. et al., “Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm” ACS Med. Chem. Lett. 5:1138 - 1142.” (2014).

[0278] Figures 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 J.G. et al., “Potent and Selective Inhibitors of Mth1 Probe its Role in Cancer Cell Survival.” J. Med. Chem. 59:2346 (2016); Huber K.V.M. et al., “Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.” Nature 508:222 (2014); Gad H. et al., “MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.” Nature 508:215-221 (2014); Nissink J.W.M. et al., “Mth1 Substrate Recognition--an Example of Specific Promiscuity.” Plos One 11:51154 (2016); and Manuel Ellermann et al., “Novel class of potent and selective inhibitors efface MTH1 as broad-spectrum cancer target.” AACR National Meeting Abstract 5226, 2017.

[0279] Figures 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 G.M. et al., “Structures of low molecularweight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX / MDM2 antagonist drug discovery.” Cell Cycle, 9 (2010); Miyazaki M. et al., “Synthesisand 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 interactioninhibitor.” Bioorg Med Chem. 23:2360-7 (2015); Holzer P. et al., “Discovery of aDihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and SelectiveMDM2 Inhibitor Undergoing Phase 1Clinical Trials in p53wt Tumors.” J.Med.Chem. 58:6348-6358 (2015); Gonzalez-Lopez de Turiso F. et al., “Rational Designand Binding Mode Duality of MDM2-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 a distinct binding mode.” Bioorg.Med.Chem.Lett. 25:3621-3625 (2015); Fry D.C.Ding Q., et 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).

[0280] Figures 2AAAAA - 2EEEEEExamples of PARP1, PARP2, and / or PARP3 targeting ligands are shown, where R is the point of attachment of the 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 / 2 inhibitors.” Febs Lett. 579:1389-1393 (2005); crystal structure PDB 2RCW (PARP complexed with A861695, Park C.H.); crystal structure PDB 2RD6 (PARP complexed with A861696, Park C.H.); crystal structure PDB 3GN7; Miyashiro J. et al., “Synthesis and SAR of novel tricyclic quinoxalinone inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)” Bioorg. Med. Chem. Lett. 19:4050-4054 (2009); Gandhi V.B. et al., “Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.” Bioorg. Med. Chem. Lett. 20:1023-1026 (2010); Penning T.D. et al., “Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492) a highly potent and efficacious inhibitor.” J. Med. Chem. 53:3142-3153 (2010); Ye N.et al., "Design, Synthesis, and Biological Evaluation of a Series of Benzo[de]

[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 PDB 4RV6 ("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 A.R. et al., “Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose) polymerase inhibitors.” Bioorg. Med. Chem. Lett. 23:4501-4505(2013).

[0281] Figures 2FFFFF - 2GGGGG Examples of PARP14-targeting ligands are shown, where R is the point of attachment of the linker.

[0282] Figure 2HHHHH Examples of PARP15-targeting ligands are shown, where R is the point of attachment of the linker.

[0283] Figure 2IIIII Examples of PDZ domain-targeting ligands are shown, where R is the point of attachment of one or more linkers.

[0284] Figure 2JJJJJ Examples of phospholipase A2 domain-targeting ligands are shown, where R is the point of attachment of the linker.

[0285] Figure 2KKKKK Examples of protein S100-A7 2WOS-targeting ligands are shown, where R is the point of attachment of the linker.

[0286] Figures 2LLLLL - 2MMMMM Examples of Saposin-B-targeting ligands are shown, where R is the point of attachment of the linker.

[0287] Figures 2NNNNN - 2OOOOO Examples of Sec7-targeting ligands are shown, where R is the point of attachment of the linker.

[0288] Figures 2PPPPP - 2QQQQQ Examples of pp60 Src's SH2 domain-targeting ligands are shown, where R is the point of attachment of the linker.

[0289] Figure 2RRRRR Examples of Tank1-targeting ligands are shown, where R is the point of attachment of the linker.

[0290] Figure 2SSSSS Examples of Ubc9 SUMO E2 ligase SF6D-targeting ligands are shown, where R is the point of attachment of the linker.

[0291] Figure 2TTTTT Examples of Src-targeted ligands are shown, including AP23464, where R is the attachment point of the linker.

[0292] Figures 2UUUUU - 2XXXXX Examples of Src-AS1 and / or Src AS2-targeted ligands are shown, where R is the attachment point of the linker.

[0293] Figure 2YYYYY Examples of JAK3-targeted ligands are shown, including tofacitinib, where R is the attachment point of the linker.

[0294] Figure 2ZZZZZ Examples of ABL-targeted ligands are shown, including tofacitinib and ponatinib, where R is the attachment point of the linker.

[0295] Figures 3A - 3B Examples of MEK1-targeted ligands are shown, including PD318088, trametinib, and G-573, where R is the attachment point of the linker.

[0296] Figure 3C Examples of KIT-targeted ligands are shown, including regorafenib, where R is the attachment point of the linker.

[0297] Figures 3D - 3E Examples of HIV reverse transcriptase-targeted ligands are shown, including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir, where R is the attachment point of the linker.

[0298] Figures 3F - 3G Examples of HIV protease-targeted ligands are shown, including ritonavir, raltegravir, and atazanavir, where R is the attachment point of the linker.

[0299] Figures 3H - 3I Examples of KSR1-targeted ligands are shown, where R is the attachment point of the linker.

[0300] Figures 3J - 3L Examples of CNNTB1-targeted ligands are shown, where R is the attachment point of the linker.

[0301] Figure 3M Examples of BCL6-targeted ligands are shown, where R is the attachment point of the linker.

[0302] Figures 3N - 3O Examples of PAK1-targeted ligands are shown, where R is the attachment point of the linker.

[0303] Figures 3P - 3R Examples of PAK4-targeted ligands are shown, where R is the attachment point of the linker.

[0304] Figures 3S - 3TExamples of TNIK - targeting ligands are shown, where R is the point of attachment of the linker.

[0305] Figure 3U Examples of MEN1 - targeting ligands are shown, where R is the point of attachment of the linker.

[0306] Figures 3V - 3W Examples of ERK1 - targeting ligands are shown, where R is the point of attachment of the linker.

[0307] Figure 3X Examples of IDO1 - targeting ligands are shown, where R is the point of attachment of the linker.

[0308] Figure 3Y Examples of CBP - targeting ligands are shown, where R is the point of attachment of the linker.

[0309] Figures 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 structural analysis of target proteins.” J. Med. Chem. 56:9635-9645 (2013); Friberg A. et al., “Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.” J. Med. Chem. 56:15-30 (2013); Petros A.M. et al., “Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.” Bioorg. Med. Chem. Lett. 24:1484-1488 (2014); Burke J.P. et al., “Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design.” J. Med. Chem. 58:3794-3805 (2015); Pelz N.F. et al., “Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.” J. Med. Chem. 59:2054-2066 (2016); Clifton M.C. et al., “A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1.”Plos One 10:e0125010-e0125010(2015); Kotschy A et al., “The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 538:477-482(2016); EP 2886545 A1 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); US 2016 / 0068545, titled "Tetrahydronaphthalene derivatives that inhibit mcl-1 protein"; WO 2016207217A1, titled "Preparation of new bicyclic derivatives as pro-apoptotic agents"; Gizem. et al., "Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain" Nature Chemical Biology 12:931–936(2016).

[0310] Figure 3TT Examples of ASH1L targeting ligands are shown, where R is the point of attachment of the linker. See, for example, the crystal structure PDB 4YNM ("Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)" Rogawski D.S. et al.).

[0311] Figures 3UU - 3WWExamples of ATAD2 targeting ligands are shown, where R is the point of attachment of the 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 M.J. et al., “Fragment-Based Screening of the Bromodomain of ATAD2.” J. Med. Chem. 57:9687-9692 (2014); Demont E.H. et al., “Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors.” J. Med. Chem. 58:5649 (2015); and Bamborough P. et al., “Structure-Based Optimization of Naphthyridones into Potent Atad2 Bromodomain Inhibitors.” J. Med. Chem. 58:6151 (2015).

[0312] Figures 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, F.M. et al., "Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain.", J. Med. Chem. 56:10183-10187 (2013); Marchand J.R. et al., "Derivatives of 3-Amino-2-methylpyridine as BAZ2B Bromodomain 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 of GSK2801 a selective chemical probe for the bromodomains BAZ2A and BAZ2B.", J. Med. Chem. 59:1410-1424 (2016).

[0313] 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 Fragment 4-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).

[0314] Figures 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.

[0315] Figures 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 K.G. et al., “RVX-208: an Inducer of ApoA-I in Humans is a BET Bromodomain Antagonist.” Plos One 8:e83190-e83190 (2013); Baud M.G. et al., “Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes” Science 346:638-641 (2014); Baud M.G. et al., “New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition” J. Med. Chem. 59:1492-1500 (2016); 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 a hydroquinolinone inhibitor”, Tallant C. et al.); crystal structure PDB 5BT5; crystal structure PDB 5dfd; Baud M.G.et al., “New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition” J. Med. Chem. 59:1492-1500 (2016).

[0316] Figures 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.

[0317] Figures 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 C.W. 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).

[0318] 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.

[0319] Figures 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.

[0320] Figure 3RRR Examples of SMARCA4 PB1 and / or SMARCA2 targeting ligands are shown, where 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.

[0321] Figures 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, WO2015 / 011084.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] Figure 3CCCCExamples of TRIM24 (TIF1a)-targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Palmer W.S. et al., “Structure-Guided Design of IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.” J. Med. Chem. 59:1440-1454 (2016).

[0327] Figures 3DDDD - 3FFFF Examples of BRPF1-targeting ligands are shown, where 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.

[0328] 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).

[0329] Figures 3HHHH - 3OOOOExamples of CREBBP - targeting ligands are shown, where 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 3p1d; crystal structure PDB 3svh; crystal structure PDB 4nr4; crystal structure PDB 4nr5; crystal structure PDB 4ts8; crystal structure PDB 4nr6; crystal structure PDB 4nr7; crystal structure PDB 4nyw; crystal structure PDB 4nyx; crystal structure PDB 4tqn; crystal structure PDB 5cgp; crystal structure PDB 5dbm; crystal structure PDB 5ep7; crystal structure PDB 5i83; crystal structure PDB 5i86; crystal structure PDB 5i89; crystal structure PDB 5i8g; crystal structure PDB 5j0d; crystal structure PDB 5ktu; crystal structure PDB 5ktw; crystal structure PDB 5ktx; crystal structure PDB 5tb6.

[0330] Figure 3PPPP 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.

[0331] Figure 3QQQQ Examples of PCAF - targeting ligands are 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).

[0332] 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).

[0333] 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).

[0334] Figure 3TTTTExamples of histone deacetylase 2 (HDAC2)-targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Lauffer B. E. J. Biol. Chem. 288:26926-26943 (2013); Wagner F. F. Bioorg. Med. Chem. 24:4008-4015 (2016); Bressi J. C. Bioorg. Med. Chem. Lett. 20:3142-3145 (2010); and Lauffer B. E. J. Biol. Chem. 288:26926-26943 (2013).

[0335] Figures 3UUUU - 3VVVV Examples of histone deacetylase 4 (HDAC4)-targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Burli R. W. J. Med. Chem. 56:9934 (2013); Luckhurst C. A. ACS Med. Chem. Lett. 7:34 (2016); Bottomley M. J. J. Biol. Chem. 283:26694-26704 (2008).

[0336] 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 R. J. (to be published); Hai Y. Nat. Chem. Biol. 12:741-747, (2016); and Miyake Y. Nat. Chem. Biol. 12:748 (2016).

[0337] Figures 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).

[0338] Figures 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 A.A. J. Struct. Biol. 195:373-378 (2016); Dowling D.P. Biochemistry 47, 13554-13563 (2008); Somoza J.R. Biochemistry 12, 1325-1334 (2004); Decroos C. Biochemistry 54:2126-2135 (2015); Vannini A. Proc. Natl Acad. Sci. 101:15064 (2004); Vannini A. EMBO Rep. 8:879 (2007); crystal structure PDB 5BWZ; Decroos A. ACS Chem. Biol. 9:2157-2164 (2014); Somoza J.R. Biochemistry 12:1325-1334 (2004); Decroos C. Biochemistry 54:6501-6513 (2015); Decroos A. ACS Chem. Biol. 9:2157-2164 (2014); and Dowling D.P. Biochemistry 47:13554-13563 (2008).

[0339] Figure 3EEEEE Examples of histone acetyltransferase (KAT2B) targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Chaikuad A. J. Med. Chem. 59:1648-1653 (2016); crystal structure PDB 1ZS5; and Zeng L. J. Am. Chem. Soc. 127:2376-2377 (2005).

[0340] Figures 3FFFFF - 3GGGGG Examples of histone acetyltransferase (KAT2A) targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Ringel A.E. Acta Crystallogr. D. Struct. Biol. 72:841-848 (2016).

[0341] Figure 3HHHHHExamples of ligands targeted to the catalytic unit of histone acetyltransferase B (HAT1) are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structure PDB 2P0W.

[0342] Figure 3IIIII Examples of ligands targeted to the cyclic AMP-dependent transcription factor (ATF2) are shown, where R is the point of attachment of the linker.

[0343] Figure 3JJJJJ Examples of ligands targeted to histone acetyltransferase (KAT5) are shown, where R is the point of attachment of the linker.

[0344] Figure 3 KKKKK - 3 MMMMM Examples of ligands targeted to lysine-specific histone demethylase 1A (KDM1A) are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see Mimasu S. Biochemistry 49:6494 - 6503 (2010); Sartori L. J. Med. Chem. 60:1673 - 1693 (2017); and Vianello P. J. Med. Chem. 60:1693 - 1715 (2017).

[0345] Figure 3 NNNNN Examples of ligands targeted to the HDAC6 Zn finger domain are shown, where R is the point of attachment of the linker.

[0346] Figure 3 OOOOO - 3 PPPP Examples of ligands targeted to the general lysine methyltransferase are shown, where R is the point of attachment of the linker.

[0347] Figure 3 QQQQQ - 3 TTTTT Examples of ligands targeted to DOT1L are shown, where 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 the crystal structure PDB 5MVS (“Dot1L in complex with adenosine and inhibitor CPD1” Be C. et al.); the crystal structure PDB 5MW4 (“Dot1L in complex inhibitor CPD7” Be C. et al.); the crystal structure PDB 5DRT (“Dot1L in complex inhibitor CPD2” Be C. et al.); Be C. et al., ACS Med. Lett. 8:338 - 343 (2017); the crystal structure PDB 5JUW “(Dot1L in complex with SS148” Yu W. et al., Structural Genomics Consortium).

[0348] Figure 3 UUUUU Examples of EHMT1 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 5TUZ (“EHMT1 in complex with inhibitor MS0124”, Babault N. et al.).

[0349] Figure 3 VVVVV Examples of EHMT2 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 5TUY (“EHMT2 in complex with inhibitor MS0124”, Babault N. et al.); PDB crystal structure 5TTF (“EHMT2 in complex with inhibitor MS012”, Dong A. et al.); PDB crystal structure 3RJW (Dong A. et al., Structural Genomics Consortium); PDB crystal structure 3K5K; Liu F. et al., J. Med. Chem. 52:7950 - 7953 (2009); and, PDB crystal structure 4NVQ (“EHMT2 in complex with inhibitor A - 366” Sweis R.F. et al.).

[0350] Figure 3 WWWWW Examples of SETD2 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the PDB crystal structure 5LSY (“SETD2 in complex with cyproheptadine”, Tisi D. et al.); Tisi D. et al., ACS Chem. Biol. 11:3093 - 3105 (2016); crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6, 5LT7 and 5LT8; PDB crystal structure 4FMU; and, Zheng W. et al., J. Am. Chem. Soc. 134:18004 - 18014 (2012).

[0351] Figure 3 XXXXX - 3 YYYYYExamples 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).

[0352] Figure 3 ZZZZZ 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).

[0353] Figure 4A - 4B Examples of SETDB1 targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 5KE2 (“SETDB1 in complex with inhibitor XST06472A”, Iqbal A. et al.); PDB crystal structure 5KE3 (“SETDB1 in complex with fragment MRT0181a”, Iqbal A. et al.); PDB crystal structure 5KH6 (“SETDB1 in complex with fragment methyl 3-(methylsulfonylamino)benzoate”, Walker J.R. et al., Structural Genomics Consortium); and PDB crystal structure 5KCO (“SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide”, Walker J.R. et al.).

[0354] Figure 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 S.D. et al.); PDB crystal structure 5KJM (“SMYD2 in complex with AZ931”, Cowen S.D. et al.); PDB crystal structure 5KJN (“SMYD2 in complex with AZ506”, Cowen S.D. et al.); PDB crystal structure 5ARF (“SMYD2 in complex with N-[3-(4-chlorophenyl)-1-{N'-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-4,5-dihydro-1H-pyrazol-4-YL]-N-ethyl-2-hydroxyacetamide”, Eggert E. et al.); PDB crystal structure 5ARG (“SMYD2 in complex with BAY598”, Eggert E. et al.); PDB crystal structure 4YND (“SMYD2 in complex with A-893”, Sweis R.F. et al.); PDB crystal structure 4WUY (“SMYD2 in complex with LLY-507”, Nguyen H. et al.); and, PDB crystal structure 3S7B (“N-cyclohexyl-N~3~-[2-(3,4-dichlorophenyl)ethyl]-N-(2-{[2-(5-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide”, Ferguson A.D. et al.).

[0355] 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 G.S. et al.); crystal structure 5CCL (“SMYD3 in complex with oxindole compound”, Mitchell L.H. et al.); and, crystal structure 5CCM (“Crystal structure of SMYD3 with SAM and EPZ030456”).

[0356] 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 K.D. et al.).

[0357] 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 incomplex with 4-(pyrrolidin-1-yl)benzonitrile derivatives”, Asano M. et al.); Asano M. et al., Bioorg. Med. Chem. Lett. 27:1897-1901 (2017); PDB crystal structure 5JJM (“AndrogenReceptor”, Nadal M. et al.); PDB crystal structure 5CJ6 (“Androgen Receptor in complex with 2-Chloro-4-[[(1R 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile derivatives”, Saeed A. et al.); PDB crystal structure 4QL8 (“Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolines derivatives”, Ullrich T. et al.); PDB crystal structure 4HLW (“Androgen Receptor Binding Function 3 (BF3) Site of the Human AndrogenReceptor through Virtual Screening”, Munuganti R.S. et al.); PDB crystal structure 3V49 (“Androgen Receptor lbd with activator peptide and sarm inhibitor 1”, Nique F. et al.); Nique F. et al., J. Med. Chem. 55:8225-8235 (2012); PDB crystal structure 2YHD (“AndrogenReceptor 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 C.E. et al.); Bohl C.E. et al., J. Med. Chem.54:3973 - 3976(2011); PDB crystal structure 3B5R (“Androgen Receptor ligand binding domain in complex with SARM C - 31”, Bohl C.E. et al.); Bohl C.E. et al., Bioorg. Med. Chem. Lett. 18:5567 - 5570(2008); PDB crystal structure 2PIP (“Androgen Receptor ligand binding domain in complex with small molecule”, Estebanez - Perpina E. et al.); Estebanez - Perpina.E., Proc. Natl. Acad. Sci. 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 P.M. et al., “Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor(Ar(Ccr))Derived from an Androgen - Independent Prostate Cancer.” J. Med. Chem. 45:1439(2002); Sack J.S. et al., “Crystallographic structures of the ligand - binding domains of the androgen receptor and its T877A mutant 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-[[(1R,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen Receptor Modulator (SARM) for Muscle Atrophy." J. Med. Chem. 59:750-755 (2016); 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).

[0358] Figure 4BBExamples of mutant T877A 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 structure 4OGH (‘Androgen Receptor T877A-AR-LBD”, Hsu C.L. et al.) and PDB crystal structure 2OZ7(“Androgen Receptor T877A-AR-LBD”, Bohl C.E. et al.).

[0359] Figure 4CC Examples of mutant W741L 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 structure 4OJB(“Androgen Receptor T877A-AR-LBD”, Hsu C.L. et al.).

[0360] Figure 4DD - 4EE Examples of estrogen and / or androgen targeting ligands are shown, where R is the point of attachment of the linker.

[0361] Figure 5A Examples of afatinib (a targeting ligand for EGFR and ErbB2 / 4 receptors) are shown. R is the point of attachment of the linker.

[0362] Figure 5B Examples of axitinib (a targeting ligand for VEGFR1 / 2 / 3, PDGFRβ and Kit receptors) are shown. R is the point of attachment of the linker.

[0363] Figure 5C - 5D Examples of bosutinib (a targeting ligand for BCR-Abl, Src, Lyn and Hck receptors) are shown. R is the point of attachment of the linker.

[0364] Figure 5E Examples of cabozantinib (a targeting ligand for RET, c-Met, VEGFR1 / 2 / 3, Kit, TrkB, Flt3, Axl and Tie2 receptors) are shown. R is the point of attachment of the linker.

[0365] Figure 5F Examples of ceritinib (a targeting ligand for ALK, IGF-1R, InsR and ROS1 receptors) are shown. R is the point of attachment of the linker.

[0366] Figure 5G Examples of crizotinib (a targeting ligand for ALK, c-Met, HGFR, ROS1 and MST1R receptors) are shown. R is the point of attachment of the linker.

[0367] Figure 5HExamples of dabrafenib (a targeted ligand for the B-Raf receptor) are shown. R is the point of attachment of the linker.

[0368] Figure 5I Examples of dasatinib (a targeted ligand for the BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors) are shown. R is the point of attachment of the linker.

[0369] Figure 5J Examples of erlotinib (a targeted ligand for the EGFR receptor) are shown. R is the point of attachment of the linker.

[0370] Figure 5K - 5M Examples of everolimus (a targeted ligand for the HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor) are shown. R is the point of attachment of the linker.

[0371] Figure 5N Examples of gefitinib (a targeted ligand for the EGFR and PDGFR receptors) are shown. R is the point of attachment of the linker.

[0372] Figure 5O Examples of ibrutinib (a targeted ligand for the BTK receptor) are shown. R is the point of attachment of the linker.

[0373] Figure 5P - 5Q Examples of imatinib (a targeted ligand for the BCR-Abl, Kit, and PDGFR receptors) are shown. R is the point of attachment of the linker.

[0374] Figure 5R - 5S Examples of lapatinib (a targeted ligand for the EGFR and ErbB2 receptors) are shown. R is the point of attachment of the linker.

[0375] Figure 5T Examples of lenvatinib (a targeted ligand for the VEGFR1 / 2 / 3, FGFR1 / 2 / 3 / 4, PDGFRα, Kit, and RET receptors) are shown. R is the point of attachment of the linker.

[0376] Figure 5U - 5V Examples of nilotinib (a targeted ligand for the BCR-Abl, PDGRF, and DDR1 receptors) are shown. R is the point of attachment of the linker.

[0377] Figure 5W - 5X Examples of nintedanib (a targeted ligand for the FGFR1 / 2 / 3, Flt3, Lck, PDGFRα / β, and VEGFR1 / 2 / 3 receptors) are shown. R is the point of attachment of the linker.

[0378] Figure 5Y - 5ZExamples of palbociclib (a targeted ligand for the CDK4 / 6 receptor) are shown. R is the point of attachment of the linker.

[0379] Figure 5AA Examples of pazopanib (a targeted ligand for VEGFR1 / 2 / 3, PDGFRα / β, FGFR1 / 3, Kit, Lck, Fms and Itk receptors) are shown. R is the point of attachment of the linker.

[0380] Figure 5BB - 5CC Examples of ponatinib (a targeted ligand for BCR-Abl, T315I VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2 and Flt3 receptors) are shown. R is the point of attachment of the linker.

[0381] Figure 5DD Examples of regorafenib (a targeted ligand for VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf(V600E), Kit, PDGFRα / β, RET, FGFR1 / 2, Tie2 and Eph2A) are shown. R is the point of attachment of the linker.

[0382] Figure 5EE Examples of ruxolitinib (a targeted ligand for the JAK1 / 2 receptor) are shown. R is the point of attachment of the linker.

[0383] Figure 5FF - 5GG Examples of sirolimus (a targeted ligand for the FKBP12 / mTOR receptor) are shown. R is the point of attachment of the linker.

[0384] Figure 5HH Examples of sorafenib (a targeted ligand for B-Raf, CDK8, Kit, Flt3, RET, VEGFR1 / 2 / 3 and PDGFR receptors) are shown. R is the point of attachment of the linker.

[0385] Figure 5II - 5JJ Examples of sunitinib (a targeted ligand for PDGFRα / β, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, RET) are shown. R is the point of attachment of the linker.

[0386] Figure 5KK - 5LL Examples of temsirolimus (a targeted ligand for FKBP12 / mTOR) are shown. R is the point of attachment of the linker.

[0387] Figure 5MM Examples of tofacitinib (a targeted ligand for the JAK3 receptor) are shown. R is the point of attachment of the linker.

[0388] Figure 5NNExamples of trametinib (a targeted ligand for the MEK1 / 2 receptor) are shown. R is the point of attachment of the linker.

[0389] Figure 5OO - 5PP Examples of vandetanib (a targeted ligand for EGFR, VEGFR, RET, Tie2, Brk, and EphR) are shown. R is the point of attachment of the linker.

[0390] Figure 5QQ Examples of vemurafenib (a targeted ligand for A / B / C-Raf, KSR1, and B-Raf (V600E) receptors) are shown. R is the point of attachment of the linker.

[0391] Figure 5RR Examples of Idelasib (a targeted ligand for the PI3Ka receptor) are shown. R is the point of attachment of the linker.

[0392] Figure 5SS Examples of Buparlisib (a targeted ligand for the PI3Ka receptor) are shown. R is the point of attachment of the linker.

[0393] Figure 5TT Examples of Taselisib (a targeted ligand for the PI3Ka receptor) are shown. R is the point of attachment of the linker.

[0394] Figure 5UU Examples of Copanlisib (a targeted ligand for PI3Ka) are shown. R is the point of attachment of the linker.

[0395] Figure 5VV Examples of Alpelisib (a targeted ligand for PI3Ka) are shown. R is the point of attachment of the linker.

[0396] Figure 5WW Examples of niclosamide (a targeted ligand for CNNTB1) are shown. R is the point of attachment of the linker.

[0397] Figure 6A - 6BExamples of targeted ligands of 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 PCAFBromodomain 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 Selectivep300 / CBP-Associated Factor (PCAF) / General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe”); and, Humphreys, P.G. et al., J. Med. Chem. 60:695 (2017).

[0398] Figure 6C - 6D Examples of targeted ligands of G9a (EHMT2) are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see PDB crystal structure 3k5k; (“Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysinemethyltransferase G9a”); Liu, F. et al., J. Med. Chem. 52:7950 (2009); PDB crystal structure 3rjw (“Achemical probe selectively inhibits G9a and GLP methyltransferase activity incells”); Vedadi, M. et al., Nat. Chem. Biol. 7:566 (2011); PDB crystal structure 4nvq (“Discovery anddevelopment of potent and selective inhibitors of histone methyltransferaseg9a”); and, Sweis, R.F. et al., ACS Med Chem Lett 5:205 (2014).

[0399] Figure 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 with inhibitor reveals a mechanism of activation and drug resistance”); Brooun, A. et al., Nat Commun 7:11384 (2016); PDB crystal structure 5ls6 (“Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas”); Vaswani, R.G. et al., J. Med. Chem. 59:9928 (2016); and, the PDB crystal structures 5ij8 and 5ls6.

[0400] Figure 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 Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED”); Li, L. et al., PLoS ONE 12:e0169855 (2017); and, PDB crystal structure 5h19.

[0401] Figure 6J Examples of KMT5A (SETD8)-targeting ligands are shown, where R is the point of attachment of the linker. See, for example, PDB crystal structure 5t5g.

[0402] Figure 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, S.R. et al., Blood 122:1017 (2013); PDB crystal structure 5dry ("Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach") Chen, C. et al., ACS Med. Chem. Lett. 7:735 (2016); PDB crystal structure 5dt2 ("Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach"); and, Chen, C. et al., ACS Med. Chem. Lett. 7:735 (2016).

[0403] Figure 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 arginine methyltransferase 3"); Siarheyeva, A. et al., Structure 20:1425 (2012); PDB crystal structure 4ryl ("A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)"); and, Kaniskan, H.U. et al., Angew. Chem. Int. Ed. Engl. 54:5166 (2015).

[0404] 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, J.S. et al., Biochem. J. 436:331 (2011).

[0405] 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).

[0406] 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, L.H. et al., ACS Med. Chem. Lett. 6:655 (2015).

[0407] 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).

[0408] Figure 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).

[0409] 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 HumanKdm5B 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 “Aninhibitor of KDM5 demethylases reduces survival of drug-tolerant cancercells”. Vinogradova, M. et al., Nat. Chem. Biol. 12:531 (2016).

[0410] 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).

[0411] Figure 6X Examples of L3MBTL3-targeting ligands are shown, where R is the point of attachment of the linker. See, for example, PDB crystal structure 4fl6.

[0412] 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).

[0413] 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.

[0414] Figure 6BB Examples of HDAC7-targeting ligands are shown, where R is the point of attachment of the linker. For additional 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 IIa Histone Deacetylase Inhibition Via a Non-Chelating Zinc Binding Group". Lobera, M. et al., Nat. Chem. Biol. 9:319 (2013).

[0415] Figure 7A - 7CShows examples of protein tyrosine phosphatase, non-receptor type 1, PTP1B targeting ligands, 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, M.R. 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 inhibitors." Moretto, A.F. 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, P.J. et al., J. Biol. Chem. 281:32784 (2006); PDB crystal structures 2f6t and 2f6w, described in "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors".Klopfenstein, S.R. et al., Bioorg. Med. Chem. Lett. 16:1574 - 1578 (2006); PDB crystal structures 2h4g, 2h4k, 2hb1, described in "Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48." Wan, Z.K. et al., Bioorg. Med. Chem. Lett. 16:4941 - 4945 (2006); PDB crystal structure 2zn7, described in "Structure-based optimization of protein tyrosine phosphatase-1B inhibitors: capturing interactions with arginine 24". Wan, Z.K. et al., Chem Med Chem. 3:1525 - 9 (2008); PDB crystal structures 2nt7, 2nta, described in "Probing acid replacements of thiophene PTP1B inhibitors." Wan, Z.K. et al., Bioorg. Med. Chem. Lett. 17:2913 - 2920 (2007); and, WO2008148744 A1 assigned to Novartis AG, titled "Thiadiazole derivatives as antidiabetic agents". Also see, PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 1l8g, and described in "2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases". Andersen, H.S. et al., J. Biol. Chem. 275:7101 - 7108 (2000); "Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B." Iversen, L.F. et al., J. Biol. Chem.275:10300-10307(2000); and, "Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases". Iversen, L.F. et al., Biochemistry 40:14812-14820(2001).

[0416] Figure 7D Examples of protein tyrosine phosphatase non-receptor type 11, SHP2 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 4pvg and 305x, described in "Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)." Zhang, X. et al., J. Med. Chem. 53:2482-2493(2010); and, the crystal 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). Also see, the crystal structure PDB 5ehr, described in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." Garcia Fortanet, J. et al., J. Med. Chem. 59:7773-7782(2016) and “Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.” Chen, Y.P. et al., Nature 535:148-152(2016).

[0417] Figure 7E Examples of ligands targeting protein tyrosine phosphatase, non-receptor type 22 are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structure PDB 4j51, described in “A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases.” He, Y. et al., J. Med. Chem. 56:4990-5008 (2013).

[0418] Figure 7F Examples of ligands targeting 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 the crystal structures PDB 3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb and related ligands, described in “DcpS as a therapeutic target for spinal muscular atrophy." Singh, J. et al., ACS Chem. Biol. 3:711-722 (2008).

[0419] Figure 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 the crystal structures PDB 3u5k and 3u51 and related ligands, described in Filippakopoulos, P. et al., “Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family”, Bioorg. Med. Chem. 20:1878-1886 (2012); crystal structure PDB 3u5l; crystal structure PDB 3zyu and related ligands, described in Dawson, M.A. et al., ”Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for Mll-Fusion Leukaemia.“ Nature 478:529 (2011); crystal 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 Ly294002 is an Inhibitor of Bet Bromodomains” ACS Chem. Biol. 9:495 (2014); crystal structure PDB 4e96 and related ligands, described in Fish, P.V. et al., “Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.” J. Med. Chem. 55:9831-9837 (2012); crystal structure PDB 4clb and related ligands, described in Atkinson, S.J. et al., “The Structure Based Design of Dual Hdac / Bet Inhibitors as Novel Epigenetic Probes.”Medchemcomm 5:342(2014); crystal structure PDB 4f3i and related ligands, described in Zhang, G. et al., “Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.” J. Biol. Chem. 287:28840-28851(2012); crystal structure PDB 4hxl and related ligands, described in Zhao, L. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.” J. Med. Chem. 56:3833-3851(2013); crystal structure PDB 4hxs and related ligands, described in Zhao, L. et al., “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.” J. Med. Chem. 56:3833-3851(2013); crystal structure PDB 4lrg and related ligands, described in Gehling, V. S. 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, L. R. “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, S. W. et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4(BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem. Biol.9:1160 - 1171(2014); The crystal structure PDB 4o7a and related ligands are described in Ember, S.W. et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4(BRD4) Interacts with Diverse Kinase Inhibitors.” ACS Chem. Biol. 9:1160 - 1171(2014); The 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, S.W. et al., (2014) ACS Chem. Biol. 9:1160 - 1171; The crystal structure PDB 4o7c and related ligands are described in Ember, S.W. et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4(BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem. Biol. 9:1160 - 1171(2014); The crystal structure PDB 4gpj; The crystal structure PDB 4uix and related ligands are described in Theodoulou, N.H. et al., “The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”. J. Med. Chem. 59:1425(2016); The crystal structure PDB 4uiz and related ligands are described in Theodoulou, N.H., et al., “The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”. J. Med. Chem. 59:1425(2016); The crystal structure PDB 4wiv and related ligands are described in McKeown, M.R.et 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, A. M. et al., “Discovery of Benzotriazolo[4,3 - d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.” ACS Med. Chem. Lett. 7:145 - 150 (2016); crystal structure PDB 4yh3; and related ligands, described in Duffy, B. C. “Discovery of a new chemical series of BRD4(1) inhibitors using protein - ligand docking and structure - guided design.” Bioorg. Med. Chem. Lett. 25:2818 - 2823 (2015); crystal structure PDB 4yh4 and related ligands, described in Duffy, B. C. “Discovery of a new chemical series of BRD4(1) inhibitors using protein - ligand docking and structure - guided design.” Bioorg. Med. Chem. Lett. 25:2818 - 2823 (2015); crystal structure PDB 4z1q and related ligands, described in Taylor, A. M. “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, E. H. “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); the crystal structure PDB 5acy and related ligands are described in Sullivan, J.M. "Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice." J. Exp. Med. 212:1771 (2015); the crystal structure PDB 5ad2 and related ligands are described in Waring, M.J. et al., "Potent and Selective Bivalent Inhibitors of Bet Bromodomains". Nat. Chem. Biol. 12:1097 (2016); the crystal structure PDB 5cfw and related ligands are described in Chekler, E.L. et al., "Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities." Chem. Biol. 22:1588-1596 (2015); the 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); the 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); The crystal structure PDB 5dlx and related ligands are described in Milhas, S. et al., "Protein - Protein Interaction Inhibition(2P2I)-Oriented Chemical Library Accelerates Hit Discovery." (2016) ACS Chem. Biol. 11:2140 - 2148; The crystal structure PDB 5dlz and related ligands are described in Milhas, S. et al., "Protein - Protein Interaction Inhibition(2P2I)-Oriented Chemical Library Accelerates Hit Discovery." ACS Chem. Biol. 11:2140 - 2148(2016); The crystal structure PDB 5dw2 and related ligands are described in Kharenko, O.A. et al., "RVX - 297 - a novel BD2 selective inhibitor of BET bromodomains." Biochem. Biophys. Res. Commun. 477:62 - 67(2016); The crystal structure PDB 5dlx; The crystal structure PDB 5his and related ligands are described in Albrecht, B.K. 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); The crystal structure PDB 5ku3 and related ligands are described in Crawford, T.D. 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); The 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); The crystal structure PDB 5dlx and related ligands are 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, titled “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, titled “Azolodiazepine derivatives and their preparation, compositions and methods for treating neoplasia, inflammatory disease and other disorders”, assigned to Dana-Farber Cancer Institute, Inc, USA.

[0420] Figure 8T - 8VExamples of ALK-targeted ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structures PDB 2xb7 and 2xba and related ligands, described in Bossi, R.T. et al., "Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors" Biochemistry 49:6813-6825 (2010); the crystal structures PDB 2yfx, 4ccb, 4ccu and 4cd0 snd 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); the crystal structures PDB, 4cli, 4cmo and 4cnh and related ligands, described in Johnson, T.W. 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); the crystal structure PDB 4fny and related ligands, described in Epstein, L.F. 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); The crystal structure PDB 4dce and related ligands are described in Bryan, M.C. et al., "Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors." J. Med. Chem. 55:1698 - 1705(2012); The crystal structure PDB 4joa and related ligands are described in Gummadi, V.R. et al., "Discovery of 7 - azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode." (2013) Bioorg. Med. Chem. Lett. 23:4911 - 4918; and, The crystal structure PDB 5iui and related ligands are described in Tu, C.H. et al., "Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)." J. Med. Chem. 59:3906 - 3919(2016).

[0421] Figure 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, D.J. et al., "Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases." Protein Sci. 19:429-439 (2010) and Kuglstatter, A. et al., "Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures” Protein Sci. 20:428-436" (2011); 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." ACS Med. 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 tyrosine kinase from multiple ligand complex structures." Protein Sci.20:428-436(2011); and, the crystal structure PDB 3pij and related ligands are described in Bujacz, A. et al., "Crystal structures of the apo form of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose." Febs J. 278:1728-1744(2011).

[0422] Figure 8Y Examples of FLT3-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 4xuf and 4rt7 and related ligands, described in Zorn, J.A. et al., "Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)". Plos One 10:e0121177-e0121177(2015).

[0423] 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 the crystal structure PDB 2x7f; the 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).

[0424] 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 the crystal structure PDB 4aoj and related ligands, described in Wang, T. et al., “Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors.” ACS Med. Chem. Lett. 3:705 (2012); the crystal structures PDB 4pmm, 4pmp, 4pms, and 4pmt and related ligands, described in Stachel, S.J. et al., “Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.” J. Med. Chem. 57:5800-5816 (2014); the crystal structures PDB 4yps and 4yne and related ligands, described in Choi, H.S. et al., “(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med. Chem. Lett. 6:562-567 (2015); the crystal structures 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, the crystal structures PDB 3v5q and 4ymj and related ligands, described in Albaugh, P. et al., “Discovery of GNF-5837, a selective TRK Inhibitor with efficacy in rodent cancer tumor models.” ACS Med. Chem. Lett. 3:140–145 (2012) and Choi, H.S.Et al., “(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med Chem Lett 6:562-567 (2015).

[0425] Figure 8DD - 8EEExamples of FGFR1-targeted ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structures PDB 3tto and 2fgi and related ligands, described in Brison, Y. et al., “Functional and structural characterization of alpha-(1-2)branching sucrase derived from DSR-E glucansucrase.” J. Biol. Chem. 287:7915-7924 (2012) and Mohammadi, M. et al., “Crystal structure of an angiogenesis inhibitor bound to the FGFR tyrosine kinase domain.” EMBO J. 17:5896-5904 (1998); crystal structure PDB 4fb3; crystal structure PDB 4rwk and related ligands, described in Harrison, C. et al., “Polyomavirus large T antigen binds symmetrical repeats at the viral origin in an asymmetrical manner.” J. Virol. 87:13751-13759 (2013); crystal structure PDB 4rwl and related ligands, described in Sohl, C. D. et al., “Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.” ACS Chem. Biol. 10:1319-1329 (2015); crystal structure PDB 4uwc; crystal structure PDB 4v01 and related ligands, described in Tucker, J. A. 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, described in Klein, T.et al., “Structural and Dynamic Insights Into the Energetics of ActivationLoop Rearrangement in Fgfr1 Kinase.” Nat. Commun. 6:7877 (2015); and, crystal structure PDB 5ew8 and associated ligands, described in Patani, H. et al., “Landscape of activating cancer mutationsin FGFR kinases and their differential responses to inhibitors in clinicaluse.” Oncotarget 7:24252 - 24268 (2016).

[0426] Figure 8FF Examples of FGFR2 - targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and associated ligands, see crystal structure PDB 2pvf and associated ligands, described in Chen, H. et al., “A molecular brake inthe kinase hinge region regulates the activity of receptor tyrosine kinases.” Mol. Cell 27:717 - 730 (2007).

[0427] Figure 8GG Examples of FGFR4 - targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and associated ligands, see crystal structure PDB 4tyi and associated ligands, described in Lesca, E. et al., “Structural analysisof the human fibroblast growth factor receptor 4kinase.” J. Mol. Biol. 426:3744 - 3756 (2014).

[0428] 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, E.A. et al., "Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors." J. Med. Chem. 58:2417-2430 (2015) and Cui, J.J. et al., "Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2,4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with High Protein Kinase Selectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats." J. Med. Chem. 56:6651 (2013); crystal structure PDB 5eyd and related ligands, described in Boezio, A.A. et al., "Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]p yridin-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, described in Kim, K.S.Et 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); the crystal structure PDB 2rfn and related ligands are described in Bellon, S.F. 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, the crystal structure PDB 5dg5 and related ligands are described in Smith, B.D. et al., "Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment - Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2." Mol. Cancer Ther. 14:2023 - 2034 (2015).

[0429] 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 the crystal structure PDB 4ivd and related ligands, described in Zak, M. et al., “Identification of C-2Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors withFavorable Physicochemical Properties and High Selectivity over JAK2.” J.Med.Chem. 56:4764-4785 (2013); the crystal structure PDB 5e1e and related ligands, described in Vasbinder, M.M. et al., "Identification of azabenzimidazoles as potent JAK1 selectiveinhibitors." Bioorg.Med.Chem.Lett. 26:60-67 (2016); the crystal structure PDB 5hx8 and related ligands, described in Simov, V., et al., "Structure-based design and development of(benz)imidazolepyridones as JAK1-selective kinase inhibitors." Bioorg.Med.Chem.Lett. 26:1803-1808 (2016); the crystal structure PDB 5hx8 and related ligands, described in Caspers, N.L. et al., "Development ofa high-throughput crystal structure-determination platform for JAK1 using anovel metal-chelator soaking system". Acta Crystallogr.Sect.F 72:840-845 (2016); and, Kettle, J.G. “Discovery of the JAK1 selective kinase inhibitorAZD4205”, AACR National Meeting, April 2017.

[0430] Figure 8KK - 8LLExamples of JAK2-targeted ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structure PDB 3ugc and related ligands, described in Andraos, R. et al., "Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent." Cancer Discov 2:512-523 (2012); the crystal structures PDB 5cf4, 5cf5, 5cf6, and 5cf8 and related ligands, described in Hart, A.C. et al., "Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors." ACS Med. Chem. Lett. 6:845-849 (2015); the crystal structure PDB 5aep and related ligands, described in Brasca, M.G. et al., "Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders” Bioorg. Med. Chem. 23:2387 (2015); the crystal structures PDB 4ytf, 4yth, and 4yti and related ligands, described in Farmer, L.J. et al., "Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases." J. Med. Chem. 58:7195-7216 (2015); the crystal structures PDB 4ytf, 4yth, 4yti and related ligands, described in Menet, C.J. et al., "Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634." J. Med. Chem. 57:9323-9342 (2014); the crystal structure PDB 4ji9 and related ligands, described in Siu, M. et al., "2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors." Bioorg. Med.Chem.Lett.23:5014-5021(2013); and, crystal structures PDB 3io7 and 3iok and related ligands are described in Schenkel, L.B. et al., "Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors." J. Med. Chem. 54:8440-8450(2011).

[0431] 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, S.M. et al., "Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the Jak Family and the Kinome." Bioorg. Med. Chem. Lett. 23:2793(2013); and, crystal structures PDB 4hvd, 4i6q and 3zep and related ligands described in Soth, M. et al., "3-Amido Pyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1 Selective Inhibitor and Evaluation in Cellular and in Vivo Models." J. Med. Chem. 56:345-356(2013) and Jaime-Figueroa, S. et al., "Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors." Bioorg. Med. Chem. Lett. 23:2522-2526(2013).

[0432] Figure 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 the crystal structure PDB 1t46 and related ligands, described in Mol, C.D. et al., "Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase." J. Biol. Chem. 279:31655-31663 (2004); and, the crystal structure PDB 4u0i and related ligands, described in Garner, A.P. et al., "Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients." Clin. Cancer Res. 20:5745-5755 (2014).

[0433] Figure 88PP-8VV shows examples of EGFR-targeted ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structures PDB 5hcy, 4rj4, and 5cav; Heald, R., “Noncovalent MutantSelective Epidermal Growth Factor Receptor Inhibitors: A Lead OptimizationCase Study”, J. Med. Chem. 58, 8877–8895 (2015); Hanano, E. J., “Discovery of Selectiveand Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth FactorReceptor Containing the T790M Resistance Mutation.“ J. Med. Chem., 57, 10176–10191 (2014); Chan, B. K. et al., “Discovery of a Noncovalent, Mutant-Selective EpidermalGrowth Factor Receptor Inhibitor" J. Med. Chem. 59, 9080 (2016); the crystal structure PDB 5d41 and related ligands, described in Jia, Y. et al, "Overcoming EGFR(T790M) and EGFR(C797S) resistancewith mutant-selective allosteric inhibitors" Nature 534, 129 (2016); Ward, R. A. "Structure-and reactivity-based development of covalent inhibitors of theactivating and gatekeeper mutant forms of the epidermal growth factorreceptor (EGFR)“ J. Med. Chem.56,7025-7048(2013); The crystal structure PDB 4zau and related ligands are described in "Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor" J. Med. Chem., 57(20), 8249–8267(2014); The crystal structure PDB 5em7 and related ligands are described in Bryan, M.C. et al., "Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR" ACS Med. Chem. Lett., 7(1), 100–104(2016); The crystal structure PDB 3IKA and related ligands are described in Zhou, W. et al., "Novel mutant-selective EGFR kinase inhibitors against EGFR T790M" Nature 462(7276), 1070–1074(2009); The crystal structure can be seen in PDB 5feq and related ligands are 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 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); The crystal structure PDB 5j7h and related ligands are described in Huang, W-S. 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); The crystal structure PDB 4v0g and related ligands are described in Hennessy, E.J. 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); The crystal structure PDB 5hg7 and related ligands are described in Cheng, H. "Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants." J. Med. Chem. 59:2005-2024(2016); Hao, Y. "Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R / T790M Resistance Mutation." J. Med. Chem. 59:7111-7124(2016); The crystal structures PDB 5ug8, 5ug9 and 5ugc and related ligands are described in Planken, S."Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR." J. Med. Chem. 60:3002-3019 (2017); the crystal structure PDB 5gnk and related ligands 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).

[0434] 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 Chem Lett. 22;6(7):776-81(2015).

[0435] 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).

[0436] 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, E.W. et al., “Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model.” J. Med. Chem. 52, 7364-7367 (2009); Tojo, S. et al., “Crystal structures and structure, and activity relationships of imidazothiazole derivatives as IDO1 inhibitors.” ACS Med. Chem. Lett. 5, 1119-1123 (2014); Mautino, M.R. et al., “NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy” Abstract 491, AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC; and, WO2012142237, titled “Fused imidazole derivatives useful as IDO inhibitors”.

[0437] Figure 8BBB - 8EEEExamples of ERK1 and ERK2 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 5K4I and 5K4J and related ligands, described in Blake, J.F. et al., “Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1 / 2 (ERK1 / 2) Inhibitor in Early Clinical Development” J. Med. Chem. 59:5650-5660 (2016); the crystal structure PDB 5BVF and related ligands, described in Bagdanoff, J.T. et al., “Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase” Bioorg. Med. Chem. Lett. 25, 3788-3792 (2015); the 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); the 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); the 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); the crystal structures PDB 4ZZM, 4ZZN, 4ZZO and related ligands, described in Ward, R.A.et al., "Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1 / 2." J. Med. Chem. 58:4790 (2015); 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, S. V. et al., "Discovery of LY3214996, a selective and novel ERK1 / 2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations." AACR National Meeting 2017; crystal structures PDB 3FHR and 3FXH and associated 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 associated ligands, described in Ward, R. A. 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 associated ligands, described in Oubrie, A. et al., "Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series." Bioorg. Med. Chem.Lett.22:613-618(2012).

[0438] 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 the crystal structures PDB 1fpu and 2e2b and related ligands, described in Schindler, T. et al., “Structural mechanism for STI - 571 inhibition of abelson tyrosine kinase”, Science 289:1938 - 1942 (2000); and Horio, T. et al., “Structural factors contributing to the Abl / Lyn dual inhibitory activity of 3 - substituted benzamide derivatives”, Bioorg. Med. Chem. Lett. 17:2712 - 2717 (2007); the crystal structures PDB 2hzn and 2hiw and related ligands, described in Cowan - Jacob, S. W. et al., “Structural biology contributions to the discovery of drugs to treat chronic myelogenous 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); the crystal structure PDB 3cs9 and related ligands, described in Weisberg, E. et al., “Characterization of AMN107, a selective inhibitor of native and mutant Bcr - Abl”, Cancer Cell 7:129 - 14 (2005); the crystal structure PDB 3ik3 and related ligands, 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); the crystal structure PDB 3mss and related ligands, 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); the 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); the crystal structures PDB 3qri and 3qrk and related ligands are described in Chan, W. W. et al., “Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”, Cancer Cell 19:556-568 (2011); the crystal structures PDB 5hu9 and 2f4j and related ligands are described in Liu, F. et al., “Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”, Oncotarget 7:45562-45574 (2016) and Young, M. A. et al., “Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680”, Cancer Res. 66:1007-1014 (2006); the crystal structures PDB 2gqg and 2qoh and related ligands are described in Tokarski, J. S.etc., "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. etc., "Crystal Structure of the T315I Mutant of Abl Kinase", Chem. Biol. Drug Des. 70:171-181 (2007); the crystal structures PDB 2gqg and 2qoh and the related ligands are described in Tokarski, J.S. etc., "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. etc., "Crystal Structure of the T315I Mutant of Abl Kinase", Chem. Biol. Drug Des. 70:171-181 (2007); the crystal structures PDB 2gqg and 2qoh and the related ligands are described in Tokarski, J.S. etc., "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. etc., "Crystal Structure of the T315I Mutant of Abl Kinase", Chem. Biol. Drug Des. 70:171-181 (2007); the crystal structures PDB 3dk3 and 3dk8 and the related ligands are described in Berkholz, D.S.et al., "Catalytic cycle of human glutathione reductase near 1A resolution" J. Mol. Biol. 382: 371 - 384 (2008); the crystal structure PDB 3ue4 and related ligands are described in Levinson, N.M. 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); the crystal structure PDB 4cy8 and related ligands are described in Jensen, C.N. et al "Structures of the Apo and Fad - Bound Forms of 2 - Hydroxybiphenyl 3 - Monooxygenase (Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution", Chembiochem 16: 968 (2015); the crystal structure PDB 2hz0 and related ligands are described in Cowan - Jacob, S.W. 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); the crystal structure PDB 3pyy and related ligands are described in Yang, J. et al., "Discovery and Characterization of a Cell - Permeable, Small - Molecule c - Abl Kinase Activator that Binds to the Myristoyl Binding Site", Chem. Biol. 18: 177 - 186 (2011); and, the crystal structure PDB 5k5v and related ligands are described in Kim, M.K., etc., "Structural basis for dual specificity of yeast N-terminal amidase in the N-end rule pathway", Proc. Natl. Acad. Sci. U.S.A. 113: 12438-12443 (2016).

[0439] 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 the crystal structure PDB 2xyn and related ligands, described in Salah, E. et al., "Crystal Structures of Abl-Related Gene (Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type I Inhibitor of the Triazole Carbothioamide Class", J. Med. Chem. 54: 2359 (2011); the crystal structure PDB 4xli and related ligands, described in Ha, B.H. et al., "Structure of the ABL2 / ARG kinase in complex with dasatinib" Acta Crystallogr. Sect. F 71: 443-448 (2015); and, the crystal structure PDB 3gvu and related ligands, described in Salah, E. et al., "The Crystal structure of human ABL2 in complex with Gleevec", to be published.

[0440] 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, K. D. et al., “Design of selective, ATP-competitive inhibitors of Akt”, J. Med. Chem. 53:4615-4622 (2010); Blake, J. F. et al., “Discovery of pyrrolopyrimidine inhibitors of Akt”, Bioorg. Med. Chem. Lett. 20:5607-5612 (2010); Kallan, N. C. et al., “Discovery and SAR of spirochromane Akt inhibitors”, Bioorg. Med. Chem. Lett. 21:2410-2414 (2011); Lin, K “An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt”, Sci. Signal. 5:ra37-ra37 (2012); Addie, M. et al., “Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases”, J. Med. Chem. 56:2059-2073 (2013); Wu, W. I., et al., “Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Plos One 5:12913-12913 (2010); Ashwell, M. A.et al., "Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors", J. Med. Chem. 55:5291-5310 (2012); and Lapierre, J.M. et al., "Discovery of 3-(3-(4-(1-Amino cyclobutyl)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).

[0441] 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 crystal structures PDB 2jdo and 2jdr and related ligands, described in Davies, T.G. et al., “A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera”, J. Mol. Biol. 367:882 (2007); 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); crystal structures PDB 2x39 and 2xh5 and related ligands, described in McHardy, T. et al., “Discovery of 4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides as Selective, Orally Active Inhibitors of Protein Kinase B (Akt)”, J. Med. Chem. 53:2239d (2010); crystal structure PDB 3d03 and related ligands, described in Hadler, K.S. 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, M.B. et al., “Aminofurazans as potent inhibitors of AKT kinase” Bioorg. Med. Chem. Lett. 19:1508-1511 (2009).

[0442] Figure 8PPPExamples of BMX 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 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).

[0443] 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 the crystal structures PDB 2i0v and 2i1m and related ligands, described in Schubert, C. et al., “Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors”, J. Biol. Chem. 282:4094-4101 (2007); the crystal structure PDB 3bea and related ligands, described in Huang, H. et al., “Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors”, Bioorg. Med. Chem. Lett. 18:2355-2361 (2008); the crystal structure PDB 3dpk and related ligands, described in M.T., McKay, D.B. Overgaard, “Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon”, to be published; the crystal structures PDB 3krj and 3krl and related ligands, described in Illig, C.R. et al., “Optimization of a Potent Class of arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141”, J. Med. Chem. 54:7860-7883 (2011); the crystal structure PDB 4r7h and related ligands, described in Tap, W.D.et al., "Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor:, N Engl J Med 373:428-437(2015); the crystal structures PDB 3lcd and 3lcoa and associated ligands are described in Meyers, M.J. et al., "Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mod", Bioorg. Med. Chem. Lett. 20:1543-1547(2010); the crystal structure PDB 4hw7 and associated ligands are described in Zhang, C. et al., "Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor", Proc. Natl. Acad. Sci. USA 110:5689-5694(2013); and, the crystal structure PDB 4r7i and associated ligands are described in Tap, W.D. et al., "Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor", N Engl J Med 373:428-437(2015).

[0444] Figure 8TTT Examples of CSK-targeting ligands are shown, where R is the point of attachment of the linker. For additional examples and associated ligands, see Levinson, N.M. et al., "Structural basis for the recognition of c-Src by its inactivator Csk", Cell 134:124-134(2008).

[0445] 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 the crystal structures PDB 3zos and 4bkj and related ligands, described in Canning, P. et al., “Structural Mechanisms Determining Inhibition of the Collagen Receptor Ddr1 by Selective and Multi-Targeted Type II Kinase Inhibitors”, J. Mol. Biol. 426:2457 (2014); the crystal structure PDB 4ckr and related ligands, described in Kim, H. et al., “Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor”, ACS Chem. Biol. 8:2145 (2013); the crystal structures PDB 5bvk, 5bvn and 5bvw and related ligands, described in Murray, C.W et al., “Fragment-Based Discovery of Potent and Selective DDR1 / 2 Inhibitors”, ACS Med. Chem. Lett. 6:798-803 (2015); the 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, the crystal structure PDB 5fdx and related ligands, described in Bartual, S.G. et al., “Structure of DDR1 receptor tyrosine kinase in complex with D2164 inhibitor at 2.65 Angstroms resolution”, to be published.

[0446] 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 the crystal structures PDB 5i9x, 5i9y, 5ia0, and 5ia1 and related ligands, described in Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem. Biol. 11:3400 - 3411 (2016); the crystal structure PDB 5i9z and related ligands, described in Heinzlmeir, S. et al., “Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with danusertib (PHA739358)”, ACS Chem Biol 11 3400 - 3411 (2016); and, the crystal structures PDB 5ia2, 5ia3, 5ia4, and 5ia5 and related ligands, described in Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem. Biol. 11:3400 - 3411 (2016).

[0447] 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 the crystal structures PDB 4g2f and the related ligand, described in Zhao, H. et al., “Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics”, ACS Med. Chem. Lett. 3:834-838 (2012); the crystal structures PDB 4gk2 and 4gk3 and the related ligand, described in Lafleur, K. et al., “Optimization of Inhibitors of the Tyrosine Kinase EphB4.2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography”, J. Med. Chem. 56:84-96 (2013); the crystal structure PDB 4gk3 and the related ligand, described in Lafleur, K. et al., “Optimization of Inhibitors of the Tyrosine Kinase EphB4.2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography”, J. Med. Chem. 56:84-96 (2013); the crystal structures PDB 4p4c and 4p5q and the related ligand, described in Unzue, A. et al., “Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation”, J. Med. Chem. 57:6834-6844 (2014); the crystal structure PDB 4p5z and the related ligand, described in Unzue, A.et al., "Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2 and II Eph Tyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in Vivo Validation", J. Med. Chem. 57:6834-6844 (2014); the crystal structure PDB 4twn and related ligands, 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); the crystal structure PDB 3dzq and related ligands, described in Walker, J.R. "Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex with ALW-II-38-3", to be published.

[0448] 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 the crystal structure PDB 2y60 and related ligands, described in Clifton, I.J. et al., "The Crystal Struture of Isopenicillin N Synthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals Thioether Coordination to Iron", Arch. Biochem. Biophys. 516:103 (2011) and the crystal structure PDB 2xyu and related ligands, described in Van Linden, O.P et al., "Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase", Eur. J. Med. Chem. 47:493 (2012).

[0449] 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, J.R. et al. “Kinase domain of human ephrin type-a receptor 7 (epha7) in complex with ALW-II-49-7”, to be published.

[0450] Figure 8IIII - 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, described in Overman, R.C. et al., “Completing the Structural Family Portrait of the Human Ephb Tyrosine Kinase Domains”, Protein Sci. 23:627 (2014); crystal structure PDB 4aw5 and related ligands, described in Kim, M.H. 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, described in Vasbinder, M.M.et 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 associated ligands, 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 associated 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); and, crystal structure PDB 2vxo and associated ligands, described in Welin, M. et al., "Substrate Specificity and Oligomerization of Human Gmp Synthetas", J. Mol. Biol. 425:4323 (2013).

[0451] 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 structures and related ligands described in Aertgeerts, K. et al., “Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein”, J. Biol. Chem. 286:18756-18765 (2011), and the crystal structures 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).

[0452] 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).

[0453] Figure 8OOOOExamples of ERBB4-targeted 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).

[0454] Figure 8PPPP - 8QQQQ Examples of FES-targeted 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-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation.” Cell 134:793-803 (2008), and Hellwig, S. et al., “Small-Molecule Inhibitors of the c-Fes Protein-Tyrosine Kinase”, Chem. Biol. 19:529-540 (2012).

[0455] Figure 8RRRR Examples of FYN-targeted 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).

[0456] Figure 8SSSS - 8VVVVExamples of GSG2 (Haspin) 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 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; the 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, the 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).

[0457] 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 the crystal structure PDB 1qcf and related ligands, described in Schindler, T. et al., “Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor”, Mol. Cell 3:639-648 (1999); the crystal structures PDB 2c0i and 2c0t and related ligands, described in Burchat, A. et al., “Discovery of A-770041, a Src-Family Selective Orally Active Lck Inhibitor that Prevents Organ Allograft Rejection”, Bioorg. Med. Chem. Lett. 16:118 (2006); the crystal structure PDB 2hk5 and related ligands, described in Sabat, M. et al., “The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck)”, Bioorg. Med. Chem. Lett. 16:5973-5977 (2006); the crystal structures PDB 3vry, 3vs3, 3vs6 and 3vs7 and related ligands, described in Saito, Y. et al., “A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo”, Sci Transl Med 5:181ra52-181ra52 (2013); and, the crystal structure PDB 4lud and related ligands, described in Parker, L.J. et al., “Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002”,. Acta Crystallogr., Sect. D 70:392-404 (2014).

[0458] Figure 8BBBBB - 8FFFFFExamples of IGF1R-targeted ligands are shown, where R is the point of attachment of the linker. For additional examples and related ligands, see crystal structure PDB 2oj9 and related ligands, described in Velaparthi, U. et al., “Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R)”, Bioorg. Med. Chem. Lett. 17:2317-2321 (2007); crystal structure PDB 3i81 and related ligands, described in Wittman, M.D. et al., “Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.”, J. Med. Chem. 52:7360-7363 (2009); crystal structure PDB 3nw5 and related ligands, described in Sampognaro, A.J. et al., “Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase”, Bioorg. Med. Chem. Lett. 20:5027-5030 (2010); crystal structure PDB 3qqu and related ligands, described in Buchanan, J.L. et al., “Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors”, Bioorg. Med. Chem. Lett. 21:2394-2399 (2011); crystal structure PDB 4d2r and related ligands, described in Kettle, J.G.et al., “Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a Mek Resistance Hypothesis”. J. Med. Chem. 58:2834 (2015); the crystal structure PDB 3fxq and related ligands, described in Monferrer, D. et al., “Structural studies on the full-length LysR-type regulator TsaR from Comamonas testosteroni T-2 reveal a novel open conformation of the tetrameric LTTR fold”, Mol. Microbiol. 75:1199-1214 (2010); the 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; the crystal structure PDB 2zm3 and related ligands, described in Mayer, S.C. et al., “Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment”, Bioorg. Med. Chem. Lett. 18:3641-3645 (2008); the crystal structure PDB 3f5p and related ligands, described in “Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment” Bioorg. Med. Chem. Lett. 19:62-66 (2009); the crystal structure PDB 3lvp and related ligands, described in Nemecek, C.et al., "Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles" Chem.Biol.Drug Des. 76: 100-106 (2010); the crystal structure PDB 3o23 and related ligands are described in Lesuisse, D. et al., "Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: Advantages in comparison with competitive inhibitors", Bioorg.Med.Chem.Lett. 21: 2224-2228 (2011); the crystal structure PDB 3d94 and related ligands are described in Wu, J. et al., "Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor", Embo J. 27: 1985-1994 (2008); and, the crystal structure PDB 5hzn and related ligands are described in Stauffer, F. et al., "Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors", Bioorg.Med.Chem.Lett. 26: 2065-2067 (2016).

[0459] Figure 8GGGGG - 8JJJJJ shows examples of INSR targeting ligands, where R is the point of attachment of the linker. For additional examples and related ligands, see the crystal structure PDB 2z8c and related ligands, described in Katayama, N. et al., “Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors”, Proteins 73:795-801 (2008); the crystal structure PDB 3ekk and related ligands, described in Chamberlain, S.D. et al., “Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase”, (2009) Bioorg. Med. Chem. Lett. 19:469-473; the crystal structure PDB 3ekn and related ligands, described in Chamberlain, S.D. et al., “Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity”, Bioorg. Med. Chem. Lett. 19:360-364 (2009); the crystal structure PDB 5e1s and related ligands, described in Sanderson, M.P. 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); the 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 growthfactor-1receptor(IGF-1R)tyrosine kinase", Bioorg. Med. Chem. Lett. 19:3136-3140(2009); the crystal structure PDB 5hhw and related ligands are described in Stauffer, F. et al., "Identification of a5-[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, the crystal structure PDB 4ibm and related ligands are described in Anastassiadis, T. et al., "A highly selective dualinsulin receptor(IR) / insulin-like growth factor 1receptor(IGF-1R)inhibitorderived from an extracellular signal-regulated kinase(ERK)inhibitor", J. Biol. Chem. 288:28068-28077(2013).

[0460] 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, S.J.; Zlotnick, A. “BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly.” J. Mol. Recognit. 19, 542-548 (2006); Stray, S.J. et al., “Heteroaryl dihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly.” Proc. Natl. Acad. Sci. U.S.A., 102, 8138-8143 (2005); Guan, H. et al., “The novel compound Z060228 inhibits assembly of the HBV capsid.” Life Sci. 133, 1-7 (2015); Wang, X.Y. et al., “In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations.” Antiviral Ther. 17, 793-803 (2012); Klumpp, K. et al., “High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein.”112,15196 - 15201(2015); Qiu, Z. et al., “Design and synthesis of orally bioavailable 4 - methyl 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 2013096744 A1, 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 "Azepane derivatives and methods of treating hepatitis B infections"; and, WO 2015057945 "Hepatitis B viral assembly effector".

[0461] Figure 9 is a dendrogram of the human bromodomain family proteins that are divided into eight subfamilies, which is related to epigenetic signaling and chromatin biology. Figure 9 Any protein of the bromodomain family in can be selected as the target protein according to the present invention.

[0462] Figure 10 are 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

[0463] I. Definitions

[0464] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0465] Compounds in any of the formulas described herein can 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.

[0466] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or". Unless otherwise stated herein, the recitation of numerical ranges is only intended to be a shorthand method for separately referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were recited herein individually. All endpoints of the ranges are included within the range and can be combined independently. Unless otherwise clearly stated herein or clearly contradicted by the context, all methods described herein can be performed in a suitable order. Unless otherwise indicated, the use of examples or exemplary language (e.g., "such as") is merely for the purpose of better illustrating the invention and does not constitute a limitation on the scope of the invention.

[0467] The present invention encompasses compounds 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, and Formula XXII, which have at least one isotope substitution of a desired atom and an isotope content higher than the natural abundance of that isotope, i.e., are 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.

[0468] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. In one non-limiting embodiment, the isotope-labeled compounds can be used for metabolic studies (e.g., 14 C), reaction kinetics 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 determination of drug or substrate tissue distribution, or for radiotherapy of patients. In particular, for PET or SPECT studies, 18 F-labeled compounds may be particularly desirable. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by substituting non-isotope-labeled reagents with readily available isotope-labeled reagents, by implementing the procedures disclosed in the protocols described below or the examples and preparations disclosed.

[0469] 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, among the isotopes at any target position, the isotope is enriched 90%, 95%, or 99% or higher. In one non-limiting embodiment, at the desired position, deuterium is enriched 90%, 95%, or 99%.

[0470] In a non-limiting embodiment, deuterium atom substitution of a hydrogen atom can be provided in any 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.

[0471] In a non-limiting embodiment, the substitution 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 contains, by substitution, for example, methyl, ethyl, or methoxy, the alkyl residue can 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 combine to form a ring, the unsubstituted carbon atom can be deuterated.

[0472] The compounds of the present invention can form solvates with solvents (including water). Thus, 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 salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. Solvates can be in liquid or solid form.

[0473] A dash ("-") 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.

[0474] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specified range indicates that alkyl groups having each member within that range are described as separate species. For example, the term C1-C6 alkyl as used herein means a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as a separate species, and thus each subset is considered separately disclosed. For example, the term C1-C4 alkyl as used herein means a straight-chain or branched-chain alkyl group having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of them is described as a separate 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 is optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when the term used includes "alk", "cycloalkyl" or "carbocyclic" can be considered part of this definition, unless the context clearly excludes it. For example but not limited to, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless the context clearly excludes it.

[0475] 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.

[0476] In one embodiment, "alkyl" has one carbon.

[0477] In one embodiment, "alkyl" has two carbons.

[0478] In one embodiment, "alkyl" has three carbons.

[0479] In one embodiment, "alkyl" has four carbons.

[0480] In one embodiment, "alkyl" has five carbons.

[0481] In one embodiment, "alkyl" has six carbons.

[0482] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0483] Other non-limiting examples of "alkyl" include: isopropyl, isobutyl, isopentyl, and isohexyl.

[0484] Other non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0485] Other non-limiting examples of "alkyl" include: tert-butyl, tert-pentyl, and tert-hexyl.

[0486] Other non-limiting examples of "alkyl" include: neopentyl, 3-pentyl, and active pentyl.

[0487] In another embodiment, "alkyl" is "optionally substituted" by 1, 2, 3, or 4 substituents.

[0488] 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.

[0489] In one embodiment, "cycloalkyl" has three carbons.

[0490] In one embodiment, "cycloalkyl" has four carbons.

[0491] In one embodiment, "cycloalkyl" has five carbons.

[0492] In one embodiment, "cycloalkyl" has six carbons.

[0493] In one embodiment, "cycloalkyl" has seven carbons.

[0494] In one embodiment, "cycloalkyl" has eight carbons.

[0495] In one embodiment, "cycloalkyl" has nine carbons.

[0496] In one embodiment, "cycloalkyl" has ten carbons.

[0497] Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0498] Other non-limiting examples of "cycloalkyl" include indane and tetralin, where the point of attachment of each group is on the cycloalkyl ring.

[0499] For example: is a "cycloalkyl" group.

[0500] However, is an "aryl" group.

[0501] In another embodiment, "cycloalkyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0502] "Alkenyl" is a straight-chain or branched-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which can occur at stable points along the chain. The specified ranges used herein indicate that alkenyls having each member within that range are described as separate species, as described above for the alkyl moiety. Examples of alkenyls include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also encompasses "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.

[0503] "Alkynyl" is a branched-chain or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can occur at any stable point along the chain. The specified ranges used herein indicate that alkynyls having each member within that range are described as separate species, as described above for the alkyl moiety. Examples of alkynyls 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 having at least one triple bond. In another embodiment, "alkynyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0504] "Alkylene" is a divalent saturated hydrocarbon. Alkylene can be, for example, a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, a 1 to 6 carbon moiety, 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.

[0505] "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.

[0506] "Alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylene 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 alkynylene.

[0507] "Halogenated" and "halogen" mean fluorine, chlorine, bromine or iodine.

[0508] "Halogenated alkyl" is a branched or straight-chain alkyl group substituted with one or more of the above halogen atoms up to the maximum allowable number of halogen atoms. Examples of halogenated alkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perhalogenated alkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0509] In one embodiment, "halogenated alkyl" is C1-C 10 halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0510] In one embodiment, "halogenated alkyl" has one carbon.

[0511] In one embodiment, "halogenated alkyl" has one carbon and one halogen.

[0512] In one embodiment, "halogenated alkyl" has one carbon and two halogens.

[0513] In one embodiment, "halogenated alkyl" has one carbon and three halogens.

[0514] In one embodiment, "halogenated alkyl" has two carbons.

[0515] In one embodiment, "halogenated alkyl" has three carbons.

[0516] In one embodiment, "halogenated alkyl" has four carbons.

[0517] In one embodiment, "halogenated alkyl" has five carbons.

[0518] In one embodiment, "halogenated alkyl" has six carbons.

[0519] Non-limiting examples of "halogenated alkyl" include:

[0520] Other non-limiting examples of "halogenated alkyl" include:

[0521] Other non-limiting examples of "haloalkyl" include:

[0522] Other non-limiting examples of "haloalkyl" include:

[0523] "Chain" means a linear chain, and all other chains (long or short or both) can be considered side chains of the linear chain. In cases where two or more chains can equivalently be considered the main chain, "chain" is the one that gives the simplest representation of the molecule.

[0524] "Haloalkoxy" means a haloalkyl as defined herein attached through an oxygen bridge (the oxygen of the alcohol group).

[0525] "Heterocycloalkyl" is an alkyl as defined herein substituted with a heterocyclic group as defined herein.

[0526] "Arylalkyl" is an alkyl as defined herein substituted with an aryl as defined herein.

[0527] Non-limiting examples of "arylalkyl" include:

[0528]

[0529] In one embodiment, "arylalkyl" is

[0530] In one embodiment, "arylalkyl" refers to an alkyl of 2 carbons substituted with an aryl.

[0531] Non-limiting examples of "arylalkyl" include:

[0532]

[0533] In one embodiment, "arylalkyl" refers to an alkyl of 3 carbons substituted with an aryl.

[0534] "Heteroarylalkyl" is an alkyl as defined herein substituted with a heteroaryl as defined herein.

[0535] 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 a cyclic array) having from 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C 6-14 aryl"). In some embodiments, the aryl has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms ("C14 "Aryl"; for example, anthryl). "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the group or point of attachment is on the aromatic ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. One or more fused carbocyclic or heterocyclic groups can be 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic 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, aryl is a side group. An example of a side group ring is phenyl substituted with phenyl. In an alternative embodiment, aryl is optionally substituted as described above. In certain embodiments, aryl is unsubstituted C 6-14 aryl. In certain embodiments, aryl is substituted C 6-14 aryl. Aryl can be optionally substituted with one or more functional groups including, but not limited to, halogen, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocycle.

[0536] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0537] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0538] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, where the point of attachment is on the aromatic ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring.

[0539] For example is an "aryl" group.

[0540] However, is a "heterocyclic group" group.

[0541] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, where the point of attachment is on the aromatic ring. Non-limiting examples of "aryl" include indane and tetrahydronaphthalene, where the point of attachment of each group is on the aromatic ring.

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

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

[0544] In another embodiment, "aryl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0545] The terms "heterocyclic group", "heterocycle" and "heterocyclo" include saturated and partially saturated ring groups containing heteroatoms, where 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 systems (which can include bridged fused and spiro fused bicyclic systems). It does not include rings containing -O-O-, -O-S- or -S-S- moieties. The "heterocyclic group" can optionally be substituted by, for example, 1, 2, 3, 4 or more substituents, including but not limited to hydroxy, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy and amino.

[0546] 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, pyrroline, 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.

[0547] Examples of partially saturated and saturated heterocyclic groups include but are not limited to pyrrolidinyl, imidazolidinyl, piperidinyl, pyrroline, 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)-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-benzo[d]imidazol-2-one, benzo[d]thiazol-2(3H)-one, 1,2-dihydro-3H-pyrazol-3-one, 2(1H)-pyridone, 2-piperazinone, indolinyl and dihydrothiazolyl.

[0548] The terms "heterocyclic group", "heterocycle" and "heterocyclo" groups also include portions in which the heterocyclic group is fused / fused with an aryl or heteroaryl group: for example, unsaturated fused heterocyclic groups containing 1, 2, 3, 4 or 5 nitrogen atoms such as, for example, 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.

[0549] In one embodiment, "heterocycle" refers to a ring having one nitrogen and 3, 4, 5, 6, 7 or 8 carbon atoms.

[0550] In one embodiment, "heterocycle" refers to a ring having one nitrogen, one oxygen and 3, 4, 5, 6, 7 or 8 carbon atoms.

[0551] In one embodiment, "heterocycle" refers to a ring having two nitrogens and 3, 4, 5, 6, 7 or 8 carbon atoms.

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

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

[0554] Non-limiting examples of "heterocycle" include aziridine, ethylene oxide, ethylene sulfide, azetidine, 1,3-diazetidine, oxetane and thietane.

[0555] Other non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine and imidazolidine.

[0556] Other non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane and 1,3-oxathiolane.

[0557] Other non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine and thiomorpholine.

[0558] Other non-limiting examples of "heterocycle" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.

[0559] For example, is a "heterocyclic group" group.

[0560] However, is an "aryl" group.

[0561] Non-limiting examples of "heterocyclic group" also include:

[0562]

[0563] Other non-limiting examples of "heterocyclic group" include:

[0564]

[0565] Other non-limiting examples of "heterocyclic group" include:

[0566]

[0567] Non-limiting examples of "heterocyclic group" also include:

[0568]

[0569] Non-limiting examples of "heterocyclic group" also include:

[0570]

[0571] Other non-limiting examples of "heterocyclic group" include:

[0572]

[0573] Other non-limiting examples of "heterocyclic group" include:

[0574]

[0575] In another embodiment, the "heterocyclic group" is "optionally substituted" with 1, 2, 3 or 4 substituents.

[0576] 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 a cyclic array), with 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, where ring nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered hetero monocyclic 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 hetero monocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered hetero monocyclic groups containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered hetero monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- or 6-membered hetero monocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 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]pyridyl, benzimidazolyl, 4(3H)-quinazolinone, quinolinyl, isoquinolinyl, isoindolyl, thienothiophenyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridyl.

[0577] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0578] 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.

[0579] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0580]

[0581] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0582] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0583]

[0584] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0585] Non-limiting examples of the bicyclic "heteroaryl" group include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0586] Other non-limiting examples of the bicyclic "heteroaryl" group include:

[0587]

[0588] Other non-limiting examples of the bicyclic "heteroaryl" group include:

[0589]

[0590] Other non-limiting examples of the bicyclic "heteroaryl" group include:

[0591]

[0592] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0593] Non-limiting examples of the bicyclic "heteroaryl" group include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0594] Other non-limiting examples of the bicyclic "heteroaryl" group include:

[0595]

[0596]

[0597] In another embodiment, "heteroaryl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0598] 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 12Heterocyclic alkenyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1-C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonylamino, arylsulfonylamino, C1-C 10 Alkylimino, arylimino, C1-C 10 Alkylsulfonylimino, arylsulfonylimino, hydroxy, halogen, thio, C1-C 10 Alkylthio, arylthio, C1-C 10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothiocarbonyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thiocarbonyl, acyloxy, carboxyl and carboxylate ester.

[0599] In another embodiment, if forming a stable molecule and meeting the desired objectives of the present invention is indicated, any suitable group may be present at the "substituted" or "optionally substituted" position, including but not limited to, for example, halogen (which may 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 having one or more thioether bonds; alkylsulfinyl; alkylsulfonyl, including those having one or more sulfonyl bonds; aminoalkyl, including groups having more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring being substituted or unsubstituted); aralkyl having, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, where benzyl is an exemplary aralkyl; aryloxyalkyl, for example, having 1 to 3 separate or fused rings, where benzyloxy is an exemplary aryloxyalkyl; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings having one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings having one or more N, O or S atoms, for example, coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, 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, by hydroxy, alkyl, alkoxy, halogen and amino.

[0600] In certain embodiments, "optionally substituted" includes one or more substituents independently selected from the following: halogen, hydroxyl, 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(heterocycle), 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" are divalent, including but not limited to oxo(=O), =S, =CH2, etc. Suitable groups at the "substituted" or "optionally substituted" positions can be monovalent, divalent, or trivalent such that they form stable molecules and serve the desired purposes of the present invention.

[0601] In one embodiment, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0602] In one embodiment, a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

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

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

[0605] "Aliphatic" refers to saturated or unsaturated straight-chain, branched-chain, or cyclic hydrocarbons. "Aliphatic group" is intended herein to include, but not be limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, "aliphatic group" is used to denote those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or poly-unsaturated or alkynyl. Unsaturated aliphatic groups can be in cis or trans configurations. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms.

[0606] In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specified range indicates that aliphatic groups having each member within that range are described as separate species. For example, the term C1-C6 aliphatic group as used herein means a straight or branched chain alkyl, alkenyl or alkynyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and is intended to mean that each of these is described as a separate species. For example, the term C1-C4 aliphatic group as used herein means a straight or branched chain alkyl, alkenyl or alkynyl group having 1, 2, 3 or 4 carbon atoms, and is intended to mean that each of these is described as a separate species. In one embodiment, the aliphatic group is substituted with one or more functional groups that result in the formation of a stable moiety.

[0607] 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 that replaces 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.

[0608] "Heteroaliphatic group" is intended herein to include, but not be limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl and heterocycloalkynyl. In one embodiment, "heteroaliphatic group" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or straight chain) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic groups are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0609] "Dosage form" refers to a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, emulsions, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gels, mucosal, etc. "Dosage form" can also include implants, such as ophthalmic implants.

[0610] As used herein, "effective amount" means an amount that provides a therapeutic or prophylactic benefit.

[0611] As used herein, "endogenous" refers to any material that is derived from or produced within an organism, cell, tissue or system.

[0612] As used herein, the term "exogenous" refers to any material that is introduced from outside of an organism, cell, tissue, or system or is produced outside of an organism, cell, tissue, or system.

[0613] As used herein, the term "modulate" means to mediate a detectable increase or decrease in the level of response of an individual as compared to the level of response of the individual in the absence of treatment or compound and / or as compared to the level of response of an otherwise identical but untreated individual. The term encompasses perturbing and / or affecting a natural signal or response such that a beneficial therapeutic response is mediated in an individual (preferably a human).

[0614] "Parenteral" administration of a pharmaceutical composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrasternal injection, or infusion techniques.

[0615] As used herein, the terms "peptide", "polypeptide", and "protein" are used interchangeably and refer to a compound composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present in a protein or peptide sequence is generally comparable to the number of amino acids in nature. Polypeptides include 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 and long chains, with short chains commonly referred to in the art as, for example, peptides, oligopeptides, and oligomers, and long chains commonly referred to in the art as proteins, of which there are many types. "Polypeptide" includes, for example, bioactive 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.

[0616] As used herein, the term "treat" a disease means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by an individual (i.e., palliative treatment) or to reduce the cause or effect of the disease or disorder (i.e., disease modifying treatment).

[0617] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as limiting the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as the individual numerical values within that range. For example, the description of a range such as from 1 to 6 should be considered to have specifically 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 the individual numbers within that range, for example 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is regardless of the breadth of the range.

[0618] As used herein, "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance such as a carrier. "Pharmaceutical combination" is a combination of at least two active agents and has instructions for using the active agents together for treating any of the disorders described herein, and the active agents may be combined in a single dosage form or provided together in separate dosage forms.

[0619] As used herein, "pharmaceutically acceptable salt" is a derivative of the disclosed compound, wherein the parent compound is modified by preparing its inorganic and organic, non-toxic, acid or base addition salts. The salts of the compounds of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Usually, when feasible, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. The salts of the compounds of the present invention further include solvates of the compounds and the compound salts.

[0620] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; base 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 compounds 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, etc.; salts formed 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 (where n is 0-4), etc., or salts prepared using different acids that produce the same counterion. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0621] The term "carrier" as applied to the pharmaceutical compositions / drug combinations of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

[0622] "Pharmaceutically acceptable excipient" refers to an excipient that can be used in the preparation of 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 veterinarily acceptable excipient is used.

[0623] "Patient" or "host" or "individual" is a human or non-human animal in need of treatment or prevention of any disease specifically described herein, e.g., according to the present invention, the disease is regulated by a natural (wild-type) or modified (non-wild-type) protein that can be degraded, thereby producing a therapeutic effect. Generally, the host is a human. "Host" alternatively refers to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0624] A "therapeutically effective amount" of the pharmaceutical composition / drug combination of the present invention refers to an amount that effectively provides a therapeutic benefit when administered to a host, such as alleviation of symptoms or reduction or attenuation of the disease itself.

[0625] II. Compounds of the present invention

[0626] In one aspect, a compound of formula I or formula II is provided:

[0627]

[0628] or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0629] wherein all variables are as defined above.

[0630] In another aspect, a compound of formula III is provided:

[0631]

[0632] or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0633] wherein all variables are as defined above.

[0634] In another aspect, a compound of formula IV is provided:

[0635]

[0636] or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0637] All variables are as defined above.

[0638] In another aspect, a compound of Formula V is provided:

[0639]

[0640] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0641] All variables are as defined above.

[0642] In another aspect, a compound of Formula VI or Formula VII is provided:

[0643]

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

[0645] All variables are as defined above.

[0646] In another aspect, a compound of Formula VIII is provided:

[0647]

[0648] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0649] All variables are as defined above.

[0650] In another aspect, a compound of Formula IX is provided:

[0651]

[0652] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0653] All variables are as defined above.

[0654] In another aspect, a compound of Formula X or Formula XI is provided:

[0655]

[0656] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0657] All variables are as defined above.

[0658] In one aspect, there is provided a compound of formula XII or XIII:

[0659]

[0660] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0661] All variables are as defined above.

[0662] In one aspect, there is provided a compound of formula XII or XIII:

[0663]

[0664] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0665] All variables are as defined above.

[0666] In another aspect, there is provided a compound of formula XIV:

[0667]

[0668] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0669] All variables are as defined above.

[0670] In another aspect, there is provided a compound of formula XV:

[0671]

[0672] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0673] All variables are as defined above.

[0674] In another aspect, there is provided a compound of formula XVI:

[0675]

[0676] or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0677] All variables are defined as above.

[0678] In another aspect, a compound of formula XVII or XVIII is provided:

[0679]

[0680] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0681] All variables are defined as above.

[0682] In another aspect, a compound of formula XIX is provided:

[0683]

[0684] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0685] All variables are defined as above.

[0686] In another aspect, a compound of formula XX is provided:

[0687]

[0688] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0689] All variables are defined as above.

[0690] In another aspect, a compound of formula XXI or XXII is provided:

[0691]

[0692] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0693] All variables are defined as above.

[0694] In any embodiment of formulae I-VIII or XII-XIX, R 1 is hydrogen. In any embodiment of formulae I-VIII or XII-XOX, R 1 is fluorine.

[0695] In any one of the embodiments of Formulas I-VIII or XII-XIX, R 2 is hydrogen. In any one of the embodiments of Formulas I-VIII or XII-XOX, R 2 is fluorine.

[0696] In any one of the embodiments of Formulas I-XI, R 3 is hydrogen. In any one of the embodiments of Formulas XII-XXII, R 3a is hydrogen.

[0697] In any one of the embodiments of Formulas I-XI, R 3 is methyl. In any one of the embodiments of I-XI, R 3 is ethyl. In any one of the embodiments of Formulas I-XI, R 3 is isopropyl. In any one of the embodiments of Formulas I-XI, R 3 is tert-butyl. In any one of the embodiments of Formulas XII-XXII, R 3a is methyl. In any one of the embodiments of Formulas XII-XXII, R 3a is ethyl. In any one of the embodiments of Formulas XII-XXII, R 3a is isopropyl. In any one of the embodiments of Formulas XII-XXII, R 3a is tert-butyl.

[0698] In any one of the embodiments of Formulas I-XI, R 3 is trifluoromethyl. In any one of the embodiments of Formulas I-XI, R 3 is trichloroethyl. In any one of the embodiments of Formulas I-XI, R 3 is trifluoroethyl. In any one of the embodiments of Formulas XII-XXII, R 3a is trifluoromethyl. In any one of the embodiments of Formulas XII-XXII, R 3a is trichloroethyl. In any one of the embodiments of Formulas XII-XXII, R 3a is trifluoroethyl.

[0699] In any one of the embodiments of Formulas I-XI, R 3 is vinyl. In any one of the embodiments of Formulas I-XI, R 3 is ethynyl. In any one of the embodiments of Formulas XII-XXII, R 3a is vinyl. In any one of the embodiments of Formulas XII-XXII, R 3a is ethynyl.

[0700] In any one of the embodiments of Formulas I-XI, R3 is cyclopropyl. In any embodiment of Formulas I-XI, R 3 is cyclobutyl. In any embodiment of Formulas I-XI, R 3 is cyclopentyl. In any embodiment of Formulas I-XI, R 3 is cyclohexyl. In any embodiment of Formulas XII-XXII, R 3a is cyclopropyl. In any embodiment of Formulas XII-XXII, R 3a is cyclobutyl. In any embodiment of Formulas XII-XXII, R 3a is cyclopentyl. In any embodiment of Formulas XII-XXII, R 3a is cyclohexyl.

[0701] In any embodiment of Formulas I-XI, R 3 is a heterocyclic group. In any embodiment of Formulas I-XI, R 3 is phenyl. In any embodiment of Formulas I-XI, R 3 is naphthyl. In any embodiment of Formulas I-XI, R 3 is pyridyl. In any embodiment of Formulas I-XI, R 3 is imidazolinyl. In any embodiment of Formulas I-XI, R 3 is pyrimidinyl. In any embodiment of Formulas XII-XXII, R 3a is a heterocyclic group. In any embodiment of Formulas XII-XXII, R 3a is phenyl. In any embodiment of Formulas XII-XXII, R 3a is naphthyl. In any embodiment of Formulas XII-XXII, R 3a is pyridyl. In any embodiment of Formulas XII-XXII, R 3a is imidazolinyl. In any embodiment of Formulas XII-XXII, R 3a is pyrimidinyl.

[0702] In any embodiment of Formulas I-XI, R 3 is hydroxy. In any embodiment of Formulas I-XI, R 3 is methoxy. In any embodiment of Formulas I-XI, R 3 is ethoxy. In any embodiment of Formulas XII-XXII, R 3a is hydroxy. In any embodiment of Formulas XII-XXII, R 3a is methoxy. In any embodiment of Formulas XII-XXII, the formula R3a is ethoxy.

[0703] In any one embodiment of Formulas I-XI, R 3 is amino. In any one embodiment of Formulas I-XI, R 3 is methylamino. In any one embodiment of Formulas XII-XXII, R 3a is amino. In any one embodiment of Formulas XII-XXII, R 3a is methylamino.

[0704] In any one embodiment of Formulas I-XI, R 3 is thio. In any one embodiment of Formulas XII-XXII, R 3a is thio.

[0705] In any one embodiment of Formulas I-XI, R 3 is acetyl. In any one embodiment of Formulas I-XI, R 3 is methyl carboxyl. In any one embodiment of Formulas XII-XXII, R 3a is acetyl. In any one embodiment of Formulas XII-XXII, R 3a is methyl carboxyl.

[0706] In any one embodiment of Formulas I-XI, R 3 is methylsulfonyl. In any one embodiment of Formulas XII-XXII, R 3a is methylsulfonyl.

[0707] In any one embodiment of Formulas I-XI, R 3 is chlorine. In any one embodiment of Formulas I-XI, R 3 is fluorine. In any one embodiment of Formulas I-XI, R 3 is bromine. In any one embodiment of Formulas I-XI, R 3 is iodine. In any one embodiment of Formulas XII-XXII, R 3a is chlorine. In any one embodiment of Formulas XII-XXII, R 3a is fluorine. In any one embodiment of Formulas XII-XXII, R 3 is bromine. In any one embodiment of Formulas XII-XXII, R 3a is iodine.

[0708] In any one embodiment of Formulas I-XI, R 3 is cyano. In any one embodiment of Formulas I-XI, R 3Azido. In any one embodiment of Formulas I-XI, R 3 is nitro. In any one embodiment of Formulas I-XI, R 3 is R 5 In any one embodiment of Formulas XII-XXII, R 3a is cyano. In any one embodiment of Formulas XII-XXII, R 3a is azido. In any one embodiment of Formulas XII-XXII, R 3a is nitro.

[0709] In any one embodiment of Formulas I-II, VIII-XIV or XIX-XXII, m is 1. In any one embodiment of Formulas I-II, VIII-XIV or XIX-XXII, m is 2. In any one embodiment of Formulas I-II, VIII-XIV or XIX-XXII, m is 3. In any one embodiment of Formulas I-II, VIII-XIV or XIX-XXII, m is 4.

[0710] In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 1. In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 2. In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 3. In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 4. In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 5. In any one embodiment of Formulas I, II, IV-XIII or XV-XXII, n is 6.

[0711] In any one embodiment of Formulas I, II, XII or XIII, o is 1. In any one embodiment of Formulas I, II, XII or XIII, o is 2. In any one embodiment of Formulas I, II, XII or XIII, o is 3.

[0712] In any one embodiment of Formulas V or XVI, p is 1. In any one embodiment of Formulas V or XVI, p is 2. In any one embodiment of Formulas V or XVI, p is 3. In any one embodiment of Formulas V or XVI, p is 4. In any one embodiment of Formulas V or XVI, p is 5.

[0713] In any one embodiment of Formulas VI, VII, XVII or XVIII, q is 1. In any one embodiment of Formulas VI, VII, XVII or XVIII, q is 2.

[0714] In any one embodiment of Formula I, II, or VI - XI, X A is CH. In any one embodiment of Formula I, II, or VI - XI, X A is N. In any one embodiment of Formula I, II, or VI - XI, X A is CR 3 .

[0715] In any one embodiment of Formula I, II, IV, or VI - XI, X B is CH2. In any one embodiment of Formula I, II, IV, or VI - XI, X B is CH R 3 . In any one embodiment of Formula I, II, IV, or VI - XI, X B is NH. In any one embodiment of Formula I, II, IV, or VI - XI, X B is NR 3 .

[0716] In any one embodiment of Formula III, VI, or VII, R 8 is hydrogen. In any one embodiment of Formula III, VI, or VII, R 8 is methyl. In any one embodiment of Formula III, VI, or VII, R 8 is R 5 .

[0717] In any one embodiment of Formula I - VIII or XII - XIX, may be selected from:

[0718]

[0719] In any one embodiment of Formula I and VIII - XI, may be selected from:

[0720]

[0721] In any one embodiment of Formula XII and XIX - XXII, may be selected from:

[0722]

[0723]

[0724] In any one embodiment of Formula I, X, or XI, may be selected from:

[0725]

[0726]

[0727] In any embodiment of Formula I, X or XI, may be selected from:

[0728]

[0729]

[0730] In any embodiment of Formula II, may be selected from:

[0731]

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

[0733]

[0734] In any embodiment of Formula III, may be selected from:

[0735]

[0736]

[0737] In any embodiment of Formula III, may be selected from:

[0738]

[0739]

[0740] In one embodiment of Formula V, may be selected from:

[0741]

[0742]

[0743] In one embodiment of Formula XVI, may be selected from:

[0744]

[0745] In any embodiment of Formula V, may be selected from:

[0746]

[0747] In any one of the embodiments of Formula VI, selected from:

[0748]

[0749] In any one of the embodiments of Formula VI, may be selected from:

[0750]

[0751] In any one of the embodiments of Formula VII, selected from:

[0752]

[0753]

[0754] In any one of the embodiments of Formula VII, may be selected from:

[0755]

[0756]

[0757] In any one of the embodiments of Formula VIII, may be selected from:

[0758] In any one of the embodiments of Formula VIII, may be selected from:

[0759]

[0760] In any one of the embodiments of Formula IX, may be selected from:

[0761]

[0762]

[0763] In any one of the embodiments of Formula IX, may be selected from:

[0764]

[0765]

[0766] In any one of the embodiments of Formula XII, may be selected from:

[0767]

[0768] In any embodiment of Formula XII, may be selected from:

[0769]

[0770] In any embodiment of Formula XIII, may be selected from:

[0771]

[0772]

[0773] In any embodiment of Formula XIII, may be selected from:

[0774]

[0775]

[0776] In any embodiment of Formula XIV, may be selected from:

[0777]

[0778] In any embodiment of Formula XV, may be selected from:

[0779]

[0780] In any embodiment of Formula XVI, may be selected from:

[0781]

[0782] In any embodiment of Formula XVII, is selected from:

[0783]

[0784] In any embodiment of Formula XVII, may be selected from:

[0785]

[0786] In any embodiment of Formula XVIII, is selected from:

[0787]

[0788]

[0789] In any embodiment of formula XVIII, may be selected from:

[0790]

[0791] In any embodiment of formula XIX, may be selected from:

[0792]

[0793] In any embodiment of formula XIX, may be selected from:

[0794]

[0795]

[0796] In any embodiment of formula XX, may be selected from:

[0797]

[0798] In any embodiment of formula XX, may be selected from:

[0799]

[0800] In any embodiment of formula XXI, may be selected from:

[0801]

[0802]

[0803] In any embodiment of formula XXI, may be selected from:

[0804]

[0805] In any embodiment of formula XXII, may be selected from:

[0806]

[0807] In any embodiment of formula XII, may be selected from:

[0808]

[0809] In certain embodiments of Formula I, X or XI, is

[0810] In certain embodiments of Formula II, is

[0811] In certain embodiments of Formula VI, is

[0812] In certain embodiments of Formula XII, is

[0813] In certain embodiments of Formula XIII, is

[0814] In certain embodiments of Formula XVIII, is

[0815] In certain embodiments of Formula XXI, is

[0816] Representative examples of compounds of Formula I include:

[0817]

[0818]

[0819]

[0820]

[0821] Representative examples of compounds of Formula II include:

[0822]

[0823] Representative examples of compounds of Formula III include:

[0824]

[0825] Representative examples of compounds of Formula IV include:

[0826]

[0827] Representative examples of compounds of Formula V include:

[0828]

[0829]

[0830] Representative examples of the compounds of Formula VI include:

[0831]

[0832] Representative examples of the compounds of Formula VII include:

[0833]

[0834] Representative examples of the compounds of Formula VIII include:

[0835]

[0836]

[0837] Representative examples of the compounds of Formula IX include:

[0838]

[0839]

[0840]

[0841] Representative examples of the compounds of Formula X include:

[0842]

[0843] Representative examples of the compounds of Formula XI include:

[0844]

[0845]

[0846] Representative examples of the compounds of Formula XII include:

[0847]

[0848]

[0849]

[0850]

[0851] Representative examples of the compounds of Formula XIII include:

[0852]

[0853] Representative examples of the compounds of Formula XIV include:

[0854]

[0855]

[0856] Representative examples of the compounds of formula XVII include:

[0857]

[0858] Representative examples of the compounds of formula XVIII include:

[0859]

[0860]

[0861] Representative examples of the compounds of formula XIX include:

[0862]

[0863]

[0864] Representative examples of the compounds of formula XX include:

[0865]

[0866] Representative examples of the compounds of formula XXI include:

[0867]

[0868]

[0869] Representative examples of the compounds of formula XXII include:

[0870]

[0871]

[0872] Representative examples of the compounds of formula XXIII include:

[0873]

[0874]

[0875] Representative examples of the compounds of formula XXIV include:

[0876]

[0877] In one aspect, there is provided a compound of one of the following formulas:

[0878]

[0879] All variables are defined as above.

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

[0881]

[0882]

[0883] All variables are defined as above.

[0884] In another aspect, a compound of one of the following formulas is provided:

[0885]

[0886] All variables are defined as above.

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

[0888]

[0889] All variables are defined as above.

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

[0891]

[0892]

[0893] All variables are defined as above.

[0894] In one aspect, a compound of one of the following formulas is provided:

[0895]

[0896]

[0897] All variables are defined as above.

[0898] In one embodiment, a compound of one of the following formulas is provided:

[0899]

[0900]

[0901] All variables are defined as above.

[0902] In one embodiment, a compound of one of the following formulas is provided:

[0903] All variables are defined as above.

[0904] In one embodiment, a compound of one of the following formulas is provided:

[0905]

[0906]

[0907] All variables are defined as above.

[0908] In one embodiment, a compound of one of the following formulas is provided:

[0909]

[0910] All variables are defined as above.

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

[0912]

[0913] All variables are defined as above.

[0914] In one aspect, a compound of one of the following formulas is provided:

[0915]

[0916] All variables are defined as above.

[0917] In one aspect, a compound of formula IA, formula IIA, formula IIIA or formula IVA is provided:

[0918]

[0919]

[0920] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0921] Wherein:

[0922] W 200 is O or S;

[0923] R 201a is selected from: -(C0-C2 alkyl)(cycloalkyl), -(C1-C2 alkyl)(monocyclic heterocyclic group), -(C1-C2 alkyl)(aryl) and -(C1-C2 alkyl)(heteroaryl), where R201a substituted by R 208 and optionally substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups), and wherein the attachment point of the monocyclic heterocyclic group is a carbon atom; or

[0924] R 201a is selected from –(CO)R 208 , -(SO)R 208 , -(SO2)R 208 and –(CS)R 208 ;

[0925] R 202a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclic group), -(C0-C2 alkyl)(aryl), and –(C0-C2 alkyl)(heteroaryl), wherein R 202a is substituted by R 208 and optionally substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups); or

[0926] R 202a is selected from –(CO)R 208 , -(SO)R 208 , -(SO2)R 208 or –(CS)R 208 ;

[0927] R 203a is selected from -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(monocyclic heterocyclic group), -(C0-C2 alkyl)(aryl), and -(C0-C2 alkyl)(heteroaryl), wherein R 203a is substituted by R 208 and optionally substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups); or

[0928] R 203a is selected from –(CO)R 208 , -(SO)R 208 , -(SO2)R 208 , –(CS)R 208 , –N(R 207 )(R 208 ) and –OR 208 ;

[0929] R 204aSelected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclic group), -(C0-C2 alkyl)(aryl), and -(C0-C2 alkyl)(heteroaryl), where R 204a is substituted by R 208 and is optionally substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups); or

[0930] R 204a is selected from –(CO)R 208 , -(SO)R 208 , -(SO2)R 208 , –(CS)R 208 , –N(R 207 )(R 208 ) and –OR 208 ;

[0931] R 201 and R 202 are each independently selected 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, where each R 201 and R 202 except hydrogen can optionally be substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups); or

[0932] R 201 is

[0933] R 203 and R 204 are independently selected from hydrogen, halogen (e.g., 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 203 and R 204 except hydrogen and halogen can optionally be substituted by one or more groups selected from R 205 (e.g., 1, 2, 3, or 4 groups);

[0934] R 205independently selected from C1-C each time it appears 12 alkyl, C1-C 12 haloalkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, C3-C 12 heterocyclic group, 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 cannot be R 208 ;

[0935] R 206 independently selected from hydrogen, C1-C each time it appears 12 alkyl, C1-C 12 haloalkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, C3-C 12 heterocyclic group, aryl, heteroaryl, hydroxy, C1-C6 alkoxy, thio, C1-C6 thioalkyl, -NH2, -NH(C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclic group, aryl or heteroaryl) and -N(independently C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 heterocyclic group, aryl or heteroaryl)2;

[0936] R 207 and R 207’ independently selected from hydrogen, C1-C each time it appears 12 alkyl, C1-C 12 haloalkyl, C1-C 12 alkenyl, C2-C 12 alkynyl, C3-C 12 cycloalkyl, C3-C 12 cycloalkenyl, C3-C 12 heterocyclic group, aryl, heteroaryl, -(CO)R 206 , -(CS)R 206 , -(C=NH)R 206, -(SO)R 206 and -(SO2)R 206 ;

[0937] Y 200 is O, S, -CH2-, -CHR 205 -, or –C(R 205 )2-;

[0938] Z 201 is selected from a hydroxyl group or an amino group;

[0939] Z 202 is selected from O, S or CR 212 R 213 ;

[0940] R 209 and R 210 are independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

[0941] R 211 is selected from hydrogen, halogen, azide, cyano and heteroaryl;

[0942] R 212 , R 213 , R 214 and R 215 are independently selected from hydrogen, -OR 207 , cyano, azide, halogen, -NHR 207 , -NR 207 R 207’ , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkyl and C1-C4 haloalkyl, or

[0943] R 212 and R 214 can together with the carbon to which it is attached form a carbon-carbon double bond; or

[0944] R 212 and R 214 can together with the carbon to which it is attached form a 3- to 6-membered carbon ring;

[0945] wherein if R 212 is a hydroxyl group, then at least one of R 213 , R 214 and R 215 is not hydrogen;

[0946] wherein if R 213 is a hydroxyl group, then at least one of R 212 , R 214 and R 215 is not hydrogen;

[0947] R 216Selected from hydrogen, methyl, hydroxymethyl and fluoromethyl;

[0948] Selected from a single bond or a double bond each time it appears;

[0949] Each R 208 is independently – linker - targeting ligand;

[0950] The linker is a divalent chemical group that attaches R 208 to the targeting ligand; and

[0951] The targeting ligand is a molecule that binds to a target protein, where the target protein is a mediator of a host disease.

[0952] In one embodiment, the linker is a divalent chemical group that attaches a degron to the targeting ligand.

[0953] In one embodiment, the linker is selected from

[0954] X 1 and X 2 are independently selected from a bond, NR 4 , CH2, CHR 4 , C(R 4 )2, O and S;

[0955] R 20 , R 21 , R 22 , R 23 , and R 24 are 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(-O-R 26 )-, -CH(-NR 4 R 4’ )-, -C(-O-R 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 )-, -NR4 C(O)NR 4’ -, alkene, haloalkyl, alkoxy, alkynyl heteroarylalkyl, aryl, arylalkyl, heterocyclic group, aliphatic group, heteroaliphatic group, heteroaryl, lactic acid, glycolic acid, carbocyclic ring, -(ethylene glycol) 1-6 -, -(lactic acid - 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-, where 1 - 6 can independently be 1, 2, 3, 4, 5 or 6, where 1 - 2 can independently be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and where 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 groups, aryl groups, heteroaryl groups or cycloaliphatic groups in the chain.

[0956] Some non - limiting examples include -O-CH(CH3)-CH(CH3)CH-O-, -O-CH2-CH(CH3)CH-O-, -O-CH(CH3)-CH2CH-O-, etc.;

[0957] where each R 20 、R 21 、R 22 、R 23 and R 24 is optionally substituted by one or more substituents selected from R 101 or the substituents as described in the definition section;

[0958] R 101 independently, each time it appears, is selected from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxy, aryl, heteroaryl, heterocyclic group, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COO alkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NH alkyl, N(alkyl)2, aliphatic group and heteroaliphatic group;

[0959] R 26Selected from hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic;

[0960] R 27 and R 28 are independently selected from hydrogen, alkyl, and amine; or together with the carbon atom to which it is attached form C(O), C(S), C═CH2, C3-C6 spirocarbocyclic ring, or a 4-, 5-, or 6-membered spiroheterocyclic ring containing 1 or 2 heteroatoms selected from N and O, or form a 1- or 2-carbon bridged ring; and

[0961] R 40 is independently selected from hydrogen, alkyl, alkene, alkyne, halogen, hydroxy, alkoxy, azido, amino, cyano, -NH(aliphatic group, including alkyl), -N(aliphatic group, including alkyl)2, -NHSO2(aliphatic group, including alkyl), -N(aliphatic group, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl, or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic group, heteroaliphatic group, aryl, heteroaryl, heteroalkyl, heterocyclic group, and carbocyclic group each time it appears; and wherein all other variables are as described herein.

[0962] In one embodiment, the targeting ligand is a small molecule that binds to the targeted protein.

[0963] In one embodiment, the targeted protein is a mediator of abnormal cell proliferation in a host in need of such treatment.

[0964] In another aspect, there is provided a compound of formula VA, formula VIA, or formula VIIA;

[0965]

[0966] (VIA); or

[0967]

[0968] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0969] wherein:

[0970] Z 200A is selected from –OR 207 and –N(R 207 )(R 207’ );

[0971] Z 200BSelected 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 ;

[0972] R 213a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclic group), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl), where R 213a is substituted by R 208 and is optionally substituted by one or more groups (e.g., 1, 2, 3 or 4 groups) selected from R 205 ; or

[0973] R 213a is 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 is –OR 208 , then at least one of R 212 、R 214 and R 215 cannot be hydrogen;

[0974] R 215a is selected from C1-C6 alkyl, -(C0-C2 alkyl)(cycloalkyl), -(C0-C2 alkyl)(heterocyclic group), -(C0-C2 alkyl)(aryl) and -(C0-C2 alkyl)(heteroaryl); where R 215a is substituted by R 208 and is optionally substituted by one or more groups (e.g., 1, 2, 3 or 4 groups) selected from R 205 ;

[0975] Or R 215a is selected from –(CO)R208 、 -(SO)R 208 、 -(SO2)R 208 、 –(CS)R 208 、 –N(R 207 )(R 208 ) and –OR 208 ; and

[0976] wherein all other variables are as defined above.

[0977] In another aspect, there is provided a compound of formula VIIIA:

[0978]

[0979] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0980] wherein:

[0981] R 250 and R 251 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclic group, aryl, heteroaryl, halogen, azide, cyano, -OR 207 , -N(R 207 )(R 207’ ) and –SR 207 ;

[0982] R 253 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclic group, aryl, heteroaryl and cyano;

[0983] R 252 is selected from –N(R 207 )(R 208 ) and –OR 208 ; or

[0984] R 252 is a heterocyclic group or heteroaryl group substituted by at least one R 208 group and optionally substituted by one or more groups (e.g., 1, 2, 3 or 4 groups) selected from R 205 , said heterocyclic group or heteroaryl group containing at least one nitrogen atom attached thereto;

[0985] and wherein all other variables are as defined above.

[0986] In another aspect, there is provided a compound of formula IXA:

[0987]

[0988] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[0989] Wherein:

[0990] R 254 is selected from:

[0991] wherein

[0992] Q 201 each instance of which is independently selected from N, CH, CR 205 and CR 255a and wherein at least one Q 201 is CR 255a ;

[0993] Q 202 each instance of which is independently selected from N, CH, CR 205 and CR 255b and wherein at least one Q 202 is CR 255b ;

[0994] R 255a is a heterocyclic moiety that contains at least one nitrogen atom and is attached through a carbon atom, wherein said heterocyclic moiety may be substituted by one or more (e.g., 1, 2, 3 or 4) R 205 groups, and wherein said heterocyclic moiety may be substituted by one or more oxo groups where valence permits;

[0995] R 255b is a heterocyclic moiety that contains at least one nitrogen atom, wherein said heterocyclic moiety may be substituted by one or more (e.g., 1, 2, 3 or 4) R 205 groups, and wherein said heterocyclic moiety may be substituted by one or more oxo groups where valence permits;

[0996] and wherein all other variables are as defined above.

[0997] Non-limiting examples of the compounds of the present invention include:

[0998]

[0999]

[1000]

[1001]

[1002]

[1003] Non-limiting examples of the compounds of the present invention include:

[1004]

[1005]

[1006] In another aspect, compounds of formula I-B or formula I-C are provided:

[1007]

[1008] wherein the linker is a bond or a divalent or polyvalent chemical group that attaches the degron to the targeting ligand as described herein;

[1009] Linker B is selected from –(linker) as defined herein B ; in one embodiment, the linker B is covalently attached to at least one degron and is not attached to the targeting ligand;

[1010] The targeting ligand is a molecule that binds to a target protein, wherein the target protein is a mediator of a host disease;

[1011] The degron is selected from:

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024] wherein the degrading stator may optionally be substituted by one or more substituents (e.g., 1, 2, 3, or 4) selected from R 101 ;

[1025] wherein the linker is covalently linked to the degrading stator where valence allows; and

[1026] wherein all other variables are as defined above.

[1027] In another embodiment, degrading stators are provided selected from:

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041] In one embodiment, a compound of formula A is provided:

[1042]

[1043] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[1044] wherein:

[1045] Q A is selected from NR 8 , O, S, C═O, S═O, and SO2;

[1046] QB is CR 3 or N; and

[1047] wherein all other variables are as defined above.

[1048] In another embodiment, a compound of formula B is provided:

[1049]

[1050] or a pharmaceutically acceptable salt, N-oxide, isotopic derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition;

[1051] wherein:

[1052] Q A1 is selected from NR 8a 、O、S、C=O、S=O and SO2;

[1053] Q B1 is CR 3a or N; and

[1054] wherein all other variables are as defined above.

[1055] III. Linker

[1056] The degrading agents of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X and formula XI include a linker. The linker is a bond or a chemically stable divalent group that connects the degrader to the targeting ligand. In some embodiments, the linker may have a closed valence and thus will contain one or more covalent bonds to ensure a complete valence, which may be one or more hydrogen atoms, or in the case of a carboxyl, sulfonyl, thiol, thiophenol, alcohol or phenol group, may also be the deprotonated species and its salts, and for an amine, may also be the ammonium species and its salts.

[1057] The linker as described herein can be used in either orientation, i.e., either the left end is connected to the degrader and the right end is connected to the target linker, or the left end is connected to the target linker and the right end is connected to the degrader. In one embodiment, the linker is a divalent chemical group. According to the present invention, any desired linker can be used as 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.

[1058] In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, where one or more of the carbons can be replaced by a heteroatom 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 contiguous atoms in the chain. For example, the chain can include one or more ethylene glycol units (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units) that can be contiguous, partially contiguous, or non - contiguous. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous linkages that can have branches that can independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclic substituents.

[1059] In other embodiments, the linker can comprise or consist of one or more of the following: ethylene glycol, propylene glycol, lactic acid, and / or glycolic acid. Generally, propylene glycol increases hydrophobicity, while ethylene glycol increases hydrophilicity. Lactic acid segments tend to have a longer half - life than glycolic acid segments. Block and random lactic - co - glycolic moieties as well as ethylene glycol and propylene glycol are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half - life and hydrophilicity. In certain aspects, other moieties are present on either side of or interspersed among these units as needed to achieve appropriate drug properties, such other moieties being, for example, aliphatic groups (including alkyl), heteroaliphatic groups, aryl, heteroaryl, heterocyclic groups, cycloalkyl groups, etc.

[1060] 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:

[1061]

[1062] wherein all variables are as defined above.

[1063] In other embodiments, the linker is a moiety selected from Formula LVIII, LIX, and LX:

[1064]

[1065] wherein all variables are as defined above.

[1066] In other embodiments of LVIII, LIX, and LX, a carbocyclic ring is used in place of the heterocyclic ring.

[1067] 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 linkers to achieve the objects of the present invention.

[1068] As some non - limiting examples, Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI or Formula LVII include:

[1069]

[1070]

[1071]

[1072] In other embodiments, the linker is selected from:

[1073]

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

[1075]

[1076] In one embodiment, X 1 is attached to the targeting ligand. In another embodiment, X 2 is attached to the targeting ligand.

[1077] R 20 、R 21 、R 22 、R 23 and R 24 Non - limiting examples of the moieties include:

[1078] R 20 、R 21 、R 22 、R 23 and R 24 Other non - limiting examples of the moieties include:

[1079]

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

[1081]

[1082] In additional 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 an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the two sides of the linker are substituted with or interspersed with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups. In certain embodiments, the linker can be asymmetric or symmetric. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group having a size range of 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 of the embodiments of the compounds described herein, the linker group can be any suitable moiety described herein.

[1083] In other embodiments, the linker is selected from:

[1084] -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-(heterocyclic group)-CH2, -NR 61 (CH2CH2) n1 -(heterocyclic group)-(heterocyclic group)-CH2 and -NR 61 -(heterocyclic group)-CH2;

[1085] where n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1086] R 61 is H, methyl or ethyl.

[1087] In other embodiments, the linker is selected from:

[1088] -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-; wherein

[1089] m1, n2, o1, p1, q1 and r1 are independently 1, 2, 3, 4 or 5; and

[1090] R 61 is H, methyl or ethyl.

[1091] In other embodiments, the linker is selected from:

[1092]

[1093]

[1094] wherein

[1095] m1, n2, o1, p1, q2 and r1 are independently 1, 2, 3, 4 or 5.

[1096] In other embodiments, the linker is selected from:

[1097]

[1098]

[1099] In other embodiments, the linker is selected from:

[1100] In other embodiments, the linker is selected from:

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107] wherein R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic or -Nme.

[1108] In other embodiments, the linker is selected from:

[1109]

[1110]

[1111] In other embodiments, the linker is selected from:

[1112]

[1113]

[1114]

[1115]

[1116] In other embodiments, the linker is selected from:

[1117]

[1118]

[1119] In other embodiments, the linker is selected from:

[1120]

[1121] In other embodiments, the linker is selected from:

[1122]

[1123]

[1124] In other embodiments, the linker is selected from:

[1125]

[1126] In other embodiments, the linker is selected from:

[1127]

[1128] In certain embodiments, the linker is selected from:

[1129]

[1130] In certain embodiments, the linker is selected from:

[1131]

[1132]

[1133] In the above structure, represents

[1134] In certain embodiments, the linker 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, fluorocarbon, etc., such as the following:

[1135]

[1136]

[1137]

[1138] In certain embodiments, the linker can be non-straight chain and can be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[1139] In certain embodiments, the linker can include contiguous, partially contiguous or non-contiguous ethylene glycol unit groups, with a size range of 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, such as 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[1140] 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 the fluorinated linker moiety include:

[1141]

[1142]

[1143] In certain embodiments, when a target ligand binds to more than one protein (i.e., is not completely selective), selectivity can be enhanced by varying the length of the linker, where the ligand binds some of its targets in different binding pockets (e.g., binding pockets that are deeper or shallower than other pockets). Thus, the length can be adjusted as needed.

[1144] In another embodiment, the - linker - targeting ligand is –(linker) B , where -(linker) B is a monovalent group. In one embodiment, -(linker) B is covalently attached to at least one degron and not attached to the targeting ligand. In another embodiment, the - linker - targeting ligand is –(linker) C , where –(linker) C is covalently attached to the targeting ligand and one or more other targeting ligands and / or degrons.

[1145] In one embodiment, -(linker) B is selected from

[1146] where all variables are defined as above.

[1147] 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:

[1148]

[1149] where all variables are defined as above.

[1150] In other embodiments, -(linker) B is a moiety selected from Formula LBVIII, LBIX, and LBX:

[1151]

[1152] where all variables are defined as above. In other embodiments of L B VIII, L B IX, and L B X, a carbocycle is used in place of a heterocycle.

[1153] The following are -(linker) BNon-limiting examples of the portion. Based on this detailed description, those skilled in the art should understand how to use the full-length-(linker) that would achieve the objectives of the present invention B portion

[1154] 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, formula L B VI or formula L B VII includes:

[1155]

[1156]

[1157]

[1158] In other embodiments, –(linker) B is selected from:

[1159]

[1160] In other embodiments, –(linker) B is selected from:

[1161]

[1162] amount

[1163] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of the portion include:

[1164] R 20 , R 21 , R 22 , R 23 and R 24 Other non-limiting examples of the portion include:

[1165]

[1166]

[1167] R 20, R 21 , R 22 , R 23 and R 24 Other non - limiting examples of the moieties of

[1168]

[1169] 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 is flanked by, substituted with 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, 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 of the embodiments of the compounds described herein, the -(linker) B group can be any suitable moiety described herein.

[1170] In other embodiments, –(linker) B is selected from:

[1171] -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 -(heterocyclic alkyl)-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-(heterocyclic group)-CH2-X 22 、-NR 61 (CH2CH2) n1 -(heterocyclic group)-(heterocyclic group)-CH2-X 22 and -NR 61 -(heterocyclic group)-CH2-X 22 ;

[1172] wherein n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and

[1173] R 61 is H, methyl or ethyl.

[1174] In other embodiments, –(linker) B选自:

[1175] -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;-(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) p1 O(CH2) q1 OCH2-X 22 ;和-O(CH2) m1 O(CH2) n2 O(CH2) p1O(CH2) q1 OCH2-X 22 ; wherein

[1176] m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and

[1177] R 61 is H, methyl, or ethyl.

[1178] In other embodiments, –(linker) B is selected from:[[]]

[1179]

[1180]

[1181] wherein m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

[1182] In other embodiments, –(linker) B is selected from:[[]]

[1183]

[1184]

[1185] In other embodiments, –(linker) B is selected from:[[]]

[1186]

[1187] In other embodiments, –(linker) B is selected from:[[]]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194] wherein R 71 is -O-, -NH, N-alkyl, heteroaliphatic, aliphatic, or -NMe.

[1195] In other embodiments, –(linker) B is selected from:[[]]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201] In other embodiments, –(connector) B Selected from:

[1202]

[1203]

[1204] In other embodiments, –(connector) B Selected from:

[1205] In other embodiments, –(connector) B Selected from:

[1206]

[1207]

[1208]

[1209] In other embodiments, –(connector) B Selected from:

[1210]

[1211] In the above embodiments, X is selected 22 such that the compound is sufficiently stable or achieves the intended use.

[1212] In other embodiments, –(connector) B Selected from:

[1213]

[1214] In certain embodiments, –(connector) B Selected from:

[1215]

[1216] In certain embodiments, –(connector) B Selected from:

[1217]

[1218]

[1219] In the above structure, represents

[1220] In certain embodiments, -(linker) B can be a straight chain of 4-24 carbon atoms, where one or more of the carbon atoms in the straight chain can be replaced or substituted by oxygen, nitrogen, amide, fluorocarbon, etc., such as the following:

[1221]

[1222]

[1223]

[1224] In certain embodiments, -(linker) B can be non-straight chain and can be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[1225] In certain embodiments, -(linker) B can include contiguous, partially contiguous or non-contiguous ethylene glycol unit groups, with a size range of 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, such as 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[1226] In certain embodiments, -(linker) B can have 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 is a partially or fully fluorinated polyether. The fluorinated -(linker) B non-limiting examples of the moiety include:

[1227]

[1228] In certain embodiments, the length can be adjusted as needed or as found necessary for the desired application.

[1229] IV. Target Protein

[1230] Cellular homeostasis and normal cellular functions, such as proliferation, differentiation, and cell death, require cellular protein degradation. When this system malfunctions or fails to recognize and reduce abnormal protein behavior in the body, disease states can arise 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 proposed in scientific reports, a wide range of proteins can cause, regulate, or enhance diseases in the body.

[1231] Accordingly, 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 a disease to be treated. The selected protein target can modulate a human disease by a mechanism of action such as altering a biological pathway, pathogenic signal transduction, or regulating a signal cascade or cell entry.

[1232] 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 amenable to allosteric control. In another embodiment, the target protein is a protein that is druggable in the classical sense, but for therapeutic purposes, degradation of the protein is preferably inhibited.

[1233] 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.

[1234] In one embodiment, the selected target protein is expressed by a gene that has undergone an amplification, translocation, deletion, or inversion event, which causes or is caused by a medical disease. In certain aspects, the selected target protein has been post-translationally modified by phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation and polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylation, ubiquitination, ubiquitin-like modification, or sulfation, either singly or in combination, which causes or is caused by a medical disease.

[1235] As contemplated herein, the present invention includes degrading agents having a targeting ligand that binds to a target protein of interest. The target protein is any amino acid sequence to which the degrading agent can bind and that causes a beneficial therapeutic effect in the body by degradation of the target protein.

[1236] In one embodiment, the target protein is a non-endogenous peptide, such as a peptide from a pathogen or a toxin. In another embodiment, the target protein can be an endogenous protein that mediates a disease. The endogenous protein can be in its normal form or an abnormal form. For example, the target protein can be a mutant protein found in cancer cells, or a protein in which a gain or loss of function, in part or in whole, 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.

[1237] In another embodiment, the target protein can mediate an inflammatory disease or an immune disease, including an autoimmune disease.

[1238] In one embodiment, the target protein is a non-endogenous protein from a virus, as non-limiting examples, HIV, HBV, HCV, RSV, HPV, CMV, flavivirus, pestivirus, coronavirus, norovirus, etc.

[1239] 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 bacteria, and can be a drug-resistant form of the bacterium.

[1240] 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 eukaryotic pathogens such as protists and parasitic worms, etc.

[1241] In one aspect, the target protein mediates chromatin structure and function. The target protein can mediate epigenetic effects, such as DNA methylation or covalent modification of histones. An example is histone deacetylase (HDAC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11). Optionally, the target protein can be a bromodomain, which is a reader of lysine acetylation (e.g., BRD1, 2, 3, 4, 5, 6, 7, 8, 9 and T). Figure 9 Proteins of the bromodomain family are shown, for example, which can be used as target proteins according to the present invention.

[1242] Other non-limiting examples of target proteins are structural proteins, receptors, enzymes, cell surface proteins, proteins involved in apoptotic signaling, aromatase, helicases, mediators of metabolic processes (anabolic or catabolic), antioxidants, proteases, kinases, oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, enzyme modulators, signal transducers, structural molecules, binding activities (protein, lipid, carbohydrate), cell motility proteins, membrane fusion proteins, cell communication mediators, biological process modulators, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transporter, ion transporter, channel transporter, carrier activity, permease, secretase or secretory mediator, electron transporter, chaperone modulator, nucleic acid binding, transcriptional modulator, extracellular tissue and biogenesis modulator, and translational modulator).

[1243] In one embodiment, the target protein is a modulator of a signaling cascade associated with a known disease state. In another embodiment, the target protein mediates disease by a mechanism different from modulating a signaling cascade. As described elsewhere 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.

[1244] In one embodiment, the target protein is RXR, DHFR, Hsp90, kinase, HDM2, MDM2, a protein containing a BET bromodomain, HDAC, IDH1, Mcl-1, a human lysine methyltransferase, a nuclear hormone receptor, an aryl hydrocarbon receptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, BCL.

[1245] In one embodiment, the protein containing a bromodomain has histone acetyltransferase activity.

[1246] In one embodiment, the protein containing a bromodomain is BRD2, BRD3, BRD4, BRDT, or ASH1L.

[1247] In one embodiment, the protein containing a bromodomain is a non-BET protein.

[1248] In one embodiment, the non-BET protein is BRD7 or BRD9.

[1249] 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.

[1250] In one embodiment, the target protein is selected from: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[1251] In another embodiment, the target protein is not selected from: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[1252] In one embodiment, the targeting ligand is an EGFR ligand, an FLT3 ligand, a RAF1 ligand, an SMRCA2 ligand, a KSR1 ligand, an NF2L2 ligand, a CTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

[1253] In one embodiment, the targeting ligand is not an EGFR ligand, an FLT3 ligand, a RAF1 ligand, an SMRCA2 ligand, a KSR1 ligand, an NF2L2 ligand, a CTNB1 ligand, a CBLB ligand, a BCL6 ligand, or a RASK ligand.

[1254] The present invention can be used to treat a wide range of disease states and / or disorders, including any disease state and / or disorder in which a protein is dysregulated and the patient would benefit from protein degradation.

[1255] For example, a target protein that is a target for a known human therapeutic agent can be selected, and when the therapeutic agent is incorporated into the degrader according to the present invention, the therapeutic agent can be used as a targeting ligand. These include proteins that can be used to restore the function of polygenic diseases, including, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, Bcl2 / Bax and other partners in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase 4 type, 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 serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, 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, neuropeptide and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MER / ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3RNA 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, neuropeptide Y and receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranylgeranyl transferase, TrkA receptor of NGK, β-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-2 / neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, an ion channel of the GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and phosphoenolpyruvate shikimate phosphate synthase.

[1256] 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 tyrosine kinases (such as AATK, ABL, ABL2, ALK, AXL, BLK, BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, ILK, 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, PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1 or ZAP70).

[1257] 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 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, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-beta, TLK2, TSSK1, TSSK2, ULK1 or ULK2).

[1258] 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 cyclin-dependent kinases, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12 or CDK13.

[1259] 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 leucine-rich repeat kinases (e.g., LRRK2).

[1260] 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 lipid kinases (e.g., PIK3CA, PIK3CB) or sphingosine kinases (e.g., S1P).

[1261] In certain embodiments, the target protein is derived from a BET-bromodomain-containing protein to which a targeting ligand is capable of binding or binds, 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.

[1262] In certain embodiments, the target protein is derived from a nuclear protein to which a targeting ligand is capable of binding or binds, including but not limited to BRD2, BRD3, BRD4, antennapedia homeodomain protein, BRCA1, BRCA2, CCAAT-enhancer-binding protein, histone, polycomb group protein, high mobility group protein, telomere-binding protein, FANCA, FANCD2, FANCE, FANCF, hepatocyte nuclear factor, Mad2, NF-κB, nuclear receptor coactivator, CREB-binding protein, p55, p107, p130, Rb protein, p53, c-fos, c-jun, c-mdm2, c-myc, and c-rel.

[1263] 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.

[1264] In certain embodiments, the target protein is dihydrofolate reductase (DHFR), and the disease being treated is cancer. In certain embodiments, the target protein is dihydrofolate reductase (DHFR), and the disease being treated is caused by a microorganism.

[1265] In certain embodiments, the target protein is dihydrofolate reductase from Bacillus anthracis (BaDHFR), and the disease being treated is anthrax.

[1266] In certain embodiments, the target protein is heat shock protein 90 (HSP90), and the disease being treated is cancer.

[1267] In certain embodiments, the target protein is a kinase or phosphatase, and the disease being treated is cancer.

[1268] In certain embodiments, the target protein is HDM2 and / or MDM2, and the disease being treated is cancer.

[1269] In certain embodiments, the target protein is a protein containing a BET bromodomain, and the disease being treated is cancer.

[1270] In certain embodiments, the target protein is a lysine methyltransferase, and the disease being treated is cancer.

[1271] In certain embodiments, the target protein belongs to the RAF family, and the disease being treated is cancer.

[1272] 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.

[1273] In certain embodiments, the target protein is an androgen receptor, and the disease being treated is cancer.

[1274] In certain embodiments, the target protein is an estrogen receptor, and the disease being treated is cancer.

[1275] 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.

[1276] In certain embodiments, the target protein is an AP-1 or AP-2 transcription factor, and the disease being treated is cancer.

[1277] In certain embodiments, the target protein is an HIV protease, and the disease being treated is HIV infection. In certain embodiments, the target protein is an HI...

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof; Wherein: m is 1 or 2; R 1 and R 2 is hydrogen; is a single bond or a double bond; Y 1 is CH or N; R 3 independently selected from hydrogen, C1-C6 alkyl, C1-C2 haloalkyl, -OR each time it appears 4 , -N(R 4 )(R 4’ ), -SR 4 , -C(O)R 6 , F, Cl, Br, cyano and nitro; R 4 and R 4’ are each independently selected from hydrogen and C1-C6 alkyl each time they appear; R 6 is independently selected, at each occurrence, from hydrogen, C1-C6 alkyl, C1-C2 haloalkyl, hydroxy, C1-C6 alkoxy, -NH2, -NH(C1-C6 alkyl), and -N(C1-C6 alkyl)2; and R 8 is hydrogen or a C1-C6 alkyl group.

2. The compound according to claim 1, wherein R 8 is C1-C6 alkyl.

3. The compound according to claim 1 or 2, wherein R 3 is selected from hydrogen and C1-C6 alkyl.

4. The compound according to claim 1 or 2, wherein R 3 is Br.

5. The compound according to claim 1 or 2, wherein is 6. The compound according to claim 1, wherein m is 1.

7. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 - 7 and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 - 7 or the pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of a disorder treatable by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex, wherein the disorder is cancer or a tumor.

10. Use of the compound according to any one of claims 1 - 7 or the pharmaceutical composition according to claim 8 for the preparation of a cereblon-binding agent medicament for the treatment of a disorder selected from cancer and a tumor.

11. The use according to claim 9 or 10, wherein the disorder is cancer.

12. The use according to claim 9 or 10, wherein the disorder is a tumor.

13. The use according to claim 9 or 10, wherein the disorder is multiple myeloma.

14. The use according to claim 11, wherein the cancer is selected from Burkitt's lymphoma, non-Hodgkin lymphoma, myeloproliferative diseases, angiosarcoma, and Hodgkin's disease.

15. The use according to claim 11, wherein the cancer is selected from leukemia and lymphoma.

16. The use according to claim 11, wherein the cancer is selected from squamous cell carcinoma, basal cell carcinoma, and adenocarcinoma.

17. The use according to claim 11, wherein the cancer is selected from hepatocellular carcinoma, renal cell carcinoma, bladder cancer, bowel cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer.

18. The use according to claim 11, wherein the cancer is melanoma.

19. The use according to claim 11, wherein the cancer is selected from liposarcoma, sarcoma, peripheral neuroepithelioma, and synovial sarcoma.

20. The use according to claim 11, wherein the cancer is selected from glioma, glioblastoma, and neuroblastoma.

21. The use according to claim 11, wherein the cancer is selected from breast cancer, uterine cancer, testicular cancer, thyroid cancer, Wilms' tumor, and teratocarcinoma.

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