Heterocyclic degradation determinants for target protein degradation

Abstract

The present invention provides heterocyclic compounds ("degradation determinants") that bind to E3 ubiquitin ligase (typically by cerebron) that can be used as-is or linked to targeting ligands against selected target proteins for therapeutic purposes, methods of use and compositions thereof, and methods of their preparation.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201780042416.1, filed on May 10, 2017, entitled "Heterocyclic Degradation Determinant for Target Protein Degradation". Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Application No. 62 / 334,395, filed May 10, 2016, which is incorporated herein by reference for all purposes. Technical Field

[0003] This invention provides heterocyclic compounds (“degradation determinants”) that bind to E3 ubiquitin ligases (typically via cereblon) and can be used as is or linked to targeting ligands for selected target proteins for therapeutic purposes. The invention also provides methods of using these compounds, compositions thereof, and methods of their preparation. Background Technology

[0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins are achieved through the ubiquitin-proteasome pathway (UPP). The UPP is essentially central to regulating almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscular degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0005] Multiple ubiquitin molecules are covalently linked to terminal lysine residues via E3 ubiquitin ligase to label proteins for proteasomal degradation. The protein is then digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0006] More than 600 E3 ubiquitin ligases promote the ubiquitination of various proteins in vivo, and they can be divided into four families: HECT domain E3, U-box E3, monomeric RING E3, and multi-subunit E3. For general information, see Li et al. (…). PLOS One , 2008, 3, 1487), titled "Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling."; Berndsen et al. ( Nat. Struct. Mol. Biol ., 2014, 21 , 301-307), titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. ( Ann. Rev. Biochem ., 2009, 78 , 399-434), entitled "RING domain E3 ubiquitinligases."; Spratt et al. ( Biochem 2014, 458 , 421-437), entitled "RBR E3 ubiquitinligases: new structures, new insights, new questions."; and Wang et al. ( Nat. Rev. Cancer ., 2014, 14 , 233-347), titled "Roles of F-box proteins in cancer".

[0007] In 1995, Gosink et al. ( Proc. Natl. Acad. Sci. USA 1995, 92 Nawaz et al. (9117-9121) provided an in vitro proof-of-concept for engineered peptides to selectively direct the ubiquitination of intracellular proteins in a publication entitled "Redirecting the Specificity of Ubiquitination by Modifying Ubiquitin-Conjugating Enzymes". Proc. Natl. Acad. Sci. U. S. A. 1999, 96 The publication titled "Proteasome-Dependent Degradation of the Human Estrogen Receptor" by 1858–1862 describes the degradation of ER using the ubiquitin-proteasome pathway.

[0008] Proteinex, Inc. filed a patent application in February 1999, published as U.S. Patent 6,306,663, seeking protection for a method of generating compounds for activating the ubiquitination of target proteins, comprising covalently linking a target protein binding element capable of specifically binding to the target protein via a ubiquitination recognition element. Proteinex describes the invention as usable for controlling protein levels in eukaryotes. While the '663 patent may be based on a first patent application describing a high-level concept of how to manipulate a UPP system to degrade selected proteins in vivo, it does not provide sufficient detail to allow a person skilled in the art to readily construct the range of proposed compounds. For example, regarding ubiquitination recognition elements, a person skilled in the art is specifically advised to use standard methods for drug discovery and screening for suitable small molecules that will bind to the binding enzyme. Proteinex also emphasizes the use of peptides as ubiquitination recognition elements, which could pose significant difficulties for oral drug administration.

[0009] Since then, therapeutic interventions utilizing the ubiquitin-proteasome pathway have attracted significant interest from the scientific community. Zhou et al. from Harvard Medical School ( Mol. Cell 2000, 6 (751-756) In a publication entitled "Harnessing the Ubiquitination Machinery to Target the Degradation of Specific Cellular Proteins", an engineered receptor capable of directing ubiquitination in mammalian and yeast cells is described.

[0010] Following these early publications and others in the mid-to-late 1990s, Craig Crews and colleagues (Yale University) also recognized that molecules capable of binding target proteins and ubiquitin ligases could lead to the degradation of target proteins. Their first description of such a compound is provided in U.S. Patent 7,041,298, entitled “Proteolysis Targeting Chimeric Pharmaceutical,” filed by Deshaies et al. in September 2000 and granted in May 2006, which describes “PROTAC” consisting of a small molecule binder of MAP-AP-2 linked to a peptide capable of binding the F-box protein β-TRCP. Information from patent '298 is also presented in Sakamoto et al. (…). Proc. Natl. Acad. Sci. USA 2001, 98In the corresponding publication titled "Protacs: Chimeric Molecules That Target Proteins to the Skp1–Cullin–F Box Complex for Ubiquitination and Degradation" (8554-8559), Sakamoto et al. ( Mol. Cell. Proteomics 2003, 2 The publication titled "Development of Protacs to Target Cancer - Promoting Proteins for Ubiquitination and Degradation" (1350-1358) describes a similar PROTAC (PROTAC2) that degrades estrogen and androgen receptors but not MAP-AP-2.

[0011] The first E3 ligase successfully targeted with a small molecule was MDM2, which ubiquitinates the tumor suppressor p53. The targeting ligand was developed by Vassilev et al. (…). Science 2004, 303 (844-848) An HDM2 / MDM2 inhibitor identified in the article titled "In Vivo Activation of the P53 Pathway by Small-Molecule Antagonists of MDM2".

[0012] In 2004 (Schneekloth et al.) J. Am. Chem. Soc. 2004, 126 Articles 3748-3754, titled "Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation," describe other examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation upon addition to cultured cells. Schneekloth et al. describe a degrader (PROTAC3) targeting the FK506-binding protein (FKBP12) and show that both PROTAC2 and PROTAC3 hit their respective targets using green fluorescent protein (GFP) imaging. ADDINEN.CITE <endnote> <cite> <author>Schneekloth< / author> <year> 2005< / year> <recnum> 1657< / recnum> <displaytext>Schneekloth et al. ( <style face="italic">ChemBioChem< / style> 2005, <style face="italic">6< / style> , 40-46) titled"Chemical Approaches to Controlling Intracellular Protein Degradation"< / displaytext> <record> <rec-number> 1657< / rec-number> <foreign-keys> <key app="EN" db-id="02v2955poexw0peep0dxf0209dsza9d555se" timestamp="1461255874"> 1657< / key> < / foreign-keys> <ref-type name="Journal Article"> 17< / ref-type> <contributors> <authors> <author>Schneekloth, J. S., Jr.< / author> <author>Crews, C. M.< / author> < / authors> < / contributors> <auth-address>Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA. <titles> <title>Chemical approaches to controlling intracellular protein degradation< / title> <secondary-title>Chembiochem < / titles> <periodical> <full-title>ChemBioChem <abbr-1>ChemBioChem <abbr-2>ChemBioChem < / periodical> <pages> 40-6< / pages> <volume> 6< / volume> <number> 1< / number> <keywords> <keyword>Animals< / keyword> <keyword>Benzoquinones< / keyword> <keyword>Gene Silencing< / keyword> <keyword>Lactams, Macrocyclic< / keyword> <keyword>Protein Denaturation< / keyword> <keyword>Protein Processing, Post - Translational< / keyword> <keyword>Proteins / metabolism< / keyword> <keyword>Quinones / chemistry< / keyword> <keyword>RNA, Small Interfering / physiology< / keyword> <keyword>Recombinant Proteins / genetics< / keyword> < / keywords> <dates> <year> 2005< / year> <pub-dates> <date>Jan< / date> < / pub-dates> < / dates> <isbn>1439 - 4227 (Print) 1439 - 4227 (Linking)< / isbn> <accession-num> 15532104< / accession-num> <urls> <related-urls> <url>http: / / www.ncbi.nlm.nih.gov / pubmed / 15532104< / url> < / related-urls> < / urls> <custom2>PMC2556563 <electronic-resource-num>10.1002 / cbic.200,400274 < / record> < / cite> < / endnote> Schneekloth et al. ChemBioChem 2005, 6The publication titled "Chemical Approaches to Controlling Intracellular Protein Degradation" (pp. 40-46) described the state of the field at that time.

[0013] Schneekloth et al. Bioorg. Med. Chem. Lett. 2008, 18 The publication titled "Targeted Intracellular Protein Degradation Induced by a Small Molecule: EnRoute to Chemical Proteomics" (5904-5908) describes a degrading agent consisting of two small molecules linked by PEG, which degrades the androgen receptor in vivo by simultaneously binding to the androgen receptor and ubiquitin E3 ligase.

[0014] WO 2013 / 170147, submitted by Crews et al., entitled "Compounds Useful for Promoting Protein Degradation and Methods of Using Same," describes compounds containing a protein-degrading moiety covalently bound to a linker, wherein the compound's ClogP is equal to or greater than 1.5. Specifically, this specification discloses protein-degrading compounds that incorporate certain small molecules that can bind to E3 ubiquitin ligases.

[0015] In unrelated parallel studies, scientists are investigating the toxicity of thalidomide. Ito et al. ( Science 2010, 327 The study, 1345-1350, entitled "Identification of a Primary Target of Thalidomide Teratogenicity," describes cereblon as a thalidomide-binding protein. Cereblon forms part of an E3 ubiquitin ligase protein complex, which interacts with damaged DNA-binding protein 1, and forms an E3 ubiquitin ligase complex with Cullin 4 and E2-binding protein ROC1 (also known as RBX1), where it acts as a substrate acceptor to select proteins for ubiquitination. This study suggests that in vivo thalidomide-cereblon binding may be the cause of thalidomide teratogenicity. Despite the discovery of thalidomide teratogenicity in the mid-1960s, the compound and related structures have still been found to be useful as anti-inflammatory, anti-angiogenic, and anticancer agents (see Bartlett et al.). Nat. Rev. Cancer 2004,4 , 314-322), titled "The Evolution of Thalidomide and Its Imid Derivatives as Anticancer Agents").

[0016] Publicly available information about the binding of thalidomide to cereblon E3 ubiquitin ligase has led to research investigations that incorporate thalidomide and certain derivatives into compounds to target and disrupt proteins. In 2014... Science Two groundbreaking papers were published: G. Lu et al., "The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins," Science , 343, 305-309 (2014); and J. Kronke et al., Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in MultipleMyeloma Cells, Science , 343, 301-305 (2014).

[0017] US 2014 / 0356322, entitled "Compounds and Methods for the Enhanced Degradation of Target Proteins & Other Polypeptides by an E3 Ubiquitin Ligase," transferred to Yale University, GlaxoSmithKline, and Cambridge Enterprise Limited, describes protein-degrading compounds bound to a VHL E3 ubiquitin ligase. See also Buckley et al. J. Am. Chem. Soc. 2012, 134 , 4465-4468), titled "Targeting the VonHippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the Vhl / Hif-1alpha Interaction".

[0018] WO 2015 / 160845, entitled “Imide Based Modulators of Proteolysis and Associated Methods of Use”, assigned to Arvinas Inc., describes protein-degrading compounds incorporating thalidomide and certain derivatives bound to cereblon E3 ligase.

[0019] Other publications in this field include: Lu et al. Chem. Biol. 2015, 22 , 755-763), titled "Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target Brd4"; Bondeson et al. ( Nat. Chem. Biol. 2015, 11 , 611-617), titled "Catalytic in VivoProtein Knockdown by Small-Molecule Protacs"; Gustafson et al. ( Angewandte Chemie, International Edition in English 2015, 54 , 9659-9662), titled "Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging"; Lai et al. ( Angewandte Chemie, International Edition in English 2016, 55 , 807-810), titled "Modular Protac Design for the Degradation of Oncogenic Bcr-Abl"; Toure et al. ( Angew. Chem. Int. Ed. 2016, 55 , 1966–1973), entitled "Small-Molecule Protacs: New Approaches to Protein Degradation"; and Winter et al. ( Science 2015, 348 The paper, titled "Drug Development. Phthalimide Conjugation as a Strategy for inVivo Target Protein Degradation" (1376-1381), describes a thalidomide-based target protein degradation technology.

[0020] US 2016 / 0058872, entitled "Imide Based Modulators of Proteolysis and Associated Methods of Use," and US 2016 / 0045607, entitled "Estrogen-related Receptor Alpha Based PROTAC Compounds and Associated Methods of Use," assigned to Arvinas Inc., describe certain estrogen receptor degradation compounds.

[0021] While progress has been made in the regulation of UPP for protein degradation in vivo, it would be useful to have other compounds and methods to more fully utilize UPP for therapeutic purposes.

[0022] One object of the present invention is to provide novel compounds, methods, compositions, and manufacturing methods that can be used to degrade selected proteins in vivo. Summary of the Invention

[0023] Heterocyclic compounds (“degradation determinants”) that bind to E3 ubiquitin ligases (typically via cereblon) are provided, which can be used as is or linked to a targeting ligand for a selected target protein for therapeutic purposes. Methods of use and compositions thereof, as well as methods of preparation and manufacture thereof, are also provided. Degradation determinants described herein are referred to as “degradation determinants” when covalently linked (linker) to a ligand (targeting ligand) targeting a target protein, because they achieve the degradation of said target protein via the proteasome. A degradation determinant comprises a “targeting ligand” that binds to a selected target protein (typically non-covalently), a “degradation determinant” that binds to an E3 ligase (typically non-covalently), and optionally a linker that covalently links the targeting ligand to the degradation determinant.

[0024] The degradation determinants or their pharmaceutically acceptable salts or compositions provided herein may be used to treat conditions mediated by target proteins that bind to target ligands.

[0025] In one embodiment, the selected target protein is derived from a gene that has undergone an amplification, translocation, deletion, or inversion event causing or induced by a medical condition. In some aspects, the selected target protein has been post-translational modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation, myristylation, farnesylation, geranylation, ubiquitination, ubiquitin-like glycosylation, or sulfation causing or induced by a medical condition. In an alternative embodiment, the target protein is covalently modified with a targeting ligand that has been functionalized to produce a degrader, and the covalent ligand may be irreversible or reversible.

[0026] In one aspect, compounds of formula I or formula II are provided: (I) or (II) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition; in: A is CR 8 R 9 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A' is CR 1 R 2 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A'' is CR 3 R 4 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; X is independently NH, NR 11 CH2, CHR 12 C(R) 12 2. O or S; Z represents O, S, CH2, CH(C1-C4 alkyl) and C(C1-C4 alkyl)2; n is 0, 1, 2, or 3; Is it a single bond or a double bond? R 1 R2 R 3 R 4 R 6 R 7 R 8 R 9 and R 13 Independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, -NH (aliphatic group, including alkyl), -Nalkyl2; Or R 1 and R 2 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 3 and R 4 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 6 and R 7 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 8 and R 9 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 1 and R 3 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 1 and R 7 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 3 and R 7 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 13 and R 1 Forming 3, 4, 5, or 6 carbon fused rings; Or R 13 and R 6 Forming 3, 4, 5, or 6 carbon fused rings; Or R 13 and R 4 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 13 and R 5 Forming 3, 4, 5 or 6 carbon fused rings, where R 5 In R 13 On the α carbon, or a 1, 2, 3, or 4 carbon bridge ring, where R 5 Not in R 13On the α-carbon; In a typical implementation, W 1 It is C=O; In another typical implementation, W 2 It is C=O; In another typical implementation, W 1 and W 2 Both are C=O and X is NH; R 5 In each case, it is selected from: alkyl, olefin, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -NH (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)2, -NHSO2 (aliphatic group, including alkyl), -N(alkyl)SO2 (aliphatic group, including alkyl), -NHSO 2( Aryl (including heteroaryl), -N (aliphatic, including alkyl)SO2 aryl, -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and haloalkyl; Or two Rs 5 Substituents, together with the carbon atoms they are bonded to, can form 3, 4, 5, or 6-membered rings; R 10 It is a linker-targeting ligand; Q 1 Q 2 Q 3 and Q 4 Independently selected from CH and CR 12 In some embodiments, the number of nitrogen atoms in each ring is 0, 1, 2, or 3 (as the context allows), and is selected to produce stable rings and pharmaceutically acceptable degradation determinants. When Q is in a six-membered ring (unfused or fused) and at least one Q is nitrogen, in non-limiting embodiments as the context allows, the ring may be pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine, or tetraazine.

[0027] R 11 It is independently selected from alkyl, alkenyl, alkynyl, C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic; R 12Independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, -C(O)H, -C(O)OH, -C(O) (aliphatic group, including alkyl), -C(O)O (aliphatic group, including alkyl), -NH (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)2, -NHSO2 (aliphatic group, including alkyl), -N (aliphatic group, including alkyl)SO2 (aliphatic group, including alkyl), -NHSO 2( Aryl (including heteroaryl), -N (aliphatic, including alkyl)SO2aryl, -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, cyano, nitro, nitroso, -SH, -S alkyl, and haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl and heterocyclic; Linkers are chemical groups that connect degradation determinants to target ligands; A targeting ligand is a portion of a target protein that can bind or bind to the target protein, and said target protein is a mediator of disease in the host as further defined herein; In some embodiments, the compound satisfies at least one of a, b, c, d, e, f, g, h, i, j, k, l, or m: a. n is 1 or 2; b. R 1 R 2 R 3 Or R 4 At least one of them is an alkyl group; c. R 1 and R 2 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; d. R 3 and R 4 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; e. R 6 and R 7 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; f. R 8 and R 9 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; g. R 1 and R 3 Forming 1 or 2 carbon bridged rings; h. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; i. R 4 and R 13 Forming 1 or 2 carbon bridged rings; j. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; k. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2 l. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, or P(O)NH2; or m. X is O or S.

[0028] In one embodiment, the compound of formula I is selected from: , , , , ,and .

[0029] In another aspect of the invention, compounds of formula III are provided: (III) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug, optionally in a pharmaceutically acceptable carrier to form its pharmaceutically acceptable composition; Where m is 1 or 3, and the other variables are as described above.

[0030] Linkers are chemical groups that link degradation determinants to target ligands.

[0031] A targeting ligand is a portion of a target protein that can bind to or bind to the target protein, and said target protein is a mediator of disease in the host as defined in detail below.

[0032] Formulas I, II, and III are bifunctional compounds having a heterocyclic E3 ubiquitin ligase targeting portion (degradation determinant) linked via a linker to a targeting ligand (described in more detail below), the targeting ligand being used to recruit the target protein to the E3 ubiquitin ligase for degradation. In some embodiments, the condition is selected from benign growths, neoplasms, tumors, cancers, immune disorders, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, infections (including viral and bacterial infections), amyloid-based proteopathies, proteopathies, or fibrotic disorders. In a typical embodiment, the patient is a human. A non-limiting example of a condition that can be treated with such compounds is abnormal cell proliferation, such as tumors or cancers, where the target protein is an oncogenic protein or a signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0033] In one embodiment, the invention provides a heterocyclic moiety covalently linked to a target protein ligand via a linker that can have different lengths and functions. In one embodiment, the heterocyclic degradation determinant moiety is directly linked to the target ligand (i.e., the linker is a bond). In some embodiments, the linker can be any chemically stable group that links the heterocyclic degradation determinant to the target ligand. In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, wherein one or more carbon atoms may be replaced by heteroatoms such as O, N, S, or P, provided that the resulting molecule, 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 is itself pharmaceutically acceptable. In some embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive atoms in the chain. For example, the chain may include one or more ethylene glycol units, and in some embodiments, the linker may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more continuous, partially continuous, or discontinuous ethylene glycol units. In some embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches, which may be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents. In one embodiment, each branch has 10, 8, 6, 4, 3, 2 carbons, or one carbon.

[0034] In one embodiment, the target protein is a classically unmedicatable protein because it lacks a binding pocket or active site that can be inhibited or otherwise bound, and it cannot be readily controlled by allosteric variations. In another embodiment, the target protein is a classically medicinal protein. Examples of target proteins are provided below.

[0035] In an alternative embodiment, the heterocyclic degradation determinants of formula III, IV, or VI as described herein may be used alone (i.e., not as part of the degradation determinant body) as in vivo binders of cereblon, which may be administered to a host, such as a human, in an effective amount, optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition for any therapeutic indication that can be treated by modulating the function and / or activity of a cereblon E3 ubiquitin ligase protein complex, including but not limited to the known uses of cereblon binders thalidomide, pomalidomide, or lenalidomide. In some alternative embodiments, compounds of formula III, IV, or VI may activate, reduce, or alter the native activity of cereblon.

[0036] Therefore, in another aspect of the invention, compounds of formula IV or V are provided: (IV) or (V) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative, prodrug, and / or a pharmaceutically acceptable combination thereof; in: The variables mentioned above are required to be at least one of a, b, c, d, e, f, g, h, i, or j: a. R 1 and R 2 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; b. R 3 and R 4 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; c. R 6 and R 7 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; d. R 8 and R 9 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; e. R 1 and R 3 Forming 1 or 2 carbon bridged rings; f. R 1 and R 13 Forming 3, 4, 5, or 6-membered fused rings; g. R 4 and R 13 Forming 1 or 2 carbon bridged rings; h. A is P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH or P(O)NH2; i. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, or P(O)NH2; or j. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

[0037] In one embodiment, the compound of formula III is selected from: , , , , , , ,and .

[0038] In another aspect of the invention, compounds of formula VI are provided: (VI) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition; The variables are as described above, and in some embodiments, it is required that at least one of a, b, c, d, e, f, g, h, i, j, k, l, or m is: a. m is 3 and n is not 0; b. R 1 and R 2 Forming a spiral ring; c. R 3 and R 4 Forming a spiral ring; d. R 6 and R 7 Forming a spiral ring; e. R 8 and R 9 Forming a spiral ring; f. R 1 and R 3 Forming 1 or 2 carbon bridged rings; g. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; h. R 4 and R 13 Forming 1 or 2 carbon bridged rings; i. R 13 and R 5 Forming 3, 4, 5, or 6 carbon fused rings; j. R 13 and R 5 Forming 1 or 2 carbon bridged rings; k. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; l. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH, or P(O)NH2; or m. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; Compounds of formulas IV, V, and VI do not include linkers or targeting ligands. For example, when administered in effective amounts to a host, including humans, for the treatment of a medical condition, these compounds of formulas IV, V, and VI can be used as therapeutic agents for any condition that can be treated by binding to the cereblon subunit of the E3 ligase. Conditions include, but are 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, Woldanstrom macroglobulinemia, Wescott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; immune disorders, including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; and inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0039] In some embodiments, the compounds of formula I, II, III, IV, V, or VI have at least one desired atomic isotope substitution in an amount higher than the natural abundance of that isotope, i.e., are enriched. In one embodiment, the compounds of formula I, II, III, IV, V, or VI comprise one or more deuterium atoms.

[0040] 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 pertains. In the specification, singular forms include plural forms unless the context clearly requires otherwise. While similar or equivalent methods and materials to those described herein may be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed application. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting.

[0041] Other features and advantages of the invention will become apparent from the following detailed description and claims.

[0042] Therefore, the present invention includes at least the following features: (a) Heterocyclic compounds of formula I, II, III, IV, V or VI as described herein, and their pharmaceutically acceptable salts, isotope derivatives (including deuterated derivatives) and prodrugs; (b) A heterocyclic compound of Formula I, Formula II or Formula III for treating a condition mediated by a selected target protein, wherein the compound comprises a targeting ligand of the target protein, and wherein the heterocyclic compound is optionally linked to the targeting ligand via a linker. (c) Use of an effective amount of a compound of formula I, II or III in the treatment of patients (including humans) with conditions mediated by target proteins, said conditions including abnormal cell proliferation such as tumors or cancers, autoimmune diseases or inflammatory diseases, heart disease, infectious diseases or other conditions in response to such treatment. (d) Use in patients (including humans) in an effective amount of a compound of formula IV, V or VI in the treatment of other conditions, including those with abnormal cell proliferation such as tumors or cancers, autoimmune diseases or inflammatory diseases, heart disease, infectious diseases or responses to such treatment. (e) Use of compounds of formula I, II, III, IV, V or VI, and pharmaceutically acceptable salts and prodrugs thereof, in the preparation of medicaments for the treatment of medical conditions. (f) A method for preparing a medicament intended for use in treating a disease, characterized in that a compound of formula I, II, III, IV, V or VI as described herein is used in the preparation. (g) Compounds of formula I, II, III, IV, V or VI as described herein, and their pharmaceutically acceptable salts and prodrugs, which may be used to treat abnormal cell proliferation such as cancer, including any cancer described herein; (h) Use of compounds of formula I, II, III, IV, V or VI, and pharmaceutically acceptable salts and prodrugs thereof, in the preparation of medicaments for treating abnormal cell proliferation such as cancer (including any cancer described herein); (i) A method for preparing a medicament intended for the therapeutic treatment of abnormal cell proliferation such as cancer (including any cancer described herein), characterized in that a compound of formula I, II, III, IV, V or VI as described herein is used in the preparation; (j) Compounds of formula I, II, III, IV, V or VI as described herein, and their pharmaceutically acceptable salts, isotope derivatives and prodrugs, may be used to treat tumors, including any tumors described herein; (k) Use of compounds of formula I, II, III, IV, V or VI, and pharmaceutically acceptable salts and prodrugs thereof, in the preparation of medicaments for the treatment of tumors (including any tumors described herein); (l) A method for preparing a medicament intended for the therapeutic treatment of tumors (including any tumors described herein), characterized in that a compound of formula I, II, III, IV, V or VI as described herein is used in the preparation; (m) Compounds of formula I, II, III, IV, V or VI as described herein, and their pharmaceutically acceptable salts and prodrugs, which may be used to treat immune, autoimmune or inflammatory conditions. (n) Use of compounds of formula I, II, III, IV, V or VI, and pharmaceutically acceptable salts and prodrugs thereof, in the preparation of medicaments for the treatment of immune, autoimmune or inflammatory conditions. (o) A method for preparing a medicament intended for therapeutic use in treating immune, autoimmune or inflammatory conditions, characterized in that a compound of formula I, II, III, IV, V or VI as described herein is used in the preparation. (p) Compounds of formula I, II, III, IV, V or VI as described herein, and their pharmaceutically acceptable salts and prodrugs, which may be used to treat infections, including viral infections, including but not limited to HIV, HBV, HCV and RSV. (q) Use of compounds of Formula I, II or III, and pharmaceutically acceptable salts and prodrugs thereof, in the preparation of medicaments for the treatment of infections, including viral infections, including but not limited to HIV, HBV, HCV and RSV. (r) A method for preparing a medicament intended for the therapeutic treatment of infections (including viral infections, including but not limited to HIV, HBV, HCV and RSV), characterized in that a compound of formula I, II or III as described herein is used in the preparation; (s) A pharmaceutical preparation comprising an effective therapeutic amount of a compound of formula I, II, III, IV, V or VI or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or diluent. (t) Compounds of formula I, II, III, IV, V or VI as described herein, which are mixtures of enantiomers or diastereomers (as relevant), including as racemates; (u) Compounds of formula I, II, III, IV, V, or VI as described herein, in enantiomeric or diastereomeric (as associated) enriched forms, including as isolated enantiomers or diastereomers (i.e., greater than 85, 90, 95, 97, or 99% purity); and (v) A method for preparing a therapeutic product containing an effective amount of a compound of formula I, II, III, IV, V or VI as described herein. Attached Figure Description

[0043] Figure 1A-1C An example of a retinoid X receptor (RXR) targeting ligand is presented, where R is the linker point.

[0044] Figure 1D-1F Examples of typical dihydrofolate reductase (DHFR) targeting ligands are presented, where R is the linker point.

[0045] Figure 1G An example of an anthrax Bacillus dihydrofolate reductase (BaDHFR) targeting ligand is presented, where R is the linker point.

[0046] Figure 1H-1J An example of a heat shock protein 90 (HSP90) targeting ligand is presented, where R is the linker point.

[0047] Figure 1K-1Q Examples of general kinase and phosphatase targeting ligands are presented, where R is the linker point of the linker.

[0048] Figure 1R-1S Examples of tyrosine kinase targeting ligands are presented, where R is the linker point.

[0049] Figure 1T An example of an aurora kinase targeting ligand is presented, where R is the linker point.

[0050] Figure 1U Examples of protein tyrosine phosphatase targeting ligands are presented, where R is the linker point.

[0051] Figure 1V An example of an ALK-targeting ligand is presented, where R is the linker point of the linker.

[0052] Figure 1W An example of an ABL-targeting ligand is presented, where R is the linker point.

[0053] Figure 1X An instance of the JAK2 targeting ligand is presented, where R is the linker point of the linker.

[0054] Figure 1Y-1Z An example of a MET-targeting ligand is presented, where R is the linker point.

[0055] Figure 1AA Examples of mTORC1 and / or mTORC2 targeting ligands are presented, where R is the linker point.

[0056] Figure 1BB-1CC Examples of hypertrophic / stem cell growth factor receptor (SCFR) targeting ligands (also known as c-KIT receptor) are presented, where R is the linker point.

[0057] Figure 1DD Examples of IGF1R and / or IR targeting ligands are presented, where R is the linker point.

[0058] Figure 1EE-1FF Examples of HDM2 and / or MDM2 targeting ligands are presented, where R is the linker point.

[0059] Figure 1GG-1MM An example of a bromodomain-containing BET protein targeting ligand is presented, where R is the linker point.

[0060] Figure 1NN An example of an HDAC-targeting ligand is presented, where R is the linker point.

[0061] Figure 100 An example of a RAF receptor-targeting ligand is presented, where R is the linker point.

[0062] Figure 1PP An example of an FKBP receptor-targeting ligand is presented, where R is the linker point.

[0063] Figure 1 QQ-1TT Examples of androgen receptor-targeting ligands are presented, where R is the linker point.

[0064] Figure 1UU Examples of estrogen receptor-targeting ligands are presented, where R is the linker point.

[0065] Figure 1VV-1WW An example of a thyroid hormone receptor-targeting ligand is presented, where R is the linker point.

[0066] Figure 1XX An example of an HIV protease targeting ligand is presented, where R is the linker point.

[0067] Figure 1YY An example of an HIV integrase targeting ligand is presented, where R is the linker point.

[0068] Figure 1ZZ An example of an HCV protease targeting ligand is presented, where R is the linker point.

[0069] Figure 1AAA Examples of AP1 and / or AP2 targeting ligands are presented, where R is the linker point.

[0070] Figure 1BBB-1CCC An example of an MCL-1 targeting ligand is presented, where R is the linker point.

[0071] Figure 1DDD An example of an IDH1 targeting ligand is presented, where R is the linker point.

[0072] Figure 1EEE-1FFF Examples of RAS or RASK targeting ligands are presented, where R is the linker point.

[0073] Figure 1GGG Examples of MERTK or MER targeting ligands are presented, where R is the linker point.

[0074] Figure 1 HHH-1III An example of an EGFR-targeting ligand is presented, where R is the linker point.

[0075] Figure 1JJJ-1KKK An example of an FLT3-targeting ligand is presented, where R is the linker point.

[0076] Figure 1 LLL An example of an SMRCA2 targeting ligand is presented, where R is the linker point.

[0077] Figure 2A An example of a kinase inhibitor targeting ligand U09-CX-5279 (derivative) is presented, where R is the linker point.

[0078] Figure 2B-2CExamples of kinase inhibitor-targeting ligands (including the kinase inhibitor compounds Y1W and Y1X (derived)) are presented, where R is the linker site. For other examples and related ligands, see Millan et al., “Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease”. J. Med. Chem., Kinase inhibitors identified in 54: 7797 (2011).

[0079] Figure 2D Examples of kinase inhibitor targeting ligands (including the kinase inhibitor compounds 6TP and OTP (derived)) are presented, where R is the linker site. For other examples and related ligands, see Schenkel et al., “Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors”. J. Med. Chem. Kinase inhibitors identified in , 54 (24): 8440-8450 (2011).

[0080] Figure 2E Examples of kinase inhibitor targeting ligands (including the kinase inhibitor compound 07U) are presented, where R is the linker site. For other examples and related ligands, see Van Eis et al., “2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes”. Biorg. Med. Chem. Lett., Kinase inhibitors identified in 21(24): 7367-72 (2011).

[0081] Figure 2F Examples of kinase inhibitor-targeting ligands (including the kinase inhibitor compound YCF) are presented, where R is the linker site. For other examples and related ligands, see Lountos et al., “Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy”. J. Struct. Biol. The kinase inhibitor identified in , 176: 292 (2011).

[0082] Figure 2G-2H Examples of kinase inhibitor-targeting ligands (including the kinase inhibitors XK9 and NXP (derived)) are presented, where R is the linker site. For other examples and related ligands, see Lountos et al., “Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy”. J. Struct. Biol The kinase inhibitor identified in ., 176: 292 (2011).

[0083] Figure 2I-2J Examples of kinase inhibitor targeting ligands are presented, where R is the linker point.

[0084] Figure 2K-2M An example of a cyclin-dependent kinase 9 (CDK9) targeting ligand is presented, where R is the linker site. For other 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 InhibitorsRoscovitine 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 theBasis for Isotype Selectivity." J.Med.Chem . 56: 660 (2013); Lücking et al. “Identification of the potent and highly selective PTEFb inhibitor BAY1251152 for the treatment of cancer – From po to iv application viascaffold hops.” Lücking et al. U. AACR Annual Meeting, April 1–5, 2017 Washington, DC USA.

[0085] Figure 2N-2P Examples of cyclin-dependent kinase 4 / 6 (CDK4 / 6) targeting ligands are presented, where R is the linker site. For other 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)-pyrimidinesas selective inhibitors of cyclin-dependent kinase 4 / 6; Cho et al. (2010) J. Med. Chem. 53: 7938-7957; Cho YS et al. "Fragment-Based Discovery of 7-Azabenzimidazoles as Potent Highly Selective and Orally Active CDK4 / 6Inhibitors.” ACS Med Chem Lett3: 445-449 (2012); Li Z. et al. "Discovery of AMG925 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).

[0086] Figure 2Q Examples of cyclin-dependent kinase 12 and / or cyclin-dependent kinase 13 targeting ligands are presented, where R is the linker site. For other 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).

[0087] Figure 2R-2S Examples of glucocorticoid receptor-targeting ligands are presented, where R is the linker point.

[0088] Figure 2T-2U An example of a RasG12C targeting ligand is presented, where R is the linker point.

[0089] Figure 2V An example of a Her3-targeting ligand is presented, where R is the linker point and R' is... or .

[0090] Figure 2W Examples of Bcl-2 or Bcl-XL targeting ligands are presented, where R is the linker point.

[0091] Figure 2X-2NNExamples of BCL2-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Toure BB 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 AmideSubstituted Phenyl Pyrazoles as Selective Bcl-2 Inhibitors" Bioorg. Med. Chem. Lett. 19: 230 (2009); Souers AJ et al. "ABT-199 a potent and selective BCL-2inhibitor 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´mati et al. "Targeting Bcl-2 / Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts" PLoS ONE9(1): e80836; WO2015011396, titled "Novel derivatives of indole and pyrrole method for the production thereof and pharmaceutical compositions containing same"; WO2008060569A1, titled "Compounds and methods for inhibiting the interaction of Bcl proteins with binding partners"; "Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review" Expert Opinion. Ther. Patents 22(1):2008 (2012); and Porter et al. “Tetrahydroisoquinoline amidesubstituted phenyl pyrazoles as selective Bcl-2 inhibitors” Bioorg Med Chem Lett. , 19(1):230-3 (2009).

[0092] Figure 200-2UU An example of a BCL-XL targeting ligand is presented, where R is the linker site. For other 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); JoelD. Leverson et al. "Exploiting selective BCL-2 family inhibitors to dissect cellsurvival dependencies and define improved strategies for cancer therapy" Science Translational Medicine, 7:279ra40 (2015); and crystal structure PDB 3ZK6 (Guillaume Lessene et al., “Structure-guided design of a selective BCL-XL inhibitor”). Nature Chemical Biology 9: 390–397 (2013)).

[0093] Figure 2VV An example of a PPAR-γ targeting ligand is presented, where R is the linker point.

[0094] Figure 2WW-2YY Examples of EGFR targeting ligands (including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib) targeting the EGFR L858R mutant are presented, where R is the linker point.

[0095] Figure 2ZZ-2FFF Examples of EGFR-targeting ligands (including osimertinib, loczitinib, omamolinib, natratinib, nazatinib, PF-06747775, icotinib, neratinib, avitinib, tarloxotinib, PF-0645998, tesevatinib, transtinib, WZ-3146, WZ8040, and CNX-2006) targeting the EGFR T790M mutant are presented, where R is the linker point.

[0096] Figure 2GGG Examples of EGFR targeting ligands (including EAI045) targeting the EGFR C797S mutant are presented, where R is the linker point.

[0097] Figure 2HHH Examples of BCR-ABL targeting ligands (including nilotinib and dasatinib) targeting the BCR-ABL T315I mutant are presented, where R is the linker site. See, for example, crystal structure PDB 3CS9.

[0098] Figure 2III Examples of targeting ligands for BCR-ABL (including nilotinib, dasatinib, ponatinib, and bosutinib) are presented, where R is the linker point.

[0099] Figure 2JJJ-2KKK Examples of ALK-targeting ligands (including ceritinib) targeting the ALK L1196M mutant are presented, where R is the linker site. See, for example, crystal structure PDB 4MKC.

[0100] Figure 2LLL Examples of JAK2 targeting ligands (including ruxolitinib) targeting the JAK2V617F mutant are presented, where R is the linker point.

[0101] Figure 2MMMExamples of BRAF-targeting ligands (including vemurafenib) targeting the BRAF V600E mutant are presented, where R is the linker site. For other examples and related ligands, see crystal structure PBD 3OG7.

[0102] Figure 2NNN Examples of BRAF-targeting ligands (including dabrafenib) are presented, where R is the linker point.

[0103] Figure 2000 An example of an LRRK2 targeting ligand targeting the LRRK2 R1441C mutant is presented, where R is the linker point.

[0104] Figure 2 PPP An example of an LRRK2 targeting ligand targeting the LRRK2 G2019S mutant is presented, where R is the linker point.

[0105] Figure 2 QQ An example of an LRRK2 targeting ligand targeting the LRRK2 I2020T mutant is presented, where R is the linker point.

[0106] Figure 2RRR-2TTT Examples of PDGFRα targeting ligands (including AG-1478, CHEMBL94431, dovirtinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, sorafenib, sunitinib, and WHI-P180) targeting the PDGFRα T674I mutant are presented, where R is the linker point.

[0107] Figure 2UUU Examples of RET-targeting ligands (including Tauzasetti) targeting the RET G691S mutant are presented, where R is the linker point.

[0108] Figure 2VVV Examples of RET-targeting ligands (including Tauzasetti) targeting the RET R749T mutant are presented, where R is the linker point.

[0109] Figure 2 WWW Examples of RET-targeting ligands (including Tauzasetti) targeting the RET E762Q mutant are presented, where R is the linker point.

[0110] Figure 2XXX Examples of RET-targeting ligands (including Tauzasetti) targeting the RET Y791F mutant are presented, where R is the linker point.

[0111] Figure 2YYYExamples of RET-targeting ligands (including Tauzasetti) targeting the RET V804M mutant are presented, where R is the linker point.

[0112] Figure 2ZZZ Examples of RET-targeting ligands (including Tauzasetti) targeting the RET M918T mutant are presented, where R is the linker point.

[0113] Figure 2 AAAA Examples of fatty acid-binding protein targeting ligands are presented, where R is the linker point.

[0114] Figure 2BBBB Examples of 5-lipoxygenase-activating protein (FLAP) targeting ligands are presented, where R is the linker point.

[0115] Figure 2CCCC An example of a Kringle domain V 4BVV targeting ligand is presented, where R is the linker point.

[0116] Figure 2DDDD An example of a lactylglutathione lyase targeting ligand is presented, where R is the linker point.

[0117] Figure 2EEEE-2FFFF An example of an mPGES-1 targeting ligand is presented, where R is the linker point.

[0118] Figure 2GGGG-2JJJJ An example of a factor Xa targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Maignan S. et al., “Crystal structures of human factor Xa complexed with potent inhibitors.” J. Med. Chem. 43: 3226-3232 (2000); Matsusue T. et al., “Factor Xa Specific Inhibitor that Induces the Novel Binding Model in Complex with Human Fxa.” (forthcoming); Crystal structures PDB 1iqh, 1iqi, 1iqk and 1iqm; Adler M. et al., “Crystal Structures of Two Potent Nonamidine Inhibitors Bound to Factor Xa.” Biochemistry41: 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).

[0119] Figure 2KKKKAn example of a Kallikrein 7 targeting ligand is presented, where R is the linker site. For other 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).

[0120] Figure 2LLLL-2MMMM Examples of cathepsin K targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Rankovic Z. et al., “Design and optimization of aseries 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 forketoamide-based cathepsin S inhibitors.” Bioorg. Med. Chem. Lett. 20: 6890-6894 (2010).

[0121] Figure 2NNNN An example of a Cathepsin L-targeting ligand is presented, where R is the linker site. For other 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).

[0122] Figure 20000 Examples of Cathepsin S targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Jadhav PK et al., “Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm”. ACS Med. Chem. Lett. 5: 1138-1142.” (2014).

[0123] Figure 2PPPP-2SSSS Examples of MTH1-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Kettle JG et al., “Potent and Selective Inhibitors of Mth1Probe its Role in Cancer Cell Survival.” J. Med. Chem. 59: 2346 (2016); HuberK.VM et al. "Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy." Nature 508: 222 (2014); Gad H. et al. "MTH1 inhibitioneradicates cancer by preventing sanitation of the dNTP pool." Nature 508: 215-221 (2014); Nissink JWM et al. "Mth1 Substrate Recognition--an Example ofSpecific Promiscuity." Plos One 11: 51154 (2016); and Manuel Ellermann et al. “Novelclass of potent and selective inhibitors efface MTH1 as broad-spectrum cancertarget.” AACR National Meeting Abstract 5226, 2017.

[0124] Figure 2TTTT-2ZZZZ Examples of MDM2 and / or MDM4 targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Popowicz GM 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., “Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors.” Bioorg. Med. Chem. 21: 4319 - 4331 (2013); Miyazaki M. et al., “Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor.” Bioorg Med Chem. 23: 2360 - 7 (2015); Holzer P. et al., “Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors.” J. Med. Chem. 58: 6348 - 6358 (2015); Gonzalez-Lopez de Turiso F. et al., “Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.” J. Med. Chem. 56: 4053 - 4070 (2);Gessier F. et al., “Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.” Bioorg. Med. Chem. Lett. 25: 3621 - 3625 (2015); Fry D.C. et al., “Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.” ACS Med Chem Lett It should be noted that there seems to be an error in the original text where "J. Med. Chem. 56: 4053 - 4070 (2)" in is not a complete citation. I have translated it as it is while pointing out this potential issue.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).

[0125] Figure 2 AAAAA-2EEEEEExamples of PARP1, PARP2, and / or PARP3 targeting ligands are presented, where R is the linker site. For further 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 CH); Crystal structure PDB 2RD6 (PARP complexed with A861696, Park CH); 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 VB et al. "Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors ofpoly(ADP-ribose) polymerase (PARP) for the treatment of cancer." Bioorg. Med. Chem. Lett. 20: 1023-1026 (2010); Penning TD 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 efficaciousinhibitor.” J. Med. Chem.53: 3142-3153 (2010); Ye N. et al., "Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors." J. Med. Chem. 56: 2885-2903 (2013); Patel M.R. et al., "Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors." J. Med. Chem . 57: 5579-5601 (2014); 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 activesite of human poly(ADP-ribose) polymerase." Febs Lett. 556: 43-46 (2004); and Gangloff AR et al. “Discovery of novel benzo[b][1 4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.” Bioorg. Med. Chem. Lett. 23: 4501-4505 (2013).

[0126] Figure 2FFFFF-2GGGGG An example of a PARP14-targeting ligand is presented, where R is the linker point.

[0127] Figure 2 HHHHH An example of a PARP15 targeting ligand is presented, where R is the linker point.

[0128] Figure 2IIIII An example of a PDZ domain-targeted ligand is presented, where R is the linker point.

[0129] Figure 2 JJJJJ An example of a phospholipase A2 domain targeting ligand is presented, where R is the linker point.

[0130] Figure 2KKKKK An example of a protein S100-A7 2WOS targeting ligand is presented, where R is the linker point.

[0131] Figure 2LLLLL-2MMMMM An example of an activator protein-B targeting ligand is presented, where R is the linker point.

[0132] Figure 2NNNNN-2OOOOO An example of a Sec7-targeting ligand is presented, where R is the linker point.

[0133] Figure 2PPPPP-2QQQQQ An instance of the SH2 domain of the pp60 Src targeting ligand is presented, where R is the linker point.

[0134] Figure 2RRRRR An example of a Tank1-targeting ligand is presented, where R is the linker point.

[0135] Figure 2 SSSSSAn example of the SF6D targeting ligand of the Ubc9 SUMO E2 ligase is presented, where R is the linker site of the linker.

[0136] Figure 2 TTTTT Examples of Src-targeting ligands (including AP23464) are presented, where R is the linker point.

[0137] Figure 2 UUUUU-2XXXXX Examples of Src-AS1 and / or Src AS2 targeting ligands are presented, where R is the linker point.

[0138] Figure 2 YYYYY Examples of JAK3-targeting ligands (including tofacitinib) are presented, where R is the linker point.

[0139] Figure 2ZZZZZ Examples of ABL-targeting ligands (including tofacitinib and ponatinib) are presented, where R is the linker point.

[0140] Figures 3A-3B Examples of MEK1-targeting ligands (including PD318088, trametinib, and G-573) are presented, where R is the linker connection point.

[0141] Figure 3C Examples of KIT-targeting ligands (including regorafenib) are presented, where R is the linker point.

[0142] Figure 3D-3E Examples of HIV reverse transcriptase targeting ligands (including efavirenz, tenofovir, emtricitabine, ritonavir, retegvir, and atazanavir) are presented, where R is the linker point.

[0143] Figure 3F-3G Examples of HIV protease-targeting ligands (including ritonavir, retegvir, and atazanavir) are presented, where R is the linker point.

[0144] Figure 3H-3I An example of a KSR1-targeting ligand is presented, where R is the linker point.

[0145] Figure 3J-3L An example of a CNNTB1-targeting ligand is presented, where R is the linker point of the linker.

[0146] Figure 3M An example of a BCL6-targeting ligand is presented, where R is the linker point.

[0147] Figure 3N-3O An example of a PAK1 targeting ligand is presented, where R is the linker point.

[0148] Figure 3P-3R An example of a PAK4 targeting ligand is presented, where R is the linker point.

[0149] Figure 3S-3T An example of a TNIK-targeting ligand is presented, where R is the linker point.

[0150] Figure 3U An example of a MEN1-targeting ligand is presented, where R is the linker point.

[0151] Figure 3V-3W An example of an ERK1-targeting ligand is presented, where R is the linker point.

[0152] Figure 3X An example of an IDO1 targeting ligand is presented, where R is the linker point.

[0153] Figure 3Y An example of a CBP-targeting ligand is presented, where R is the linker point.

[0154] Figure 3Z-3SS An example of an MCL1-targeting ligand is presented, where R is the linker site. For other 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-basedmethods and structure-based design." J. Med. Chem. 56: 15-30 (2013); Petros AM et al. "Fragment-based discovery of potent inhibitors of the anti-apoptoticMCL-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 CellLeukemia 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 ConstructYields a Robust Crystallography Platform for MCL1.” Plos One 10: e0125010-e0125010 (2015); Kotschy A et al., “The MCL1 inhibitor S63845 is tolerable andeffective in diverse cancer models. Nature 538:477-482 (2016); EP 2886545 A1, titled “New thienopyrimidine derivatives a process for their preparation andpharmaceutical 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 Affinityand Selectivity.” J. Med. Chem. 58: 2180-2194 (2015); Taekyu Lee et al. "Discovery and biological characterization of potent myeloid cell leukemia-1inhibitors." FEBS Letters 591: 240–251 (2017); Chen L. et al. “Structure-BasedDesign of 3-Carboxy-Substituted 1 2 3 4- Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukemia-1 (Mcl-1).” Org. Biomol. Chem. 14:5505-5510 (2016); US2016 / 0068545, titled "Tetrahydronaphthalene derivatives that inhibit mcl-1 protein"; WO 2016207217 A1, titled "Preparation of new bicyclic derivatives aspro-apoptotic agents"; Gizem Akçay et al., "Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain". Nature Chemical Biology 12:931–936 (2016).

[0155] Figure 3TT Examples of ASH1L targeting ligands are presented, where R is the linker site. See, for example, the crystal structure PDB 4YNM (“Human ASH1L SET domain in complex with S-adenosyl methionine (SAM)” Rogawski DS et al.) Figure 3UU-3WWAn example of an ATAD2-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see Chaikuad A. et al., “Structure-based approaches towards identification of fragments for the low-druggability ATAD2 bromodomain”. Med Chem Comm 5: 1843-1848 (2014); Poncet-Montange G. et al. “Observed bromodomainflexibility reveals histone peptide- and small molecule ligand-compatibleforms of ATAD2.” Biochem. J. 466: 337-346 (2015); Harner MJ et al. "Fragment-BasedScreening of the Bromodomain of ATAD2." J. Med. Chem. 57: 9687-9692 (2014); Demont EH et al. "Fragment-Based Discovery of Low-Micromolar Atad2 BromodomainInhibitors." J. Med. Chem . 58: 5649 (2015); and Bamborough P. et al. “Structure-BasedOptimization of Naphthyridones into Potent Atad2 Bromodomain Inhibitors.” J. Med. Chem. 58: 6151 (2015).

[0156] Figure 3XX-3AAAExamples of BAZ2A and BAZ2B targeting ligands are presented, where R is the linker site. For other examples and related ligands, see crystal structure PDB 4CUU (“Human Baz2B in Complex with Fragment-6 N09645” Bradley A. et al.); crystal structure PDB 5CUA (“Second Bromodomain of Bromodomain Adjacent to Zinc Finger Domain Protein 2B (BAZ2B) in complex with 1-Acetyl-4-(4-hydroxyphenyl)piperazine” Bradley A. et al.); Ferguson FM et al., “Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain.” J. Med. Chem. 56: 10183-10187(2013); Marchand JR et al. "Derivatives of 3-Amino-2-methylpyridine as BAZ2BBromodomain Ligands: In Silico Discovery and in Crystallo Validation." J. Med. Chem. 59: 9919-9927 (2016); Drouin L. et al. "Structure Enabled Design of BAZ2-ICRA Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B." J. Med. Chem. 58: 2553-2559 (2015); Chen P. et al. "Discovery and characterization ofGSK2801 a selective chemical probe for the bromodomains BAZ2A and BAZ2B." J. Med. Chem. 59:1410-1424 (2016).

[0157] Figure 3BBBAn example of a BRD1 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see: PDB 5AME (“The Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment 4-Acetyl-Piperazin-2-One Pearce”, NM et al.); PDB 5AMF (“Crystal Structure of the Bromodomain of Human Surface Epitope Engineered Brd1A in Complex with 3D Consortium Fragment Ethyl 4 5 6 7-Tetrahydro-1H-Indazole-5-Carboxylate”, Pearce NM et al.); 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).

[0158] Figure 3 CCC-3EEE Examples of BRD2 bromine domain 1-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see crystal structures PDB 2ydw; PDB 2yek; PDB 4a9h; PDB 4a9f; PDB 4a9i; PDB 4a9m; PDB 4akn; PDB 4alg and PDB 4uyf.

[0159] Figure 3FFF-3HHHAn example of a BRD2 bromodomain-2 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see crystal structures PDB 3oni; Filippakopoulos P. et al., “Selective Inhibition of BET Bromodomains.” Nature 468: 1067-1073 (2010); Crystal structure PDB 4j1p; McLure KG et al., “RVX-208: an Inducer of ApoA-I in Humans is a BET Bromodomain Antagonist.” Plos One 8: e83190-e83190 (2013); Baud MG et al. "Chemical biology. Abump-and-hole approach to engineer controlled selectivity of BET bromodomainchemical probes" Science 346: 638-641 (2014); Baud MG et al. "New Synthetic Routesto Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) BromodomainInhibition" J. Med. Chem. 59: 1492-1500 (2016); Gosmini R. et al. "The Discovery of I-Bet726 (Gsk1324726A) a Potent Tetrahydroquinoline Apoa1 Up-Regulator andSelective Bet Bromodomain Inhibitor" J. Med. Chem.57: 8111 (2014); Crystal structure PDB5EK9 (“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 MG et al. “New Synthetic Routes to Triazolo-benzodiazepine Analogues: Expanding the Scope of the Bump-and-Hole Approach for Selective Bromo and Extra-Terminal (BET) Bromodomain Inhibition” J. Med. Chem. 59: 1492-1500 (2016).

[0160] Figure 3III-3JJJ An example of a BRD4 bromine domain 1-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see crystal structures PDB 5WUU and PDB 5F5Z.

[0161] Figure 3KKK-3LLL An example of a BRD4 bromodomain 2-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Chung CW et al., “Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains”. J. Med. Chem. 54:3827 (2011) and Ran X. et al. "Structure-Based Design of gamma-Carboline Analoguesas Potent and Specific BET Bromodomain Inhibitors" J. Med. Chem. 58: 4927-4939 (2015).

[0162] Figure 3MMM An example of a BRDT-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see crystal structures PDB 4flp and PDB 4kcx.

[0163] Figure 3 NNN-3QQQ Examples of BRD9 targeting ligands are presented, where R is the linker point. For other examples and related ligands, see crystal structures PDB 4nqn; PDB 4uit; PDB 4uiu; PDB 4uiv; PDB 4z6h; PDB 4z6i; PDB 5e9v; PDB 5eu1; PDB 5f1h; and PDB 5fp2.

[0164] Figure 3RRR Examples of SMARCA4 PB1 and / or SMARCA2 targeting ligands are presented, where R is the linker point, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0165] Figure 3SSS-3XXX Other examples of bromodomain-targeted ligands are presented, where R is the linker site. For further examples and related ligands, see Hewings et al., “3,5-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.

[0166] Figure 3YYY Examples of PB1-targeting ligands are presented, where R is the linker point. For other examples and related ligands, see crystal structures PDB 3mb4, PDB 4q0n, and PDB 5fh6.

[0167] Figure 3ZZZ An example of a SMARCA4 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see crystal structures 3uvd and 5dkd.

[0168] Figure 3AAAAn example of a SMARCA2 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see crystal structures 5dkc and 5dkh.

[0169] Figure 3BBBB Examples of TRIM24 (TIF1a) and / or BRPF1 targeting ligands are presented, where R is the linker point and m is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0170] Figure 3CCCC An example of a TRIM24 (TIF1a) targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Palmer WS et al., “Structure-Guided Design of IACS-9571: a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.” J. Med. Chem. 59: 1440-1454 (2016).

[0171] Figure 3DDDD-3FFFF Examples of BRPF1 targeting ligands are presented, where R is the linker point. For other examples and related ligands, see crystal structures PDB 4uye; PDB 5c7n; PDB 5c87; PDB 5c89; PDB 5d7x; PDB 5dya; PDB 5epr; PDB 5eq1; PDB 5etb; PDB 5ev9; PDB 5eva; PDB 5ewv; PDB 5eww; PDB 5ffy; PDB 5fg5; and PDB 5g4r.

[0172] Figure 3 GGGG Examples of CECR2-targeting ligands are presented, where R is the linker site. For other 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).

[0173] Figure 3HHHH-3OOOOExamples of CREBBP targeting ligands are presented, where R is the linker point, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For other examples and related ligands, see crystal structures PDB 3p1d; PDB 3svh; PDB 4nr4; PDB 4nr5; PDB 4ts8; PDB 4nr6; PDB 4nr7; PDB 4nyw; PDB 4nyx; PDB 4tqn; PDB 5cgp; PDB 5dbm; PDB 5ep7; PDB 5i83; PDB 5i86; PDB 5i89; PDB 5i8g; PDB 5j0d; PDB 5ktu; PDB 5ktw; PDB 5ktx; PDB 5tb6.

[0174] Figure 3 PPPP An example of an EP300-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see crystal structure PDB 5BT3.

[0175] Figure 3 QQQQ Examples of PCAF-targeting ligands are presented, where R is the linker point. See, for example, M. Ghizzoni et al. Bioorg. Med. Chem. 18: 5826–5834 (2010).

[0176] Figure 3RRRR An example of a PHIP-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see [link to relevant documentation]. Mol Cancer Ther. 7(9): 2621–2632 (2008).

[0177] Figure 3SSSS Examples of TAF1 and TAF1L targeting ligands are presented, where R is the linker point. For other examples and related ligands, see Picaud S. et al. Sci Adv 2: e1600760-e1600760 (2016).

[0178] Figure 3TTTT Examples of histone deacetylase 2 (HDAC2) targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Lauffer BEJ. Biol. Chem. 288: 26926-26943 (2013); Wagner FF Bioorg. Med. Chem. 24: 4008-4015 (2016); Bressi JC Bioorg. Med. Chem. Lett. 20: 3142-3145 (2010); and Lauffer BE J. Biol. Chem. 288: 26926-26943 (2013).

[0179] Figure 3 UUUU-3VVVV An example of a histone deacetylase 4 (HDAC4) targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Burli RW. J. Med. Chem. 56: 9934 (2013); Luckhurst CA ACS Med. Chem. Lett. 7:34 (2016); Bottomley MJ J. Biol. Chem. 283: 26694-26704 (2008).

[0180] Figure 3 WWWW An example of a histone deacetylase 6 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Harding RJ (forthcoming); Hai Y. Nat. Chem. Biol. 12:741-747, (2016); and Miyake Y. Nat. Chem. Biol. 12: 748 (2016).

[0181] Figure 3XXXX-3YYYY An example of a histone deacetylase 7 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Lobera M. Nat. Chem. Biol. 9:319 (2013) and Schuetz A. J. Biol. Chem. 283: 11355-11363 (2008).

[0182] Figure 3ZZZZ-3DDDDD An example of a histone deacetylase 8 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Whitehead L. Biol. Med. Chem. 19: 4626-4634(2011); Tabackman AAJ Struct. Biol. 195: 373-378 (2016); Dowling DP Biochemistry 47, 13554-13563 (2008); Somoza JR Biochemistry12, 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 JR Biochemistry 12:1325-1334 (2004);Decroos C. Biochemistry 54: 6501-6513 (2015);Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); and Dowling DP Biochemistry 47: 13554-13563 (2008).

[0183] Figure 3 EEEEE An example of a histone acetyltransferase (KAT2B) targeting ligand is presented, where R is the linker site. For other 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).

[0184] Figure 3FFFFF-3GGGGG An example of a histone acetyltransferase (KAT2A) targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Ringel AE. Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016).

[0185] Figure 3 HHHHH An example of a target ligand for histone acetyltransferase type B catalytic unit (HAT1) is presented, where R is the linker site. For other examples and related ligands, see crystal structure PDB 2P0W.

[0186] Figure 3IIIII An example of a cyclic AMP-dependent transcription factor (ATF2) targeting ligand is presented, where R is the linker point of the linker.

[0187] Figure 3 JJJJJAn example of a histone acetyltransferase (KAT5) targeting ligand is presented, where R is the linker point.

[0188] Figure 3KKKKK-3MMMMM Examples of lysine-specific histone demethylase 1A (KDM1A) targeting ligands are presented, where R is the linker site. For other examples and related ligands, see MimasuS. Biochemistry 49: 6494-6503 (2010); Sartori L. J. Med. Chem. 60:1673-1693 (2017); and Vianello P. J. Med. Chem 60: 1693-1715 (2017).

[0189] Figure 3 NNNNN An example of a HDAC6 Zn finger domain targeting ligand is presented, where R is the linker point.

[0190] Figure 30000-3PPPPP Examples of typical lysine methyltransferase targeting ligands are presented, where R is the linker point.

[0191] Figure 3 QQQQQ-3TTTTT Examples of DOT1L targeting ligands are presented, where R is the linker site, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For other examples and related ligands, see crystal structure PDB 5MVS (“Dot1L in complex with adenosine and inhibitor CPD1” Be C. et al.); crystal structure PDB 5MW4 (“Dot1L in complex inhibitor CPD7” Be C. et al.); crystal structure PDB 5DRT (“Dot1L in complex inhibitor CPD2” Be C. et al.); Be C. et al. ACS Med. Lett. 8: 338-343 (2017); Crystal structure PDB 5JUW “(Dot1L in complex with SS148” Yu W. et al. StructuralGenomics Consortium).

[0192] Figure 3 UUUUU Examples of EHMT1 targeting ligands are presented, where R is the linker site. For other examples and related ligands, see crystal structure PDB 5TUZ (“EHMT1 in complex with inhibitor MS0124”, Babault N. et al.).

[0193] Figure 3 VVVVV Examples of EHMT2 targeting ligands are presented, where R is the linker site. For other examples and related ligands, see: PDB 5TUY crystal structure (“EHMT2 in complex with inhibitor MS0124”, Babault N. et al.); PDB 5TTF crystal structure (“EHMT2 in complex with inhibitor MS012”, Dong A. et al.); PDB 3RJW crystal structure (Dong A. et al., Structural Genomics Consortium); PDB 3K5K crystal structure; Liu F. et al. J. Med. Chem. 52: 7950-7953 (2009); and PDB crystal structure 4NVQ (“EHMT2 in complex with inhibitor A-366” Sweis RF et al.).

[0194] Figure 3 WWWWW An example of a SETD2 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 5LSY (“SETD2 in complex with cyproheptadine”, Tisi D. et al.); Tisi D. et al. ACS Chem. Biol. 11: 3093-3105 (2016); Crystal structures PDB 5LSS, 5LSX, 5LSZ, 5LT6, 5LT7 and 5LT8; PDB crystal structure 4FMU; and Zheng W. et al. J. Am. Chem. Soc. 134:18004-18014 (2012).

[0195] Figure 3XXXXX-3YYYYYExamples of SETD7-targeting ligands are presented, where R is the linker point. For other examples and related ligands, see: PDB crystal structure 5AYF (“SETD7 in complex with cyproheptadine.” Niwa H. et al.); PDB crystal structure 4JLG (“SETD7 in complex with (R)-PFI-2”, Dong A. et al.); PDB crystal structure 4JDS (Dong A. et al., Structural Genomics Consortium); PDB crystal structure 4E47 (Walker JR et al., Structural Genomics Consortium); PDB crystal structure 3VUZ (“SETD7 in complex with AAM-1.” Niwa H. et al.); PDB crystal structure 3VVO; and Niwa H. et al. Acta Crystallogr.Sect.D 69: 595-602 (2013).

[0196] Figure 3 ZZZZZ An example of a SETD8 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see PDB crystal structure 5TH7 (“SETD8 in complex with MS453”, Yu W. et al.) and PDB crystal structure 5T5G (Yu W. et al.; forthcoming).

[0197] Figures 4A-4B Examples of SETDB1 targeting ligands are presented, where R is the linker site. For other 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 JR et al., Structural Genomics Consortium); and PDB crystal structure 5KCO (“SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide”, Walker JR et al.).

[0198] Figure 4C-4P An example of a SMYD2 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see: PDB crystal structure 5KJK (“SMYD2 in complex with inhibitor AZ13450370”, Cowen SD et al.); PDB crystal structure 5KJM (“SMYD2 in complex with AZ931”, Cowen SD et al.); PDB crystal structure 5KJN (“SMYD2 in complex with AZ506”, Cowen SD et al.); PDB crystal structure 5ARF (“SMYD2 in complex with N-[3-(4-chlorophenyl)-1-{N'-cyano-N-[3-(difluoromethoxy)phenyl]carbamimidoyl}-4 5-dihydro-1H-pyrazol-4-YL]-N-ethyl-2-hydroxyacetamide”, Eggert E. et al.); PDB crystal structure 5ARG (“SMYD2 in complex with BAY598”, Eggert E. et al.); PDB crystal structure 4YND (“SMYD2 in complex with A-893”, Sweis RF et al.); PDB crystal structure 4WUY (“SMYD2 in complex with LLY-507”, Nguyen H. et al.); and PDB crystal structure 3S7B (“N-cyclohexyl-N~3~-[2-(3 4-dichlorophenyl)ethyl]- N-(2-{[2-(5-hydroxy-3-oxo-3 4-dihydro-2H-1 4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide”, Ferguson AD et al.).

[0199] Figure 4Q-4RExamples of SMYD3 targeting ligands are presented, where R is the linker site. For other 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”).

[0200] Figure 4S An example of an SUV4-20H1 targeting ligand is presented, where R is the linker point. For other examples and related ligands, see PDB crystal structure 5CPR (“SUV4-20H1 in complex with inhibitor A-196”, Bromberg KD et al.).

[0201] Figure 4T-4AA Examples of wild-type androgen receptor-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see the 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 (“Androgen Receptor”, Nadal M. et al.); PDB crystal structure 5CJ6 (“Androgen Receptor in complex with 2-Chloro-4-[[(1R 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile derivatives”, Saeed A. et al.); PDB crystal structure 4QL8 (“Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolines derivatives”, Ullrich T. et al.); PDB crystal structure 4HLW (“Androgen Receptor Binding Function 3 (BF3)Site of the Human Androgen Receptor through Virtual Screening”, Munuganti R.S. et al.); PDB crystal structure 3V49 (“Androgen Receptor lbd with Activator peptide and sarm inhibitor 1” (Nique F. et al.); Nique F. et al. J. Med. Chem. 55: 8225-8235 (2012); PDB crystal structure 2YHD (“Androgen Receptor in complex with AF2 small molecule inhibitor”, Axerio-Cilies P. et al.); PDB crystal structure 3RLJ (“Androgen Receptor ligand binding domain in complex with SARM S-22”, Bohl CE et al.); Bohl CE et al. J. Med. Chem. 54: 3973-3976 (2011); PDB crystal structure 3B5R (“Androgen Receptor ligandbinding domain in complex with SARM C-31”, Bohl CE et al.); Bohl CE et al. Bioorg. Med. Chem. Lett.18: 5567-5570 (2008); PDB crystal structure 2PIP (“AndrogenReceptor 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 in complex with EM5744”, Cantin L. et al.); and PDB crystal structure 2HVC (“Androgen Receptor ligand binding domain in complex with LGD2226”, Wang F. et al.). For other related ligands, see Matias PM et al., “Structural Basis for the Glucocorticoid Response in a Mutant Human Androgen Receptor (Ar(Ccr)) Derived from an Androgen-Independent Prostate Cancer.” J. Med. Chem. 45: 1439 (2002); Sack JS et al. "Crystallographic structures of the ligand-binding domains of the androgen receptor and itsT877A mutant complexed with the natural agonist dihydrotestosterone." Proc. Natl. Acad. Sci. 98: 4904-4909 (2001); He B. et al. "Structural basis for androgenreceptor interdomain and coactivator interactions suggests a transition innuclear receptor activation function dominance." Mol. Cell16: 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-imine 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 transdermaladministration." 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: ATransdermal 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 ProstateCancer (CRPC).” J. Med. Chem. 53: 2779–2796 (2010).

[0202] Figure 4BB Examples of mutant T877A androgen receptor targeting ligands are presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 4OGH (“Androgen Receptor T877A-AR-LBD”, Hsu CL et al.) and PDB crystal structure 2OZ7 (“Androgen Receptor T877A-AR-LBD”, Bohl C.E. et al.).

[0203] Figure 4CCAn example of the mutant W741L androgen receptor targeting ligand is presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 4OJB (“Androgen Receptor T877A-AR-LBD”, Hsu CL et al.).

[0204] Figure 4DD-4EE Examples of estrogen and / or androgen-targeting ligands are presented, where R is the linker point.

[0205] Figure 5A Examples of targeting ligands for afatinib, EGFR, and ErbB2 / 4 receptors are presented. R is the linker point.

[0206] Figure 5B Examples of targeting ligands for axitinib, VEGFR1 / 2 / 3, PDGFRβ, and Kit receptors are presented. R is the linker point.

[0207] Figures 5C-5D Examples of targeting ligands for bosutinib, BCR-Abl, Src, Lyn, and Hck receptors are presented. R is the linker point.

[0208] Figure 5E Examples of targeting ligands for cabozantinib, RET, c-Met, VEGFR1 / 2 / 3, Kit, TrkB, Flt3, Axl, and Tie 2 receptors are presented. R is the linker point.

[0209] Figure 5F Examples of targeting ligands for ceritinib, ALK, IGF-1R, InsR, and ROS1 receptors are presented. R is the linker point.

[0210] Figure 5G Examples of targeting ligands for crizotinib, ALK, c-Met, HGFR, ROS1, and MST1R receptors are presented. R is the linker point.

[0211] Figure 5H Examples of dabrafenib, a targeting ligand for the B-Raf receptor, are presented. R is the linker point.

[0212] Figure 5I Examples of targeting ligands for dasatinib, BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors are presented. R is the linker point.

[0213] Figure 5J An example of an erlotinib targeting EGFR receptor ligand is presented. R is the linker point.

[0214] Figure 5K-5M Examples of targeting ligands for everolimus, HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor are presented. R is the linker point.

[0215] Figure 5N Examples of targeting ligands for gefitinib, EGFR, and PDGFR receptors are presented. R is the linker point.

[0216] Figure 5O An example of ibrutinib, a targeting ligand for the BTK receptor, is presented. R is the linker point.

[0217] Figure 5P-5Q Examples of targeting ligands for imatinib, BCR-Abl, Kit, and the PDGFR receptor are presented. R is the linker point.

[0218] Figure 5R-5S Examples of targeting ligands for lapatinib, EGFR, and ErbB2 receptors are presented. R is the linker point.

[0219] Figure 5T Examples of targeting ligands for lenvatinib, VEGFR1 / 2 / 3, FGFR1 / 2 / 3 / 4, PDGFRα, Kit, and RET receptors are presented. R is the linker point.

[0220] Figure 5U-5V Examples of targeting ligands for nilotinib, BCR-Abl, PDGRF, and DDR1 receptors are presented. R is the linker point.

[0221] Figure 5W-5X Examples of targeting ligands for nintedanib, FGFR1 / 2 / 3, Flt3, Lck, PDGFRα / β, and VEGFR1 / 2 / 3 receptors are presented. R is the linker point.

[0222] Figure 5Y-5Z An example of a targeting ligand for palbociclib, the CDK4 / 6 receptor, is presented. R is the linker point.

[0223] Figure 5AA Examples of targeting ligands for pazopanib, VEGFR1 / 2 / 3, PDGFRα / β, FGFR1 / 3, Kit, Lck, Fms, and Itk receptors are presented. R is the linker point.

[0224] Figure 5BB-5CCExamples of targeting ligands for ponatinib, BCR-Abl, T315I, VEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2, and Flt3 receptors are presented. R is the linker point.

[0225] Figure 5DD Examples of targeting ligands for regorafenib, VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRα / β, RET, FGFR1 / 2, Tie2, and Eph2A are presented. R is the linker point.

[0226] Figure 5EE Examples of ruxolitinib, a targeting ligand for the JAK1 / 2 receptor, are presented. R is the linker point.

[0227] Figure 5FF-5GG An example of sirolimus, a targeting ligand of the FKBP12 / mTOR receptor, is presented. R is the linker point.

[0228] Figure 5HH Examples of targeting ligands for sorafenib, B-Raf, CDK8, Kit, Flt3, RET, VEGFR1 / 2 / 3, and PDGFR receptors are presented. R is the linker point.

[0229] Figure 5II-5JJ Examples of targeting ligands for sunitinib, PDGFRα / β, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, and RET are presented. R is the linker point.

[0230] Figure 5KK-5LL An example of a targeting ligand for tesimolimus, FKBP12 / mTOR, is presented. R is the linker point.

[0231] Figure 5MM Examples of targeting ligands for tofacitinib, the JAK3 receptor, are presented. R is the linker point.

[0232] Figure 5NN Examples of trametinib, a targeting ligand for the MEK1 / 2 receptor, are presented. R is the linker point.

[0233] Figure 500-5PP Examples of targeting ligands for vandetanib, EGFR, VEGFR, RET, Tie2, Brk, and EphR are presented. R is the linker point.

[0234] Figure 5 QQExamples of targeting ligands for vemurafenib, A / B / C-Raf, KSR1, and B-Raf (V600E) receptors are presented. R is the linker point.

[0235] Figure 5RR Examples of targeting ligands for Idelasib, the PI3Ka receptor, are presented. R is the linker point.

[0236] Figure 5SS Examples of targeting ligands for Buparlisib, the PI3Ka receptor, are presented. R is the linker point.

[0237] Figure 5TT Examples of targeting ligands for taselisib, the PI3Ka receptor, are presented. R is the linker point.

[0238] Figure 5UU Examples of targeting ligands for Copanlisib, PI3Ka, are presented. R is the linker point.

[0239] Figure 5VV Examples of targeting ligands for Alpelisib, PI3Ka, are presented. R is the linker point.

[0240] Figure 5WW An example of niclosamide, a targeting ligand for CNNTB1, is presented. R is the linker point.

[0241] Figures 6A-6B Examples of targeting ligands for the BRD4 bromodomain of PCAF and GCN5 receptor 1 are presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 5tpx (“Discovery of a PCAF Bromodomain Chemical Probe”); Moustakim, M. et al. Angew. Chem. Int. Ed. Engl. 56:827 (2017); PDB crystal structure 5mlj (“Discovery of a Potent, Cell Penetrant, and Selective p300 / CBP-Associated Factor (PCAF) / General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe”); and Humphreys, PG et al. J. Med. Chem. 60: 695 (2017).

[0242] Figures 6C-6DExamples of G9a (EHMT2) targeting ligands are presented, where R is the linker site. For other 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 (“A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells”); Vedadi, M. et al. Nat. Chem. Biol. 7: 566 (2011); PDB crystal structure 4nvq (“Discovery and development of potent and selective inhibitors of histone methyltransferase g9a”); and Sweis, RF et al. ACS Med Chem Lett 5: 205 (2014).

[0243] Figure 6E-6G An example of an EZH2-targeting ligand is presented, where R is the linker site. For other 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 Commun7: 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 MethyltransferaseEZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas"); Vaswani, RG et al. J. Med. Chem. 59: 9928 (2016); and PDB crystal structures 5ij8 and 5ls6.

[0244] Figure 6H-6I Examples of EED-targeting ligands are presented, where R is the linker site. For other 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.

[0245] Figure 6J An example of a KMT5A (SETD8) targeting ligand is presented, where R is the linker site. See, for example, the PDB crystal structure 5t5g.

[0246] Figure 6K-6L An example of a DOT1L targeting ligand is presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 4eki (“Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L”); Basavapathruni, A. et al. Chem. Biol. Drug Des.80: 971 (2012); PDB crystal structure 4hra (“Potent inhibition of DOT1L as treatment of MLL-fusion leukemia”); Daigle, SR et al. Blood 122: 1017 (2013); PDB crystal structure 5dry (“Discovery of NovelDot1L Inhibitors through a Structure-Based Fragmentation Approach”) Chen, C. et al. ACS Med. Chem. Lett. 7:735 (2016); PDB crystal structure 5dt2 (“Discovery of NovelDot1L Inhibitors through a Structure-Based Fragmentation Approach”); and Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016).

[0247] Figure 6M-6N An example of a PRMT3 targeting ligand is presented, where R is the linker site. For other 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 ProteinArginine Methyltransferase 3 (PRMT3)”); and Kaniskan, HU et al. Angew. Chem. Int. Ed. Engl. 54: 5166 (2015).

[0248] Figure 6O An example of a CARM1 (PRMT4) targeting ligand is presented, where R is the linker site. For other examples and related ligands, see “Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors.” Sack, JS et al. Biochem. JThe PDB crystal structures 2y1x and 2y1w and their associated ligands are described in . 436: 331 (2011).

[0249] Figure 6P Examples of PRMT5-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see "A selective inhibitor of PRMT5 with in vivo and in vitropotency in MCL models" by Chan-Penebre, E. Nat. Chem. Biol The PDB crystal structure 4x61 and related ligands are described in . 11: 432 (2015).

[0250] Figure 6Q Examples of PRMT6-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see “Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound”, Mitchell, LH et al. ACS Med. Chem. Lett The PDB crystal structure 4y30 and related ligands are described in . 6: 655 (2015).

[0251] Figure 6R An example of an LSD1 (KDM1A) targeting ligand is presented, where R is the linker site. For other examples and related ligands, see “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. The PDB crystal structure 5lgu and related ligands are described in 60: 1693 (2017).

[0252] Figure 6S-6TExamples of KDM4-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see PDB crystal structure 3rvh; "Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors." Korczynska, M., et al. J. Med. Chem. The PDB crystal structure 5a7p and related ligands described in 59:1580 (2016); and “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. The PDB crystal structure 3f3c and related ligands are described in 59:1388 (2016).

[0253] Figure 6U Examples of KDM5-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see "Structural Analysis of Human Kdm5B Guides Histone Demethylase Inhibitor Development" by Johansson, C. et al. Nat. Chem. Biol. The PDB crystal structure 3fun and related ligands described in 12:539 (2016) and “An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells”. Vinogradova, M. et al. Nat. Chem. Biol. The PDB crystal structure 5ceh and related ligands are described in 12: 531 (2016).

[0254] Figure 6V-6WExamples of KDM6-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see “A Selective Jumonji H3K27 Demethylase Inhibitor Modulates the Proinflammatory Macrophage Response”, Kruidenier, L. et al. Nature The PDB crystal structure 4ask and related ligands are described in 488:404 (2012).

[0255] Figure 6X An example of an L3MBTL3 targeting ligand is presented, where R is the linker point. See, for example, the PDB crystal structure 4fl6.

[0256] Figure 6Y Examples of Menin-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see "Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo" Borkin, D et al. Cancer Cell The PDB crystal structure 4x5y and related ligands described in 27:589 (2015) and “High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction” by He, S. et al. J. Med. Chem. The PDB crystal structure 4og8 and related ligands are described in 57: 1543 (2014).

[0257] Figure 6Z-6AA Examples of HDAC6 targeting ligands are presented, where R is the linker point. See, for example, the PDB crystal structures 5kh3 and 5eei.

[0258] Figure 6BBExamples of HDAC7-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see "Human HDAC7 harbors a class IIa histone deacetylase-specificzinc binding motif and cryptic deacetylase activity." Schuetz, A. et al. J. Biol. Chem. The PDB crystal structure 3c10 and related ligands described in 283:11355 (2008) and “Selective Class IiaHistone Deacetylase Inhibition Via a Non-Chelating Zinc Binding Group”. Lobera, M. et al. Nat. Chem. Biol The PDB crystal structure PDB 3zns and related ligands are described in . 9: 319 (2013).

[0259] Figures 7A-7C Examples of protein tyrosine phosphatase, non-receptor type 1, and PTP1B-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see “Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics” Groves, MR et al. Biochemistry 37: PDB crystal structure described in 17773-17783 (1998) 1bzj; "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. The PDB crystal structure 3cwe described in 18:3200-5 (2008); "Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors." Moretto, AF et al. Bioorg. Med. ChemThe PDB crystal structures 2azr and 2bO7 described in . 14: 2162-2177 (2006); "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 IsothiazolidinoneHeterocyclic Phosphonate Mimetics." Ala, PJ et al. J. Biol. Chem. The PDB crystal structures described in 281:32784 (2006) are PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cmb, 2cmc; "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors". Klopfenstein, SR et al. Bioorg. Med. Chem. Lett. The PDB crystal structures 2f6t and 2f6w described in 16: 1574-1578 (2006); "Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48." Wan, ZK et al. Bioorg. Med. Chem. Lett. The PDB crystal structures 2h4g, 2h4k, and 2hb1 described in 16: 4941-4945 (2006); "Structure-based optimization of protein tyrosine phosphatase-1 B inhibitors: capturing interactions with arginine 24". Wan, ZK et al. ChemMedChemSee also the PDB crystal structures 2zn7 and 2nt7 described in "Probing acid replacements of thiophene PTP1B inhibitors." Wan, ZK et al., Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007); and WO 2008148744 A1, entitled "Thiadiazole derivatives as antidiabetic agents," transferred to Novartis AG. Also see, "2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases." Andersen, HS et al. J. Biol. Chem. 275: 7101-7108 (2000); "Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selectiveinhibitor of protein-tyrosine phosphatase 1B." Iversen, LF 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, LF et al. Biochemistry The PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, and 1l8g described in 40: 14812-14820 (2001) are also mentioned.

[0260] Figure 7DExamples of non-receptor type 11 tyrosine protein phosphatases and SHP2-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see "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 The crystal structures PDB 4pvg and 305x are described in . 53: 2482-2493 (2010); and in "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." GarciaFortanet, J. et al. J. Med. Chem. The crystal structure PDB 5ehr and its associated ligands are described in 59: 7773-7782 (2016). See also "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 SHP2phosphatase inhibits cancers driven by receptor tyrosine kinases." Chen, YP et al. Nature The crystal structure PDB 5ehr is described in 535: 148-152 (2016).

[0261] Figure 7EExamples of non-receptor type 22 target ligands for tyrosine protein phosphatase are presented, where R is the linker site. For other examples and related ligands, see, “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. The crystal structure PDB 4j51 is described in 56: 4990-5008 (2013).

[0262] Figure 7F An example of a scavenger mRNA uncapping enzyme DcpS targeting ligand is presented, where R is the linker site. For other examples and related ligands, see “DcpS as a therapeutic target for spinal muscular atrophy.” Singh, J. et al. ACS Chem.Biol. The crystal structures PDB3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb and related ligands described in 3: 711-722 (2008) are described.

[0263] Figure 8A-8S An example of a BRD4 bromodomain 1-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Filippakopoulos, P. et al., “Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family”. Bioorg. Med. Chem. Crystal structures PDB 3u5k and 3u51 and related ligands in 20: 1878–1886 (2012); crystal structure PDB 3u5l; Dawson, MA et al., “Inhibition of BetRecruitment to Chromatin as an Effective Treatment for M11-Fusion Leukaemia.” NatureThe crystal structure PDB 3zyu and its associated ligands are described in 478:529 (2011); Mirguet, O. et al., “Naphthyridines as Novel Bet Family Bromodomain Inhibitors.” Chemmedchem The crystal structure PDB 4bw1 and its associated ligands are described in 9:589 (2014); Dittmann, A. et al., “The Commonly Used Pi3-Kinase Probe Ly294002 is an Inhibitor of Bet Bromodomains”. ACS Chem. Biol. The crystal structure PDB 4cfl and its associated ligands are described in 9:495 (2014); Fish, PV et al., “Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.” J. Med. Chem. The crystal structure PDB 4e96 and its associated ligands are described in 55: 9831-9837 (2012); Atkinson, SJ et al., “The Structure Based Design of Dual Hdac / Bet Inhibitors as Novel Epigenetic Probes.” Medchemcomm The crystal structure PDB 4clb and related ligands described in 5:342 (2014); Zhang, G. et al., “Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.” J. Biol. Chem. The crystal structure PDB 4f3i and related ligands described in 287: 28840-28851 (2012); Zhao, L. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4Bromodomain.” J. Med. Chem.The crystal structure PDB 4hxl and related ligands described in 56: 3833-3851 (2013); Zhao, L. et al., “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.” J. Med. Chem The crystal structure PDB 4hxs and its associated ligands are described in .56: 3833-3851 (2013); Gehling, VS et al., “Discovery, Design, and Optimization of Isoxazole Azepine BET Inhibitors.” ACS Med Chem Lett The crystal structure PDB 4lrg and related ligands described in 4: 835-840 (2013); Vidler, LR, “Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.” et al. J. Med. Chem. The crystal structure PDB4mep and related ligands described in 56: 8073-8088 (2013); Ember, SW et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem.Biol. The crystal structures PDB 4nr8 and PDB 4c77 and their associated ligands are described in 9: 1160-1171 (2014); Ember, SW et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein4 (BRD4) Interacts with Diverse Kinase Inhibitors.” ACS Chem. Biol.The crystal structure PDB 4o7a and its associated ligands are described in 9: 1160-1171 (2014); “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.” Ember, SW et al. (2014). ACS Chem. Biol. The crystal structure PDB 407b and its associated ligands described in 9: 1160-1171; Ember, SW et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem. Biol. Crystal structure PDB 4o7c and related ligands described in 9: 1160-1171 (2014); crystal structure PDB4gpj; Theodoulou, NH et al., “The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”. J. Med. Chem. The crystal structure PDB 4uix and its associated ligands are described in 59: 1425 (2016); Theodoulou, NH, et al., “The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”. J. Med. Chem. The crystal structure PDB 4uiz and its associated ligands are described in 59:1425 (2016); McKeown, MR et al., “Biased multicomponent reactions to develop novel bromodomain inhibitors.” J. Med. ChemThe crystal structure PDB 4wiv and its associated ligands are described in .57: 9019-9027 (2014); Taylor, AM et al., “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BETBromodomains.” ACS Med. Chem. Lett. The crystal structure PDB 4x2i and its associated ligands described in 7: 145-150 (2016); Duffy, BC, “Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.” Bioorg. Med. Chem. Lett. The crystal structure PDB 4yh3 and its associated ligands described in 25: 2818-2823 (2015); Duffy, BC, “Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.” Bioorg. Med. Chem. Lett The crystal structure PDB 4yh4 and its associated ligands are described in . 25:2818-2823 (2015); Taylor, AM “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BETBromodomains.” ACS Med. Chem. Lett. Crystal structure PDB 4z1q and related ligands described in 7: 145-150 (2016); crystal structure PDB 4zw1; Demont, EH “Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors”. J. Med. Chem. The crystal structure PDB 5a5s and related ligands described in 58: 5649 (2015); Bamborough, P. “Structure-Based Optimization of Naphthyridones Into Potent Atad2 Bromodomain Inhibitors”J. Med. Chem. The crystal structure PDB 5a85 and its associated ligands are described in 58:6151 (2015); Sullivan, JM, “Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice.” J. Exp. Med. The crystal structure PDB 5acy and its associated ligands are described in 212: 1771 (2015); Waring, MJ et al., “Potent and Selective Bivalent Inhibitors of Bet Bromodomains”. Nat. Chem. Biol. The crystal structure PDB 5ad2 and its associated ligands are described in 12:1097 (2016); Chekler, EL et al., “Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.” Chem. Biol. The crystal structure PDB 5cfw and its associated ligands described in 22: 1588-1596 (2015); 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. The crystal structure PDB 5cqt and related ligands described in 59: 1565-1579 (2016); 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.The crystal structure PDB 5d3r and its associated ligands described in 59: 1518-1530 (2016); Milhas, S. et al., “Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.” (2016). ACS Chem.Biol. The crystal structure PDB 5dlx and its associated ligands described in 11: 2140-2148; Milhas, S. et al., “Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.” ACS Chem. Biol. The crystal structure PDB 5dlz and its associated ligands are described in 11: 2140-2148 (2016); Kharenko, OA et al., “RVX-297 – a novel BD2 selective inhibitor of BET bromodomains.” Biochem. Biophys. Res. Commun. The crystal structure PDB 5dw2 and its associated ligands described in 477: 62-67 (2016); the crystal structure PDB 5dlx; Albrecht, BK et al., “Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.” J. Med. Chem. The crystal structure PDB5his and its associated ligands are described in 59: 1330-1339 (2016); Crawford, TD et al., “Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP / EP300”. J. Med. Chem. The crystal structure PDB 5ku3 and its associated ligands are described in 59:10549-10563 (2016); Bamborough, P. et al., “A Chemical Probe for the ATAD2 Bromodomain.” Angew. Chem. Int. Ed. Engl.The crystal structure PDB 5lj2 and its associated ligands described in 55:11382-11386 (2016); Wang, L. “Fragment-based, structure-enabled discovery of novel pyridones and pyridonemacrocycles as potent bromodomain and extra-terminal domain (BET) family bromodomain inhibitors”. J. Med. Chem. The crystal structure PDB 5dlx and its associated ligands described in WO 2015169962 A1 entitled “Benzimidazole derivatives as BRD4 inhibitors and their preparation and use for the treatment of cancer”, assigned to Boehringer Ingelheim International GmbH, Germany; and WO 2011143669 A2 entitled “Azolodiazepine derivatives and their preparation, compositions and methods for treating neoplasia, inflammatory disease and other disorders”, assigned to Dana-Farber Cancer Institute, Inc, USA.

[0264] Figure 8T-8V An example of an ALK-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Bossi, RT, et al., "Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors". BiochemistryCrystal structures PDB 2xb7 and 2xba and related ligands described in 49: 6813-6825 (2010); Huang, Q. et al., "Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib." J. Med. Chem. The crystal structures PDB 2yfx, 4ccb, 4ccu, and 4cd0 and their associated ligands are described in 57: 1170 (2014); Johnson, TW et al., “Discovery of (10R)-7-Amino-12-Fluoro-2,10,16-Trimethyl-15-Oxo-10,15,16,17-Tetrahydro-2H-8,4-(Metheno)Pyrazolo[4,3-H][2,5,11]Benzoxadiazacyclotetradecine-3-Carbonitrile (Pf-06463922), a Macrocyclic Inhibitor of Alk / Ros1 with Pre-Clinical Brain Exposure and Broad Spectrum Potency Against Alk-Resistant Mutations.” J. Med. Chem. The crystal structures PDB 4cli, 4cmo, and 4cnh and their associated ligands are described in 57:4720 (2014); Epstein, LF et al., "The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase." J. Biol. Chem. The crystal structure PDB 4fny and its associated ligands are described in 287: 37447-37457 (2012); Bryan, MC et al. "Rapid development of piperidinecarboxamides as potent and selective anaplastic lymphoma kinase inhibitors". "J. Med. Chem. The crystal structure PDB 4dce and related ligands described in 55: 1698-1705 (2012); Gummadi, VR et al., "Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode." (2013) Bioorg. Med. Chem. Lett. The crystal structure PDB 4joa and related ligands described in 23: 4911-4918; and Tu, CH et al., "Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK)." J. Med. Chem. The crystal structure PDB 5iui and its associated ligands are described in 59: 3906-3919 (2016).

[0265] Figure 8W-8X Examples of BTK-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Marcotte, DJ, et al., "Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases." Protein Sci. 19: 429-439 (2010) and Kuglstatter, A. et al. "Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures" Protein Sci.The crystal structures PDB 3gen, 3piz, and related ligands described in "20: 428-436" (2011); 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. The crystal structures PDB 3ocs, 4ot6, and related ligands described in 58: 512-516 (2015); 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. The crystal structures PDB 5fbn and 5fbo and their associated ligands are described in 7:198-203 (2016); Kuglstatter, A. et al., "Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures." Protein Sci. The crystal structure PDB 3pix and its associated ligands described in 20: 428-436 (2011); and Bujacz, A. et al., "Crystal structures of the apo form of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose." Febs J. The crystal structure PDB 3pij and its associated ligands are described in 278: 1728-1744 (2011).

[0266] Figure 8Y An example of an FLT3-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Zorn, JA et al., "Crystal Structure of the FLT3 Kinase DomainBound to the Inhibitor Quizartinib (AC220)".Plos One The crystal structures PDB 4xuf and 4rt7 and their associated ligands are described in 10: e0121177-e0121177 (2015).

[0267] Figure 8Z-8AA Examples of TNIK-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Masuda, M. et al., “TNIK inhibition abrogates colorectal cancerstemness.” Nat Commun Crystal structures PDB 2x7f, PDB 5ax9 and 5d7a, and related ligands are described in 7: 12586-12586 (2016).

[0268] Figure 8BB-8CC Examples of NTRK1, NTRK2, and NTRK3 targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Wang, T. et al., “Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors.” ACS Med. Chem. Lett. The crystal structure PDB 4aoj and its associated ligands are described in 3:705 (2012); Stachel, SJ et al., “Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.” J. Med. Chem Crystal structures PDB 4pmm, 4pmp, 4pms, and 4pmt and their associated ligands are described in .57: 5800-5816 (2014); Choi, HS et al., “(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med. Chem. Lett.The crystal structures PDB 4yps and 4yne and their associated ligands described in 6: 562-567 (2015); Bertrand, T. et al., “The Crystal Structures of Trka and Trkb Suggest Key Regions for Achieving Selective Inhibition.” J. Mol. Biol. The crystal structures PDB 4at5 and 4at3 and their associated ligands described in 423:439 (2012); and Albaugh, P. et al., “Discovery of GNF-5837, a selective TRK Inhibitor with efficacy inrodent cancer tumor models.” ACS Med. Chem. Lett. 3: 140–145 (2012) and Choi, HS et al. “(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med Chem Lett The crystal structures PDB 3v5q and 4ymj and their associated ligands are described in 6: 562-567 (2015).

[0269] Figure 8DD - 8EE An example of an FGFR1-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see 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 anangiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.” EMBO J.Crystal structures PDB 3tto and 2fgi and related ligands described in 17: 5896-5904 (1998); crystal structure PDB4fb3; Harrison, C. et al., “Polyomavirus large T antigen binds symmetrical repeats at the viral origin in an asymmetrical manner.” J. Virol. The crystal structure PDB 4rwk and its associated ligands described in 87: 13751-13759 (2013); Sohl, CD et al., “Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.” ACS Chem. Biol Crystal structures PDB 4rwl and related ligands described in .10: 1319-1329 (2015); crystal structure PDB 4uwc; Tucker, JA et al., “Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4.” Structure The crystal structure PDB 4v01 and its associated ligands are described in 22:1764 (2014); Klein, T. et al., “Structural and Dynamic Insights Into the Energetics of Activation Loop Rearrangement in Fgfr1 Kinase.” Nat. Commun The crystal structure PDB5a46 and its associated ligands are described in .6:7877 (2015); and Patani, H. et al., “Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.” OncotargetThe crystal structure PDB 5ew8 and its associated ligands are described in 7: 24252-24268 (2016).

[0270] Figure 8FF An example of an FGFR2-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Chen, H. et al., “A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.” Mol. Cell The crystal structure PDB 2pvf and its associated ligands are described in 27: 717-730 (2007).

[0271] Figure 8GG Examples of FGFR4-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Lesca, E. et al., “Structural analysis of the human fibroblast growth factor receptor 4 kinase.” J. Mol. Biol. The crystal structure PDB 4tyi and its associated ligands are described in 426: 3744-3756 (2014).

[0272] Figure 8HH - 8II Examples of MET-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see crystal structures PDB 3qti and 3zcl; Peterson, EA et al., "Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors." J. Med. Chem.58: 2417-2430 (2015) and Cui, JJ et al. "Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2, 4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with High ProteinKinase Selectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats." J. Med. Chem. The crystal structures PDB 4xmo, 4xyf, and 3zcl and their associated ligands are described in 56: 6651 (2013); Boezio, AA, et al., "Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust InVivo Antitumor Activity." J. Med. Chem. The crystal structure PDB5eyd and related ligands described in 59: 2328-2342 (2016); Kim, KS et al., "Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities." J. Med. Chem.The crystal structure PDB3ce3 and its related ligands are described in 51: 5330-5341 (2008); Bellon, SF et al., "c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations." J. Biol. Chem. The crystal structure PDB 2rfn and its associated ligands are described in 283: 2675-2683 (2008); and Smith, BD et al., "Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2." Mol. Cancer Ther. The crystal structure PDB 5dg5 and its associated ligands are described in 14: 2023-2034 (2015).

[0273] Figure 8JJ Examples of JAK1-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Zak, M. et al., “Identification of C-2 HydroxyethylImidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.” J. Med. Chem. The crystal structure of PDB 4ivd and its associated ligands are described in 56:4764-4785 (2013); Vasbinder, MM et al., "Identification of azabenzimidazoles as potent JAK1 selective inhibitors." Bioorg. Med. Chem. Lett.The crystal structure PDB 5e1e and related ligands described in 26: 60-67 (2016); Simov, V., et al., "Structure-based design and development of (benz)imidazolepyridones as JAK1-selective kinase inhibitors." Bioorg. Med. Chem. Lett. The crystal structure PDB 5hx8 and its associated ligands are described in 26:1803-1808 (2016); Caspers, NL et al., "Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system". Acta Crystallogr. Sect. F 72: 840-845 (2016); and the crystal structure PDB 5hx8 and related ligands described in Kettle, JG “Discovery of the JAK1 selective kinase inhibitor AZD4205”, AACR National Meeting, April 2017.

[0274] Figure 8KK - 8LL An example of a JAK2-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see Andraos, R. et al., "Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent." Cancer Discov The crystal structure PDB 3ugc and its associated ligands are described in 2:512-523 (2012); Hart, AC et al., "Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors." ACS Med. Chem. Lett.Crystal structures PDB 5cf4, 5cf5, 5cf6, and 5cf8 and their associated ligands described in 6: 845-849 (2015); Brasca, MG, et al., "Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders". Bioorg. Med. Chem. The crystal structure PDB 5aep and related ligands described in 23:2387 (2015); Farmer, LJ et al., "Discovery of VX-509 (Decernotinib): A Potent and Selective JanusKinase 3 Inhibitor for the Treatment of Autoimmune Diseases." J. Med. Chem. The crystal structures PDB 4ytf, 4yth, and 4yti and their associated ligands are described in 58:7195-7216 (2015); Menet, CJ et al., "Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634." J. Med. Chem. The crystal structures PDB 4ytf, 4yth, 4yti and related ligands described in 57: 9323-9342 (2014); Siu, M. et al., "2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors." Bioorg. Med. Chem. Lett. The crystal structures PDB4ji9 and related ligands described in 23: 5014-5021 (2013); and the crystal structures PDB3io7 and 3iok and related ligands described in Schenkel, LB et al., "Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors." J. Med. Chem. 54: 8440-8450 (2011).

[0275] Figure 8MMAn example of a JAK3-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see Lynch, SM et al., "Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the Jak Family and the Kinome." Bioorg. Med. Chem. Lett The crystal structure PDB 3zc6 and its associated ligands are described in .23: 2793 (2013); and Soth, M. et al., "3-AmidoPyrrolopyrazine 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 ofnovel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinaseinhibitors." Bioorg. Med. Chem. Lett. The crystal structures PDB4hvd, 4i6q and 3zep and their associated ligands are described in 23: 2522-2526 (2013).

[0276] Figure 8NN - 8OO Examples of KIT-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Mol, CD et al., “Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.” J. Biol. Chem.The crystal structure of PDB 1t46 and its associated ligands are described in 279: 31655-31663 (2004); and Garner, AP et al., "Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients." Clin. Cancer Res. The crystal structure PDB 4u0i and its associated ligands are described in 20: 5745-5755 (2014).

[0277] Figure 8PP - 8VV Examples of EGFR-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see crystal structures PDB 5hcy, 4rj4, and 5cav; Heald, R., “Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study”. J. Med. Chem. 58, 8877–8895 (2015); Hanano, EJ, “Discovery ofSelective and Noncovalent Diaminopyrimidine-Based Inhibitors of EpidermalGrowth Factor Receptor Containing the T790M Resistance Mutation. “ J. Med. Chem. , 57, 10176–10191 (2014); Chan, BK et al. "Discovery of a Noncovalent,Mutant-Selective Epidermal Growth Factor Receptor Inhibitor " J. Med. Chem. 59,9080 (2016); Jia, Y. et al. "Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors " Nature534, 129 (2016); Ward, RA "Structure- and reactivity-based development of covalent inhibitors of theactivating and gatekeeper mutant forms of the epidermal growth factorreceptor (EGFR)" J. Med. Chem. The crystal structure PDB 5d41 and its associated ligands are described in 56, 7025-7048 (2013); "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. The crystal structure PDB4zau and its associated ligands are described in , 57 (20), 8249–8267 (2014); Bryan, MC et al., “Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR”. ACS Med. Chem. Lett. The crystal structure PDB 5em7 and its associated ligands are described in , 7 (1), 100–104 (2016); Zhou, W. et al., “Novel mutant-selective EGFR kinase inhibitors against EGFR T790M”. NatureThe crystal structure PDB 3IKA and its associated ligands are described in 462(7276), 1070–1074 (2009); see 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 WTSparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell LungCancers” Med. Chem., 59 (14), 6671–6689 (2016); Lee, H.-J. “Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M” Cancer Discov. The crystal structure PDB 5feq and its associated ligands are described in 3(2): 168–181 (2013); Huang, WS. et al., "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase." J. Med. Chem The crystal structure PDB 5j7h and its associated ligands are described in .59: 4948-4964 (2016); Hennessy, EJ et al., "Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790MMutation." ​The crystal structure PDB 4v0g and related ligands described in 7: 514-519 (2016); 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." ​ 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 ​ The crystal structure PDB 5hg7 and related ligands described in 59: 7111-7124 (2016); 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." ​Crystal structures PDB 5ug8, 5ug9, and 5ugc and their associated ligands described in 60: 3002-3019 (2017); 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." ​ 60: 2944-2962 (2017); and Juchum, M. "Trisubstituted imidazoles with a rigidized hinge binding motifact as single digit nM inhibitors of clinically relevant EGFR L858R / T790M andL858R / T790M / C797S mutants: An example of target hopping." ​ The crystal structure PDB 5gnk and its associated ligands are described in DOI:10.1021 / acs.jmedchem.7b00178 (2017).

[0278] ​ Examples of PAK1-targeting ligands are presented, where R is the linker site. For other 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.” ​ 59, 5520-5541 (2016) and Karpov AS et al. ​ ​ 22;6(7):776-81 (2015).

[0279] ​Examples of PAK4-targeting ligands are presented, where R is the linker point. For other examples and related ligands, see Staben ST, et al. ​ 13;57(3):1033-45 (2014) and Guo, C. et al., “Discovery of pyrroloaminopyrazoles as novel PAK inhibitors” ​ 55,4728–4739 (2012).

[0280] ​ Examples of IDO-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Yue, EW, et al., “Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model.” ​ 52, 7364-7367 (2009); Tojo, S.; et al. “Crystal structures and structure‚ and activity relationships of imidazothiazole derivatives as IDO1 inhibitors.” ​ 5, 1119-1123 (2014); Mautino, MR et al., “NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy” Abstract 491, AACR 104th Annual Meeting 2013; April 6-10, 2013; Washington, DC; and WO2012142237, entitled “Fused imidazole derivatives useful as IDO inhibitors”.

[0281] ​Examples of ERK1 and ERK2 targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Blake, JF, et al., “Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1 / 2 (ERK1 / 2) Inhibitor in Early Clinical Development”. ​ ​ Crystal structures PDB 5K4I and 5K4J and related ligands described in 59: 5650-5660 (2016); Bagdanoff, JT et al., “Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase”. ​ ​ The crystal structure PDB 5BVF and its associated ligands described in 25, 3788-3792 (2015); Deng, Y. et al., “Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase”. ​ The crystal structure PDB 4QYY and its associated ligands described in 57: 8817-8826 (2014); Jha, S. et al., “Dissecting Therapeutic Resistance to ERK Inhibition” ​ The crystal structures PDB 5HD4 and 5HD7 and their associated ligands are described in 15: 548-559 (2016); Ren, L. et al., “Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1 / 2.” J. Med. Chem.The crystal structure PDB 4XJ0 and its associated ligands described in 58: 1976–1991 (2015); Ward, RA 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, SV et al., “Discovery of LY3214996, a selective and novel ERK1 / 2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations.” Crystal structures PDB 4ZZM, 4ZZN, 4ZZO and related ligands described in AACR National Meeting 2017; Cheng, R. et al., “High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand”. Protein Sci. The crystal structures PDB 3FHR and 3FXH and their associated ligands are described in 19: 168-173 (2010); Ward, RA et al., “Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1 / 2 from a Modestly Active and Promiscuous Chemical StartPoint.” J. Med. Chem.The crystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and 5NHV and their associated ligands are described in 60, 3438–3450 (2017); and Oubrie, A. et al., “Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout theseries.” Bioorg. Med. Chem. Lett. The crystal structures PDB 3SHE and 3R1N and their associated ligands are described in 22: 613-618 (2012).

[0282] Figure 8FFF-8III An example of an ABL1-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see 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 inhibitoryactivity of 3-substituted benzamide derivatives”, Bioorg. Med. Chem. Lett. The crystal structures PDB 1fpu and 2e2b and their associated ligands are described in 17:2712-2717 (2007); Cowan-Jacob, SW et al., “Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia”. Acta Crystallog. Sect. D 63: 80-93 (2007) and Okram, B. et al., “A general strategy for creating”, Chem. Biol. The crystal structures PDB 2hzn and 2hiw and their associated ligands are described in 13: 779-786 (2006); Weisberg, E. et al., “Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl”. Cancer CellThe crystal structure PDB 3cs9 and related ligands described in 7:129-14 (2005); O'Hare, T. et al., "AP24534, apan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance", Cancer Cell The crystal structure PDB 3ik3 and its associated ligands described in 16: 401-412 (2009); 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 The crystal structure PDB 3mss and related ligands described in . 132: 7043-7048 (2010); Zhou, T. et al., “Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance”, Chem. Biol. Drug Des. The crystal structure PDB 3oy3 and its associated ligands described in 77:1-11 (2011); Chan, WW et al., “Conformational Control Inhibition of the BCR-ABL1Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”. Cancer Cell The crystal structures PDB 3qri and 3qrk and their associated ligands are described in 19: 556-568 (2011); Liu, F. et al., “Discovery and characterization of a novel potenttype II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”. Oncotarget7: 45562-45574 (2016) and Young, MA et al. "Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680", Cancer Res. The crystal structures PDB 5hu9 and 2f4j and their associated ligands described in 66: 1007-1014 (2006); Tokarski, JS et al., “The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants”. Cancer Res. 66: 5790-5797 (2006); and Zhou, T. et al., “Crystal Structure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des. The crystal structures PDB 2gqg and 2qoh and related ligands described in 70: 171-181 (2007); Tokarski, JS et al., “The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants”, Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al., “Crystal Structure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des.The crystal structures PDB 2gqg and 2qoh and related ligands described in 70: 171-181 (2007); Tokarski, JS et al., “The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABLMutants”, Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al., “Crystal Structure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des The crystal structures PDB 2gqg and 2qoh and related ligands described in . 70: 171-181 (2007); Berkholz, DS et al., “Catalytic cycle of human glutathione reductase near 1 A resolution”. J. Mol. Biol. The crystal structures PDB 3dk3 and 3dk8 and their associated ligands are described in 382: 371-384 (2008); Levinson, NM et al., “Structura and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain”. Plos One 7: The crystal structure PDB 3ue4 and related ligands described in e29828-e29828 (2012); Jensen, CN et al., “Structures of the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase (Hbpa) LocateActivity Hotspots Identified by Using Directed Evolution”, ChembiochemThe crystal structure PDB 4cy8 and its associated ligands are described in 16:968 (2015); Cowan-Jacob, SW et al., “Structuralbiology contributions to the discovery of drugs to treat chronic myelogenous leukaemia”. Acta Crystallogr D Biol Crystallogr. The crystal structure PDB 2hz0 and its associated ligands are described in 63(Pt 1):80-93 (2007); 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. The crystal structure PDB 3pyy and its associated ligands described in 18: 177-186 (2011); and Kim, MK, et al., “Structural basis for dual specificity of yeast N-terminal amidase in the N-end rule pathway”. Proc. Natl. Acad. Sci. U.S.A. The crystal structure PDB 5k5v and its associated ligands are described in 113:12438-12443 (2016).

[0283] Figure 8JJJ Examples of ABL2-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see 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. The crystal structure PDB 2xyn and related ligands described in 54: 2359 (2011); Ha, BH et al., “Structure of the ABL2 / ARG kinase in complex with dasatinib” Acta Crystallogr. Sect.FThe crystal structure PDB4xli and related ligands described in 71: 443-448 (2015); and the crystal structure PDB3gvu and related ligands described in Salah, E. et al., “The crystal structure of human ABL2 in complex with Gleevec” (forthcoming).

[0284] Figure 8KKK-8MMM An example of an AKT1-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Lippa, B. et al., “Synthesis and structure-based optimization of novel Akt inhibitors”. Bioorg. Med. Chem. Lett. 18: 3359-3363 (2008); Freeman-Cook, KD et al. "Design of selective, ATP-competitive inhibitors of Akt", J. Med. Chem. 53: 4615-4622 (2010); Blake, JF et al. “Discovery of pyrrolopyrimidineinhibitors of Akt”, Bioorg. Med. Chem. Lett . 20: 5607-5612 (2010); Kallan, NC et al. “Discovery and SAR of spirochromane Akt inhibitors”, Bioorg. Med. Chem. Lett. 21: 2410-2414 (2011); Lin, K "An ATP-Site On-Off Switch That RestrictsPhosphatase 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 OrallyBioavailable, Potent Inhibitor of Akt Kinases”, J. Med. Chem.56: 2059-2073(2013); Wu, WI, et al. "Crystal structure of human AKT1 with an allostericinhibitor reveals a new mode of kinase inhibition. Plos One 5: 12913-12913(2010); Ashwell, MA 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, JM, et al. “Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): AnOrally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor”, J. Med. Chem. 59: 6455-6469 (2016).

[0285] Figure 8NNN-8OOO An example of an AKT2-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see Davies, TG et al., “A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera”. J. Mol. Biol The crystal structures PDB 2jdo and 2jdr and their associated ligands are described in . 367: 882 (2007); Saxty, G. et al., “Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery”, J. Med. Chem.The crystal structure PDB 2uw9 and related ligands described in 50:2293-2296 (2007); 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. The crystal structures PDB 2x39 and 2xh5 and their associated ligands are described in 53: 2239d (2010); Hadler, KS et al., “Substrate-promoted formation of a catalytically competent binuclear center and regulation of reactivity in a glycerophosphodiesterase from Enterobacteraerogenes”. J. Am. Chem. Soc The crystal structure PDB 3dO3 and its associated ligands described in . 130: 14129-14138 (2008); and Rouse, MB et al., “Aminofurazans as potent inhibitors of AKTkinase”. Bioorg. Med. Chem. Lett. The crystal structures PDB 3e87, 3e8d and 3e88 and their associated ligands are described in 19: 1508-1511 (2009).

[0286] Figure 8PPP An example of a BMX-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Muckelbauer, J. et al., “X-ray crystal structure of bone marrowkinase in the x chromosome: a Tec family kinase”. Chem. Biol. Drug Des. The crystal structures PDB 3sxr and 3sxr and their associated ligands are described in 78:739-748 (2011).

[0287] Figure 8QQQ-8SSSAn example of a CSF1R-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Schubert, C. et al., “Crystal structure of the tyrosinekinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors”. J. Biol. Chem. The crystal structures PDB 2i0v and 2i1m and their associated ligands are described in 282: 4094-4101 (2007); 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. The crystal structure PDB 3bea and related ligands described in 18: 2355-2361 (2008); the crystal structure PDB 3dpk and related ligands described in MT, McKay, DBOvergaard, “Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon” (forthcoming); Illig, CR et al., “Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141”), J. Med. Chem. The crystal structures PDB 3krj and 3krl and their associated ligands described in 54: 7860-7883 (2011); Tap, WD et al., “Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor:, N Engl J MedThe crystal structure PDB 4r7h and its associated ligands are described in 373:428-437 (2015); Meyers, MJ 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. The crystal structures PDB 3lcd and 3lcoa and their associated ligands described in 20: 1543-1547 (2010); Zhang, C. et al., “Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor”, Proc. Natl. Acad. Sci. USA The crystal structure PDB 4hw7 and its associated ligands described in 110: 5689-5694 (2013); and Tap, WD et al., “Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor”, N Engl J Med The crystal structure PDB 4r7i and its associated ligands are described in 373: 428-437 (2015).

[0288] Figure 8TTT An example of a CSK-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see Levinson, NM, et al., “Structural basis for the recognition of c-Src by its inactivator Csk”. Cell 134: 124-134 (2008).

[0289] Figure 8UUU-8YYY An example of a DDR1-targeting ligand is presented, where R is the linker point. For other examples and related ligands, see 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.The crystal structures PDB 3zos and 4bkj and their associated ligands are described in 426:2457 (2014); Kim, H. et al., “Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor”. ACS Chem.Biol The crystal structure PDB4ckr and related ligands described in .8:2145 (2013); Murray, CW et al., “Fragment-Based Discovery of Potent and Selective DDR1 / 2 Inhibitors”, ACS Med.Chem.Lett. The crystal structures PDB 5bvk, 5bvn, and 5bvw and their associated ligands described in 6: 798-803 (2015); Wang, Z. et al., “Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors”, J. Med. Chem. The crystal structure PDB5fdp and its associated ligands described in 59: 5911-5916 (2016); and the crystal structure PDB5fdx and its associated ligands described in Bartual, SG et al., “Structure of DDR1 receptor tyrosine kinasein complex with D2164 inhibitor at 2.65 Angstroms resolution” (to be published).

[0290] Figure 8ZZZ-XXXX Examples of EPHA2-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”. ACS Chem. BiolThe crystal structures PDB 5i9x, 5i9y, 5ia0, and 5ia1 and their associated ligands described in 11:3400-3411 (2016); Heinzlmeir, S. et al., “Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with danusertib (PHA739358)”. ACS Chem Biol The crystal structure PDB 5i9z and related ligands described in 11 3400-3411 (2016); and Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem. Biol. The crystal structures PDB 5ia2, 5ia3, 5ia4 and 5ia5 and their associated ligands are described in 11: 3400-3411 (2016).

[0291] Figure 8DDDD-8FFFF Examples of EPHA3-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Zhao, H. et al., “Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics”. ACS Med. Chem. Lett. The crystal structure PDB 4g2f and related ligands described in 3: 834-838 (2012); 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.The crystal structures PDB 4gk2 and 4gk3 and their associated ligands are described in 56: 84-96 (2013); 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. The crystal structure PDB 4gk3 and its associated ligands described in 56: 84-96 (2013); Unzue, A. et al., “Pyrrolo[3,2-b]quinoxaline Derivatives as Types I1 / 2 and IIEphTyrosine Kinase Inhibitors: Structure-Based Design, Synthesis, and in VivoValidation”, J. Med. Chem. Crystal structures PDB 4p4c and 4p5q and associated ligands described in 57: 6834-6844 (2014); 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. The crystal structure PDB 4p5z and its associated ligands described in 57: 6834-6844 (2014); Dong, J. et al., “Structural Analysis of the Binding of Type I, I1 / 2, and II Inhibitors to Eph Tyrosine Kinases”. ACS Med.Chem.Lett The crystal structure PDB 4twn and related ligands described in . 6: 79-83 (2015); the crystal structure PDB 3dzq and related ligands described in Walker, JR “Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex with ALW-II-38-3” (to be published).

[0292] Figure 8GGGGAn example of an EPHA4-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Clifton, IJ et al., “The Crystal Structure of Isopenicillin NSynthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals Thioether Coordination to Iron”. Arch. Biochem. Biophys. The crystal structure PDB 2y60 and its associated ligands described in 516:103 (2011) and Van Linden, OP et al., “Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase”, Eur. J. Med. Chem. The crystal structure PDB 2xyu and its associated ligands are described in 47: 493 (2012).

[0293] Figure 8HHHH An example of an EPHA7 targeting ligand is presented, where R is the linker site. For other examples and related ligands, see the crystal structure PDB3dko and related ligands described in Walker, JR et al., “Kinase domain of human ephrin type-areceptor 7 (epha7) in complex with ALW-II-49-7” (forthcoming). Figure 8IIII-8LLLL Examples of EPHB4-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-Based Discovery and Optimisation of 3,5-BisSubstituted Anilinopyrimidines”. Bioorg. Med. Chem. Lett.The crystal structure PDB 2vx1 and related ligands described in 18:5717 (2008); Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 3: Identification of Non-Benzodioxole-Based Kinase Inhibitors”, Bioorg. Med. Chem. Lett. The crystal structure PDB2x9f and related ligands described in 20: 6242-6245 (2010); Barlaam, B. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 4: Discovery and Optimization of a Benzylic Alcohol Series”, Bioorg. Med. Chem. Lett. The crystal structure PDB 2xvd and its associated ligands described in 21:2207 (2011); Overman, RC et al., “Completing the Structural Family Portrait of the Human Ephb Tyrosine Kinase Domains”, Protein Sci. The crystal structure PDB 3zew and related ligands described in 23:627 (2014); Kim, MH et al., “The Design, Synthesis, and Biological Evaluation of Potent Receptor Tyrosine Kinase Inhibitors”, Bioorg. Med. Chem. Lett. The crystal structure PDB 4aw5 and its associated ligands described in 22:4979 (2012); Vasbinder, MM et al., “Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors”. J. Med. Chem.The crystal structure PDB 4bb4 and related ligands described in 56: 1996, (2013); 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. The crystal structures PDB 2vwu, 2vwv, and 2vww and their associated ligands described in 18: 2776-2780 (2008); Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-Based Discovery and Optimisation of 3,5-BisSubstituted Anilinopyrimidines”. Bioorg. Med. Chem. Lett. The crystal structures PDB 2vwx, 2vwy, and 2vwz and their associated ligands described in 18: 5717 (2008); and Welin, M. et al., “Substrate Specificity and Oligomerization of Human Gmp Synthetas”. J. Mol. Biol. The crystal structure PDB 2vxo and its associated ligands are described in 425: 4323 (2013).

[0294] Figure 8MMMM Examples of ERBB2-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Aertgeerts, K. et al., “Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein”. J. Biol. ChemThe crystal structure and associated ligands described in . 286: 18756-18765 (2011) and Ishikawa, T. et al., “Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2) / Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing aPyrrolo[3,2-d]pyrimidine Scaffold” J. Med. Chem. The crystal structure and related ligands described in 54: 8030-8050 (2011).

[0295] Figure 8NNNN Examples of ERBB3-targeting ligands are presented, where R is the linker site. For other 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).

[0296] Figure 8OOOO Examples of ERBB4-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Qiu, C. et al., “Mechanism of Activation and Inhibition of the HER4 / ErbB4 Kinase”. Structure 16: 460-467 (2008) and Wood, ER et al. "6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines astunable covalent modifiers of ErbB kinases", Proc. Natl. Acad. Sci. Usa 105:2773-2778 (2008).

[0297] Figure 8PPPP-8QQQQExamples of FES-targeting ligands are presented, where R is the linker point. For other 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).

[0298] Figure 8RRRR Examples of FYN-targeting ligands are presented, where R is the linker site. For other 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).

[0299] Figure 8SSSS-8VVVV Examples of GSG2 (Haspin) targeting ligands are presented, where R is the linker site. For other examples and related ligands, see the crystal structures PDB3e7v, PDB3f2n, 3fmd and related ligands described in Filippakopoulos, P. et al., “Crystal Structure of Human Haspin with a pyrazolo-pyrimidine ligand” (forthcoming); and Eswaran, J. et al., “Structure and functional characterization of the atypical human kinase haspin”. Proc. Natl. Acad. Sci. USA The crystal structure PDB 3iq7 and its associated ligands described in 106: 20198-20203 (2009); and Chaikudad, A. et al., “A unique inhibitor binding site in ERK1 / 2 is associated with slow bindingkinetics”. Nat. Chem. Biol.The crystal structure of PDB 4qtc and its associated ligands are described in 10: 853-860 (2014).

[0300] Figure 8WWWW-8AAAAA An example of an HCK-targeting ligand is presented, where R is the linker site. For other examples and related ligands, see Schindler, T. et al., “Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor”. Mol. Cell The crystal structure PDB 1qcf and related ligands described in 3: 639-648 (1999); 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. The crystal structures PDB 2c0i and 2c0t and their associated ligands are described in 16:118 (2006); Sabat, M. et al., “The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck)”. Bioorg. Med. Chem. Lett. The crystal structure PDB 2hk5 and its associated ligands are described in 16: 5973-5977 (2006); Saito, Y. et al., “A Pyrrolo-Pyrimidine Derivative Targets Human Primary AMLStem Cells in Vivo”. Sci Transl Med 5: The crystal structures PDB 3vry, 3vs3, 3vs6 and 3vs7 and their associated ligands described in 181ra52-181ra52 (2013); and Parker, LJ et al., “Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002”. Acta Crystallogr.,Sect.D The crystal structure PDB 4lud and its associated ligands are described in 70: 392-404 (2014).

[0301] Figure 8BBBBB-8FFFFF Examples of IGF1R targeting ligands are presented, where R is the linker site. For other examples and related ligands, see 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. The crystal structure PDB 2oj9 and its associated ligands described in 17: 2317-2321 (2007); Wittman, MD et al., “Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.” J. Med. Chem. The crystal structure PDB 3i81 and related ligands described in 52: 7360-7363 (2009); Sampognaro, AJ et al., “Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase”. Bioorg. Med. Chem. Lett. The crystal structure PDB 3nw5 and its associated ligands described in 20: 5027-5030 (2010); Buchanan, JL et al., “Discovery of 2,4-bis-arylamino-1,3-pyrimidines asinsulin-like growth factor-1 receptor (IGF-1R) inhibitors”. Bioorg. Med. Chem. Lett.The crystal structure PDB 3qqu and related ligands described in 21: 2394-2399 (2011); Kettle, JG et al., “Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a Mek Resistance Hypothesis”. J. Med. Chem. The crystal structure PDB 4d2r and related ligands described in 58: 2834 (2015); 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. The crystal structure PDB 3fxq and related ligands described in 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” (forthcoming); and Mayer, SC et al., “Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment”. Bioorg. Med. Chem. Lett. The crystal structure PDB 2zm3 and its associated ligands described in 18: 3641-3645 (2008); "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.The crystal structure PDB 3f5p and related ligands described in 19:62-66 (2009); Nemecek, C. et al., “Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles” Chem. Biol. Drug Des. The crystal structure PDB 3lvp and related ligands described in 76: 100-106 (2010); 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. The crystal structure PDB 3o23 and its associated ligands described in 21: 2224-2228 (2011); Wu, J. et al., “Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor”, Embo J. 27: The crystal structure PDB 3d94 and related ligands described in 1985–1994 (2008); and 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. The crystal structure PDB 5hzn and its associated ligands are described in 26: 2065-2067 (2016).

[0302] Figure 8GGGGG-8JJJJJ Examples of INSR-targeting ligands are presented, where R is the linker site. For other examples and related ligands, see Katayama, N. et al., “Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors”. ProteinsThe crystal structure PDB 2z8c and its associated ligands are described in 73: 795-801 (2008); Chamberlain, SD et al., “Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase”, (2009). Bioorg. Med. Chem. Lett The crystal structure PDB 3ekk and related ligands described in . 19: 469-473; Chamberlain, SD et al., “Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosinekinase inhibitors towards JNK selectivity”, Bioorg. Med. Chem. Lett The crystal structure PDB 3ekn and its associated ligands described in . 19: 360-364 (2009); Sanderson, MP et al., “BI 885578, a novel IGF1R / INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis”. Mol. Cancer Ther. The crystal structure PDB 5e1s and related ligands described in 14: 2762-2772, (2015); Patnaik, S. et al., “Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines aspotent inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase”, Bioorg. Med. Chem. Lett.The crystal structure PDB 3eta and related ligands described in 19: 3136-3140 (2009); Stauffer, F. et al., “Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1Rinhibitors”, Bioorg. Med. Chem. Lett The crystal structure PDB5hhw and its associated ligands described in . 26: 2065-2067 (2016); and Anastassiadis, T. et al., “A highly selective dual insulin receptor (IR) / insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor”. J. Biol. Chem. The crystal structure PDB 4ibm and its associated ligands are described in 288: 28068-28077 (2013).

[0303] Figure 8 KKKKK-8PPPPP Examples of HBV-targeting ligands are presented, where R is the linker site, Y is methyl or isopropyl, and X is N or C. For other 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 ofnucleocapsids.” Science , 299, 893-896 (2003); Stray, SJ; Zlotnick, A. “BAY41-4109 has multiple effects on Hepatitis B virus capsid assembly.” J. Mol.Recognit. 19, 542-548 (2006); Stray, S. J. et al., "Heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly." Proc. Natl. Acad. Sci. U. S. A. , 102, 8138-8143 (2005); Guan, H. et al., "The novel compound Z060228 inhibits assembly of the HBV capsid." Life Sci. 133, 1-7 (2015); Wang, X. Y. et al., "In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations." Antiviral Ther. 17, 793-803 (2012); Klumpp, K. et al., "High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein." 112, 15196-15201 (2015); Qiu, Z. et al., "Design and synthesis of orally bioavailable 4-methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors." J. Med. Chem. 59, 7651-7666 (2016); Zhu, X. et al., "2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly." Bioorg. Med. Chem. Lett.20, 299-301 (2010); Campagna, MR, et al. “Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J. Virol. 87, 6931-6942 (2013); Campagna, MR, et al. “Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids.” J. Virol. 87, 6931-6942 (2013); WO 2013096744A1, titled "Hepatitis B antivial agents"; WO 2015138895, titled "Hepatitis B coreprotein allosteric modulators"; Wang, YJ et al., "A novel pyridazinonederivative inhibits hepatitis B virus replication by inducing genome-free capsid formation." Antimicrob. Agents Chemother. 59, 7061-7072 (2015); WO2014033167, entitled "Fused bicyclic sulfamoyl derivatives for the treatment of hepatitis"; US 20150132258, entitled "Azepane derivatives and methods of treating hepatitis B infections"; and WO 2015057945 "Hepatitis B viral assemblyeffector".

[0304] Figure 9 This is a dendrogram of the human bromine domain family of proteins organized into eight subfamilies, which relates to epigenetic signaling and chromatin biology. (Optional) Figure 9 Any protein of the bromine domain family may be used as a target protein according to the present invention. Detailed Implementation

[0305] I. Definition 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 pertains.

[0306] The compounds in any of the formulas described herein may be in the form of racemic mixtures, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, or isomers; for example, rotational isomers, as each is explicitly described unless explicitly excluded by the context.

[0307] The terms “a” and “an” do not indicate a limitation of quantity, but rather the presence of at least one of the mentioned items. The term “or” means “and / or”. Unless otherwise stated herein, the description of the range of values ​​is intended only as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were described individually herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise stated herein or where the context clearly contradicts, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., “such”) is intended only to better illustrate the invention and not to limit the scope of the invention.

[0308] This invention comprises compounds of formulas I, II, III, and IV having at least one desired atomic isotope substitution in amounts higher than the natural abundance of that isotope, i.e., enriched. An isotope is an atom having the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. Examples of isotopes that can be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, as follows: 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. In one non-limiting embodiment, the isotope-labeled compound can be used for metabolic studies (using, for example...) 14 C) Reaction kinetics studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or used in patient radiotherapy. Specifically,18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, through the procedures disclosed in the scheme or examples and the preparation described below.

[0309] Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched by 90, 95, or 99% or more at any site of interest. In a non-limiting embodiment, deuterium is enriched by 90, 95, or 99% at the desired site.

[0310] In one non-limiting embodiment, the substituted hydrogen atom may be provided as a deuterium atom in any compound of Formula I, II, III, IV, V, or VI. In one non-limiting embodiment, the substitution of the hydrogen atom for a deuterium atom occurs within one or more groups selected from any of the variables, linkers, and targeting ligands described herein. For example, when any group is or contains (e.g., by substitution) a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD...). 3、 (CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

[0311] The compounds of the present invention can form solvates with solvents, including water. Therefore, in one non-limiting embodiment, the present invention includes the solvated form 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 comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotopically substituted (e.g., D2O, d6-acetone, d6-DMSO). Solvates may be in liquid or solid form.

[0312] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is a carbon atom linked through a carbonyl (C=O) group.

[0313] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein refer to alkyl groups having each member of the range described as independent species. For example, the term C1-C6 alkyl as used herein refers to straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that each of these is described as an independent species, and thus each subset is considered to be disclosed separately. For example, the term C1-C4 alkyl as used herein refers to straight-chain or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and is intended to mean that each of these is described as an independent species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group may optionally be substituted. The term "alkyl" also includes cycloalkyl or carbocyclic groups. For example, when the term includes "alkane," "cycloalkyl" or "carbocyclic" may be considered as part of the definition unless explicitly excluded by the context. For example, but not limited to, the terms alkyl, alkoxy, haloalkyl, etc., may be considered to include cyclic forms of alkyl groups unless explicitly excluded by the context.

[0314] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may be present along the chain's stability point. The specified range used herein refers to alkenyl groups having each member of the range described as a separate class, as described above with respect to the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl geometries, or "E" and "Z" alkenyl geometries. In an alternative embodiment, the alkenyl group is optionally substituted. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one unsaturation point.

[0315] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can be present along any stable point of the chain. The specified range used herein refers to an alkynyl group having each member of the range described as an independent class, as described above with respect to the alkyl portion. Examples of alkynyl groups 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 an alternative embodiment, the alkynyl group is optionally substituted. The term "alkynyl" also includes a cycloalkyl or carbocyclic group having at least one triple bond.

[0316] "alkylene" is a divalent saturated hydrocarbon. For example, an alkylene can be a portion with 1, 2, 3, 4, 5, 6, 7 to 8 carbons, a portion with 1 to 6 carbons, 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.

[0317] "Alkenyl" is a divalent hydrocarbon having at least one carbon-carbon double bond. For example, an alkenyl can be a portion with 2 to 8 carbons, a portion with 2 to 6 carbons, or a specified number of carbon atoms, such as a C2-C4 alkenyl.

[0318] "Imyynyl" is a divalent hydrocarbon having at least one carbon-carbon triple bond. For example, an ynylyl group can be a moiety with 2 to 8 carbons, a moiety with 2 to 6 carbons, or a specified number of carbon atoms, such as a C2-C4 ynylyl group.

[0319] "Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0320] "Halogenated alkyl" is a branched or straight-chain alkyl group that is substituted with one or more of the aforementioned halogen atoms, up to a maximum permissible number of halogen atoms. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Hyperhalogenated 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.

[0321] The term "chain" means that all other chains (long or short, or both) can be considered as straight chains attached to its upper side. When two or more chains can be considered as the main chain, "chain" refers to the chain that results in the simplest representation of the molecule.

[0322] "Haloalkoxy" refers to a haloalkyl group as defined herein, which is connected by an oxygen bridge (the oxygen in the alcohol group).

[0323] "Heterocyclic alkyl" is an alkyl group as defined herein that has been substituted with a heterocyclic group as defined herein.

[0324] "Arylalkyl" is an alkyl group as defined herein that has been substituted with an aryl group.

[0325] "Heteroarylalkyl" is an alkyl group as defined herein that has been substituted with a heteroaryl group as defined herein.

[0326] As used in this article, "aryl" refers to a system with an aromatic ring system ("C"). 6–14 A monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) provided in the aryl group, having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C…”). 10 Aryl; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein a linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The one or more fused carbocyclic or heterocyclic groups may be 4 to 7 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 a non-limiting embodiment, the aryl group is a side group. An example of a side group ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In some embodiments, the aryl group is an unsubstituted C 6–14 Aryl. In some embodiments, the aryl group is a substituted C. 6–14 Aryl group. The aryl group may optionally be substituted with one or more functional groups, including but not limited to halogen, hydroxyl, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclic groups.

[0327] The term "heterocyclic group" (or "heterocycle") includes saturated and partially saturated cyclic groups containing heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur, and oxygen. Heterocyclic rings comprise 3- to 8-membered monocyclic rings and 5- to 16-membered bicyclic ring systems (which may include bridged fused and spirofused bicyclic ring systems). It does not include rings containing -OO-, -OS-, or -SS- motifs. The "heterocyclic group" may optionally be substituted, for example, with 1, 2, 3, 4, or more substituents, including but not limited to hydroxyl, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino groups. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heterocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolyl, imidazoalkyl, piperidinyl, pyrrololinyl, piperazineyl]; saturated 3- to 6-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazoalkyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiopheneyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazoyl, piperidinyl, pyrrololinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazoyl, dihydrothiopheneyl, 2,3-dihydro-benzo[1,4]dioxyl, indololinyl, isoyindololinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, isobenzodihydropyranyl, benzodihydropyranyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-iso... Quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl.

[0328] Heterocyclic groups also include groups in which the heterocyclic group is fused / condensed with an aryl or heteroaryl group: for example, unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms (e.g., indoline, isoindoline), unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated, and unsaturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0329] The term "heteroaryl" refers to an aryl ring system containing one or more heteroatoms selected from O, N, and S, wherein the cyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrroloyl, 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- to 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; and unsaturated 5- to 6-membered heteromonocyclic groups containing sulfur atoms. For example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic 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- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

[0330] The term "optionally substituted" means that the groups in this document are moiety-substituted, including but not limited to C1-C1 groups. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, C1–C 12 Heterocyclic alkyl, C3-C 12 Heterocyclic alkenyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1-C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonamide, arylsulfonamide, C1-C 10 Alkylimino, arylimino, C1-C 10 Alkylsulfonylimide, arylsulfonylimide, hydroxyl, halogen, thio, C1-C 10 Alkylthio, Arylthio, C1-C 10 Alkyl sulfonyl, aryl sulfonyl, acylamino, aminoacyl, aminothioacyl, amido, guanidinyl, urea, cyano, nitro, azide, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid esters.

[0331] In an alternative embodiment, any suitable group may be present at a “substituted” or “optionally substituted” position if it is shown that a stable molecule is formed and the desired purpose of the invention is satisfied, and includes, but is not limited to, halogens (which may independently be F, Cl, Br, or I); cyano; hydroxyl; nitro; azide; alkanoyl (such as C2-C6 alkanoyl); formamide; 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); having, for example, 1 to 3 independent Arylalkyl groups having 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy groups having 1 to 3 separate or fused rings, with benzyloxy being an exemplary arylalkoxy group; or saturated or partially unsaturated heterocycles having 1 to 3 separate or fused rings having one or more N, O or S atoms; or heteroaryl groups having 1 to 3 separate or fused rings having one or more N, O or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrroleyl, thiophenyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrroleyl. Such groups can be further substituted, for example, with hydroxyl, alkyl, alkoxy, halogen, and amino groups. In some 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 (heterocyclic), C1-C6 alkyl (heteroaryl), -C1-C6 alkyl (C3-C7 cycloalkyl), O-C1-C6 alkyl (C3-C7 cycloalkyl), B(OH)2, phosphate ester, phosphonate, and haloalkoxy (including C1-C6 haloalkoxy).

[0332] "Aliphatic group" refers to a saturated or unsaturated straight-chain, branched, or cyclic hydrocarbon. "Aliphatic group" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus each of these definitions is introduced. In one embodiment, "aliphatic group" is used to refer to those aliphatic groups having 1 to 20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be cis or trans configurations. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein represent aliphatic groups having each member of the range described as an independent class. For example, as used herein, the term C1-C6 aliphatic group refers to a straight-chain or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that each of these is described as a separate species. For example, as used herein, the term C1-C4 aliphatic group refers to a straight-chain or branched 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 replaced by one or more functional groups that result in the formation of a stable moiety.

[0333] The term "heteroaliphatic group" refers to an aliphatic group moiety containing at least one heteroatom in the chain, such as amine, carbonyl, carboxyl, oxo, thio, phosphate ester, phosphonate ester, nitrogen, phosphorus, silicon, or boron atoms replacing carbon atoms. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "Heteroaliphatic group" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloynyl moieties. In one embodiment, "heteroaliphatic group" is used to represent a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) 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 the heteroaliphatic portion are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolic acid, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0334] "Dosage form" refers to the unit of administration of an active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral preparations, sublingual preparations, topical preparations, gels, and mucosal preparations. "Dosage form" can also include implants, such as optical implants.

[0335] As used in this article, “effective amount” refers to the amount that provides therapeutic or preventative benefits.

[0336] As used in this article, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0337] As used herein, the term “exogenous” means any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0338] As used herein, the term "modulation" means mediating a detectable increase or decrease in response levels in a subject compared to response levels in subjects without treatment or the compound, and / or compared to response levels in otherwise identical but untreated subjects. This term includes disrupting and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in the subject (preferred).

[0339] "Parenteral" administration of the immunogenic composition includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion techniques.

[0340] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can comprise a protein or peptide sequence. A polypeptide includes any peptide or protein comprising two or more amino acids linked together by peptide bonds. As used herein, the term refers to short chains, which are generally also referred to in the art, for example, as peptides, oligopeptides, and oligomers; and longer chains, which are generally referred to in the art, as proteins, which have many types. “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, etc. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0341] "Treatment" of disease, as used in this article, means reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by the subject.

[0342] Scope: Throughout this disclosure, various aspects of the invention may be presented in a scope format. It should be understood that the scope format description is merely for convenience and should not be construed as limiting the scope of the invention. It should be assumed that the scope description specifically discloses all possible sub-scopes and individual numerical values ​​within those scopes. For example, it should be assumed that a description of a scope such as 1 to 6 specifically discloses sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numerical values ​​within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the scope width.

[0343] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent and at least one other substance such as a carrier. A “pharmaceutical combination” is a combination of at least two active agents, which may be combined in a single dosage form or provided together in separate dosage forms, and has a description of the use of the active agents together to treat any of the conditions described herein.

[0344] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compound, wherein the parent compound is modified by preparation of its inorganic and organic, non-toxic, acidic or basic addition salt. Salts of the compounds of the present invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, where feasible, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Salts of the compounds of the present invention also include the compound and a solvate of the compound salt.

[0345] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues such as amines; basic salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric 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... Remington's Pharmaceutical Sciences, Found in the 17th edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0346] The term "carrier" used in pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient, or medium provided together with the active compound.

[0347] "Pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition / combination that is generally safe and non-toxic and is not biologically or otherwise unsuitable for administration to a host (typically a human). In one embodiment, a veterinary acceptable excipient is used.

[0348] "Patient," "host," or "subject" refers to a human or non-human animal that requires treatment or prevention of any condition as explicitly described herein (e.g., a condition that produces a therapeutic effect through regulation by a natural (wild-type) or modified (non-wild-type) protein that can be degraded according to the present invention). Typically, the host is a human. Alternatively, "host" may also refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0349] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the amount that effectively provides therapeutic benefits, such as improvement of symptoms or reduction or decrease of the disease itself, when administered to a host.

[0350] II.Compounds In one aspect of the invention, compounds of formula I or formula II are provided: (I) or (II) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition; in: The variables are as defined above, wherein in some embodiments, the compound has at least one of the following: a, b, c, d, e, f, g, h, i, j, k, l, or m: a. n is 1 or 2; b. R 1 R 2 R 3 Or R 4 At least one of them is an alkyl group; c. R 1 and R 2 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; d. R 3 and R 4 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; e. R 6 and R 7 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; f. R 8 and R 9 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; g. R 1 and R 3 Forming 1 or 2 carbon bridged rings; h. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; i. R 4 and R 13 Forming 1 or 2 carbon bridged rings; j. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; k. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2 l. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, or P(O)NH2; or m. X is O or S.

[0351] Non-limiting examples of compounds of formula I include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0352] Further non-limiting examples of compounds of formula I include: , , ,and .

[0353] In one embodiment of the present invention, Selected from: , , , , , , ,and .

[0354] In another embodiment, the degradation determinant of formula I is selected from: , , , , , , , , , , , , , , , , , , , , , , , and .

[0355] In another embodiment, the degradation determinant of formula I is selected from: , , , , , , , , , , , , , , , , , , , , , , ,and .

[0356] In another embodiment, the degradation determinant of formula I is selected from: , , , , , , , , , , , , , , , ,and .

[0357] Non-limiting examples of compounds of formula II include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0358] In another aspect of the invention, compounds of formula III are provided: (III) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug, optionally in a pharmaceutically acceptable carrier to form its pharmaceutically acceptable composition; The variables mentioned therein are as defined in this document.

[0359] Non-limiting examples of compounds of formula III include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0360] Other non-limiting examples of compounds of formula III include: , , , , ,and .

[0361] In another aspect of the invention, compounds of formula IV or V are provided: (IV) or (V) Or pharmaceutically acceptable salts, N-oxides, isotope derivatives, prodrugs, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition; in: The variables are defined above, and in some implementations, it is required that a, b, c, d, e, f, g, h, i, or j are: a. R 1 and R 2Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; b. R 3 and R 4 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; c. R 6 and R 7 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; d. R 8 and R 9 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; e. R 1 and R 3 Forming 1 or 2 carbon bridged rings; f. R 1 and R 13 Forming 3, 4, 5, or 6-membered fused rings; g. R 4 and R 13 Forming 1 or 2 carbon bridged rings; h. A is P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH or P(O)NH2; i. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, or P(O)NH2; or j. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

[0362] Non-limiting examples of compounds of formula IV include: , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0363] Other non-limiting examples of compounds of formula IV include: , , ,and .

[0364] In another embodiment, the degradation determinant of formula IV is selected from: , , , , , , , , , , , , , , , , , , , , , , , and .

[0365] In another embodiment, the degradation determinant of formula IV is selected from: , , , , , , , , , , , , , , , , , , , , , , ,and .

[0366] In another embodiment, the degradation determinant of formula IV is selected from: , , , , , , , , , , , , , , , ,and .

[0367] Non-limiting examples of compounds of formula V include: , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0368] In another aspect of the invention, compounds of formula VI are provided: (VI) Or pharmaceutically acceptable salts, N-oxides, isotope derivatives, prodrugs, optionally in a pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition; in: A is CR 8 R 9C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A' is CR 1 R 2 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A'' is CR 3 R 4 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; X is independently NH, NR 11 CH2, CHR 12 C(R) 12 2. O or S; n is 0, 1, 2, 3, 4 or 5; m is 1 or 3; Is it a single bond or a double bond? R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 and R 13 Independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, -NHalkyl, -Nalkyl2 Or R 1 and R 2 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 3 and R 4 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 6 and R 7 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 8 and R 9Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 1 and R 3 Forming 1 or 2 carbon bridged rings; Or R 1 and R 7 Forming 1 or 2 carbon bridged rings; Or R 3 and R 7 Forming 1 or 2 carbon bridged rings; Or R 13 and R 1 Forming 3, 4, 5, or 6 carbon fused rings; Or R 13 and R 4 Forming 1 or 2 carbon bridged rings; Or R 13 and R 5 Forming 3, 4, 5 or 6 carbon fused rings, where R 5 In R 13 On the α carbon, or a 1, 2, 3, or 4 carbon bridge ring, where R 5 Not in R 13 On the α-carbon; In a typical implementation, W 1 It is C=O; In another typical implementation, W 2 It is C=O; In another typical implementation, W 1 and W 2 Both are C=O and X is NH; R 5 In each case, it is selected from: alkyl, olefin, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -NHalkyl, -N(alkyl)2, -NHSO2alkyl, -N(alkyl)SO2alkyl, -NHSO2aryl, -N(alkyl)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2kynyl, -N(alkyl)SO2kynyl and haloalkyl; Or two Rs 5 Substituents, together with the carbon atoms they are bonded to, can form 3, 4, 5, or 6-membered rings; Q 1 Q 2 Q 3 and Q 4 Independently selected from CH and CR 12 and N; Q 1 Q 2 Q 3 and Q4 No more than three of them are N; R 11 Independently selected from alkyl, alkenyl, alkynyl, C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl; R 12 Independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -NHalkyl, -N(alkyl)2, -NHSO2alkyl, -N(alkyl)SO2alkyl, -NHSO2aryl, -N(alkyl)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, cyano, nitro, nitroso, -SH, -Salkyl and haloalkyl; The requirement is that a, b, c, d, e, f, g, h, i, j, k, l, or m are: a. m is 3 and n is not 0; b. R 1 and R 2 Forming a spiral ring; c. R 3 and R 4 Forming a spiral ring; d. R 6 and R 7 Forming a spiral ring; e. R 8 and R 9 Forming a spiral ring; f. R 1 and R 3 Forming 1 or 2 carbon bridged rings; g. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; h. R 4 and R 13 Forming 1 or 2 carbon bridged rings; i. R 13 and R 5 Forming 3, 4, 5, or 6 carbon fused rings; j. R 13 and R 5 Forming 1 or 2 carbon bridged rings; k. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; l. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH, or P(O)NH2; or m. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

[0369] Non-limiting examples of compounds of formula VI include: , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , , , ,and .

[0370] Other non-limiting examples of compounds of formula VI include , , , , ,and .

[0371] In one implementation, the above formula Partially selected from: , , , , , , , , , , , , , , , , , , , , , , ,and .

[0372] In one embodiment, the linker is bonded to a heterocyclic degradation determinant and a targeting ligand, and the resulting molecule, 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 is itself pharmaceutically acceptable.

[0373] connector Linkers are included in the degradation determinants of formulas I, II, and III. A linker is a bond or chemically stable group that connects a degradation determinant to a target ligand.

[0374] Any linker described herein can be used in either direction, i.e., the left end connected to the degradation determinant and the right end connected to the target linker, or the left end connected to the target linker and the right end connected to the degradation determinant. According to the invention, any desired linker can be used, provided that 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 is itself pharmaceutically acceptable.

[0375] In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, wherein one or more carbon atoms may be replaced by heteroatoms such as O, N, S, or P. In some embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive atoms in the chain. For example, the chain may include one or more ethylene glycol units, which may be continuous, partially continuous, or discontinuous (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units). In some embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 consecutive chains, which may have branches, the branches of which may be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclic substituents.

[0376] In other embodiments, the linker may comprise one or more of ethylene glycol, propylene glycol, lactic acid, and / or glycolic acid, or consist thereof. Typically, propylene glycol increases hydrophobicity, while propylene glycol increases hydrophilicity. The lactic acid segment tends to have a longer half-life than the glycolic acid segment. Block and random lactic-co-glycolic acid 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 achieve the desired half-life and hydrophilicity. In some aspects, these units may be side-attached or dispersed with other moieties, such as aliphatic groups (including alkyl groups), heteroaliphatic groups, aryl groups, heteroaryl groups, heterocyclic groups, cycloalkyl groups, etc., as needed, to achieve suitable pharmaceutical properties.

[0377] In one embodiment, the connector is selected from the formulas LI, LII, LIII, LIV, LV, LVI, and LVII: (LI), in: X 1 and X 2 Independently selected from bonds, NH, NR 25 CH2, CHR 25 C(R) 25 2. O and S; R 20 R 21 R 22 R 23 and R 24Independently selected from bonds, alkyl groups, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR) 26 )-、-CH(-NHR 25 -CH(-NH2)-, -CH(-NR) 25 2) -、-C(-OR 26 )alkyl-,-C(-NHR 25 )alkyl-, -C(-NH2)alkyl-, -C(-NR 25 2) Alkyl-, -C(R) 4 R 4 )-, -alkyl (R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 -NHC(O)NH- -N(R) 25 )C(O)N(R 25 )-、-N(H)C(O)N(R 25 )-, polyethylene glycol, poly(lactic acid-co-glycolic acid), olefins, haloalkyl, alkoxy and alkynes; Or R 20 R 21 R 22 R 23 and R 24 In addition to those mentioned above, it can also be independently selected from heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocyclic, or -O-(CH2). 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O- or -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-, -NH-(CH2) 1-12-S-, (and wherein the 1-12 can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of the CH2 or NH can be modified by substituting H for methyl, ethyl, cyclopropyl, F (if on carbon), etc., as described herein), and optionally, heteroatoms, heteroalkyl, aryl, heteroaryl or cycloaliphatic groups are dispersed in the chain). Certain non-limiting examples include -O-CH(CH3)-CH(CH3)CH-O-, -O-CH2-CH(CH3)CH-O-, -O-CH(CH3)-CH2CH-O-, etc.

[0378] R 20 R 21 R 22 R 23 and R 24 Each of them is optionally selected from one or more of R 101 Substituents may be substituted, or alternatively as described in section 1. Definitions; R 25 In each case, it is selected from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, or alkynyl, or alternatively aliphatic, heteroaliphatic, aryl, heteroaryl, or heterocyclic. R 26 It is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin and alkyne; or in addition to these, it may be selected from aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic groups; R 27 and R 28 It is independently selected from hydrogen, alkyl, amine, or together with the carbon atoms to which they are attached, to form C(O), C(S), C=CH2, C3-C6 spirocarbocycles, or 4-, 5-, or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O, or to form one or two carbon-bridged rings; R 4 Independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, -NH (aliphatic group, including alkyl), -Nalkyl2; R 101 Each time it appears, it is independently selected from hydrogen, alkyl, olefin, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, heterocyclic alkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl)2, aliphatic group, heteroaliphatic group; and in addition to these, it may also be selected from aliphatic group and heteroaliphatic group.

[0379] In another embodiment, the connector is a portion selected from formulas LVIII, LIX, and LX: Each variable is defined as it is in equation LI. In alternative implementations of LVIII, LIX, and LX, a carbocyclic base ring is used instead of a heterocyclic ring.

[0380] The following are non-limiting examples of connectors that can be used in this invention. Based on this description, those skilled in the art will understand how to use all connectors that will achieve the objectives of this invention.

[0381] As some non-limiting examples, formulas LI, LII, LIII, LIV, LV, LVI, or LVII include: , , , , , , , , , , , , , , , , , , , , ,and .

[0382] In another implementation, the connector is selected from: In another implementation, the connector is selected from: , , , , , ,and .

[0383] In one implementation, X 1 Connected to the target ligand. In another implementation, X 2 Connect to the target ligand.

[0384] R20 R 21 R 22 R 23 and R 24 Some non-limiting examples include: , , , , , , , , , , , , , , , , ,and .

[0385] R 20 R 21 R 22 R 23 and R 24 Other non-limiting examples of the part include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0386] R 20 R 21 R 22 R23 and R 24 Other non-limiting examples of the part include: , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0387] R 20 R 21 R 22 R 23 and R 24 Other non-limiting examples of the part include: , , ,and .

[0388] R 20 R 21 R 22 R 23 and R 24 Other non-limiting examples of the part include: , , ,and .

[0389] In another embodiment, the linker group 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, or at least 10 ethylene glycol units, or an optionally substituted alkyl group, wherein optionally substituted O, N, S, P, or Si atoms are dispersed. In some embodiments, the linker is side-attached, substituted, or dispersed with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups. In some embodiments, the linker may be asymmetric or symmetric. In some embodiments, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, or between about 2 and 4 ethylene glycol units. In any embodiment of the compounds described herein, the linker group may be any suitable portion as described herein.

[0390] In another implementation, the connector is selected from: -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 -(heterocyclic alkyl)-,-NR 61 (CH2CH2O) n1 -(lower alkyl)-O-CH2-,-NR 61 (CH2CH2O) n1 -(heterocyclic alkyl)-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-,-NR 61 (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)-CH2,-NR 61 (CH2CH2) n1 -(heterocyclic)-(heterocyclic)-CH2, and -NR 61 -(heterocyclic)-CH2; where n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and R 61 It can be H, methyl, or ethyl.

[0391] In another implementation, the connector is selected from: -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-; where m1, n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5; and R 61 It can be H, methyl, or ethyl.

[0392] In another implementation, the connector is selected from: , , , , , , , , , , ; m1, n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.

[0393] In another implementation, the connector is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , In another implementation, the connector is selected from: , , , , , , , , , , , ,and .

[0394] In another implementation, the connector is selected from: , , , , , , , , , , , , , , , , , , , , , , , ， ， ， ， ， , ， ， ， , ， ， ， ， , ， ， , ， ， ， ， ， ， ， ， , ， ， ， ， , ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , ， ， ， ， ， ， ， ， ， ， ， ， , ， ， ， ， ， , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Where R 71 It can be -O-, -NH, Nalkyl, heteroaliphatic, aliphatic, or -NMe.

[0395] In another implementation, the connector is selected from: , , , , , , , , , , , , , , , , , , ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , , , , , , , .

[0396] In another implementation, the connector is selected from: , , , , , , ,and .

[0397] In another implementation, the connector is selected from: , , , , , , , , , , ,and .

[0398] In another implementation, the connector is selected from: , , , , , , , , , , , , ,and .

[0399] In another implementation, the connector is selected from: , , , , , , , , , , , , , ,and .

[0400] In another implementation, the connector is selected from: , , , ,and .

[0401] In some implementations, the connector is selected from: , , , , , , , , .

[0402] In some implementations, the connector is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , .

[0403] In the above structure, represent and .

[0404] In some 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, fluorinated carbon, etc., for example as follows: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0405] In some implementations, the linker may be a nonlinear chain and may be or include an aliphatic, aromatic, or heteroaromatic cyclic portion.

[0406] In some embodiments, the linker may include continuous, partially continuous or discontinuous ethylene glycol unit groups, ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

[0407] In some embodiments, the linker may 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 yet another embodiment, the linker is a partially or fully fluorinated polyether. Non-limiting examples of fluorinated linkers include: , , , , , , , , , , , ,and .

[0408] In some implementations, when the targeting ligand binds to more than one protein (i.e., not entirely selective), selectivity can be enhanced by varying the linker length, where the ligand binds to some of its targets in different binding pockets, for example, deeper or shallower than others. Therefore, the length can be adjusted as needed.

[0409] In some embodiments, this application provides a degradation determinant-linker (DL) having the following structure: DLI, DLII, DLIII, DLIa, DLIIa, DLIIIa, DLIb, DLIIb, DLIIIb, DLIc, DLIIc, DLIIIc, DLId, DLIId, DLIIId, DLIe, DLIIe, DLIIIe, DLIf, DLIIf, DLIIIf, DLIg, DLIIg, DLIIIg, In an alternative embodiment, this application provides a degradation determinant-linker (DL) having the following structure: DLIh, DLIi, DLIj, DLIk, DLIl, DLIm, DLIn, DLIo, DLIp, DLIq, Each variable is as described in Equations I, II, III and I above, and; Targeted ligands pass through the area adjacent to X 2 of Covalently bonded to DL.

[0410] target protein Cellular homeostasis and normal cellular functions such as proliferation, differentiation, and cell death require the degradation of cellular proteins. When this system becomes dysfunctional or fails to recognize and reduce abnormal protein behavior in the body, disease states may arise in a host such as a human. As is known to those skilled in the art, as published in the literature and patent applications, and as presented in scientific reports, a wide range of proteins can cause, regulate, or amplify disease in the body.

[0411] Therefore, in one embodiment, the selected degradation determinant of the present invention can be administered in vivo to a host in need of it in an effective amount to degrade the selected protein mediating the disease to be treated. The selected target protein can regulate the disease in humans through mechanisms of action such as modification of biological pathways, pathogen signaling or signaling cascades or regulation of cell entry. In one embodiment, the target protein is a classically unmedicatable protein because it does not have a binding pocket or active site that can be inhibited or otherwise bound, and it cannot be readily allosterically controlled. In another embodiment, the target protein is a classically medicinal protein, but for therapeutic purposes, degradation of the protein is preferred over inhibition.

[0412] The target protein is recruited using a targeting ligand. Typically, the degradation determinant binds to the target protein non-covalently. In an alternative implementation, the target protein covalently binds to the degradation determinant in a manner that can be irreversible or reversible.

[0413] In one embodiment, the selected target protein is expressed by a gene that has undergone an amplification, translocation, deletion, or inversion event that causes or is caused by a medical condition. In some aspects, the selected target protein has been post-translational modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotonylation), N-linked glycosylation, amidation, hydroxylation, methylation and polymethylation, O-linked glycosylation, pyroglutamylation, myristylation, farnesylation, geranylgeranylation, ubiquitination, ubiquitin-like glycosylation, or sulfation that causes or is caused by a medical condition.

[0414] As contemplated herein, the present invention includes a degradation determinant having a targeting ligand that binds to a target protein of interest. The target protein is any amino acid sequence that can bind to the degradation determinant, thereby causing a beneficial therapeutic effect in vivo through degradation. In one embodiment, the target protein is a non-endogenous peptide, such as a peptide derived from a pathogen or toxin. In another embodiment, the target protein can be an endogenous protein that mediates a disease. Endogenous proteins can be in their normal or abnormal form. For example, the target protein can be a mutant protein found in cancer cells, or a protein in which partial or complete gain or loss of function is encoded by nucleotide polymorphisms. In some embodiments, the degradation determinant targets the abnormal form of the protein rather than its normal form. In another embodiment, the target protein can mediate inflammatory or immune conditions, including autoimmune diseases. In one embodiment, the target protein is a non-endogenous protein derived from a virus; as non-limiting examples, HIV, HBV, HCV, RSV, HPV, CMV, flaviviruses, plague viruses, coronaviruses, noroviridae, etc. In one embodiment, the target protein is a non-endogenous protein derived from bacteria, such as Gram-positive bacteria, Gram-negative bacteria, or other bacteria, and may be a drug-resistant form of bacteria. In one embodiment, the target protein is a non-endogenous protein derived from fungi. In one embodiment, the target protein is a non-endogenous protein derived from a prion. In one embodiment, the target protein is a protein derived from a eukaryotic pathogen, such as a protist, helminth, etc.

[0415] In one aspect, target proteins mediate chromatin structure and function. Target proteins can mediate epigenetic processes such as DNA methylation or covalent modification of histones. One example is histone deacetylases (HDAC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11). Alternatively, target proteins can be bromodomains, which are lysine acetylation readers (e.g., BRD1, 2, 3, 4, 5, 6, 7, 8, 9, and T). Figure 9 This is a tree diagram of proteins belonging to the bromine domain family, which may, for example, serve as target proteins according to the present invention.

[0416] Other non-limiting examples of target proteins are structural proteins, receptors, enzymes, cell surface proteins, proteins involved in apoptosis signaling, aromatases, helicases, mediators of metabolic processes (anabolism or catabolism), antioxidants, proteases, kinases, oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, enzyme regulators, signal transducers, structural molecules, binding activities (proteins, lipids, carbohydrates), cell movement proteins, membrane fusion proteins, cell communication mediators, regulators of biological processes, behavioral proteins, cell adhesion proteins, proteins involved in cell death, and proteins involved in transport (including protein transporter activity, nuclear transport, ion transporters, channel transporters, carrier activity, permeases, secretases or secretory mediators, electron transporters, chaperone regulators, nucleic acid binding, transcription regulators, extracellular tissue and biogenesis regulators, and translation regulators).

[0417] In one embodiment, the target protein is a regulator of a signaling cascade associated with a known disease state. In another embodiment, the target protein mediates the condition through a mechanism different from regulating the signaling cascade. As further described herein, any protein in a eukaryotic or microbial system (including viruses, bacteria, or fungi) is a target for proteasome degradation using the present invention. The target protein may be a eukaryotic protein, and in some embodiments, it is a human protein.

[0418] In one embodiment, the target proteins are RXR, DHFR, Hsp90, kinase, HDM2, MDM2, bromine-containing domain BET protein, HDAC, IDH1, Mcl-1, human lysine methyltransferase, nuclear hormone receptor, aryl hydrocarbon receptor (AHR), RAS, RAF, FLT, SMARC, KSR, NF2L, CTNB, CBLB, and BCL.

[0419] In one embodiment, the bromine-containing domain protein has histone acetyltransferase activity.

[0420] In one embodiment, the bromine-containing domain protein is BRD2, BRD3, BRD4, BRDT, or ASH1L.

[0421] In one implementation, the bromine-containing domain protein is a non-BET protein.

[0422] In one implementation, the non-BET protein is BRD7 or BRD9.

[0423] In one implementation, FLT is not FLT3. In one implementation, RAS is not RASK. In one implementation, RAF is not RAF1. In one implementation, SMARC is not SMARC2. In one implementation, KSR is not KSR1. In one implementation, NF2L is not NF2L2. In one implementation, CTNB is not CTNB1. In one implementation, BCL is not BCL6.

[0424] In one embodiment, the target protein is selected from: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[0425] In another embodiment, the target protein is not selected from: EGFR, FLT3, RAF1, SMRCA2, KSR1, NF2L2, CTNB1, CBLB, BCL6, and RASK.

[0426] In one implementation, 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.

[0427] In one implementation, the targeting ligand is not an EGFR ligand, FLT3 ligand, RAF1 ligand, SMRCA2 ligand, KSR1 ligand, NF2L2 ligand, CTNB1 ligand, CBLB ligand, BCL6 ligand, or RASK ligand.

[0428] This invention can be used to treat a variety of disease states and / or conditions, including those in which protein dysregulation and any disease state and / or condition in which the patient would benefit from protein degradation.

[0429] For example, a target protein known as a target of a human therapeutic agent can be selected, and when incorporated into the degradation determinant according to the invention, the therapeutic agent can be used as a targeting ligand. These include proteins that can be used to restore function in polygenic diseases, such as B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G proteins such as Gq, histamine receptor, 5-lipoxygenase, trypsin-like serine proteases, thymidylate synthase, purine nucleoside phosphorylase, trypanosome GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and analogues, HIV 1 protease, HIV 1. Integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channels, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channels, VCAM, VLA-4 integrase, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / MER / ERK pathway, interleukin-1 transferase, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycine ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transporter inhibitor, bile acid transporter inhibitor, 5α-reductase inhibitor, angiotensin-11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptides Y receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geraniol geraniol transferase, TrkA receptor for NGF, β-amyloid, tyrosine kinase Flk-IIKDR, porphyrin receptor, integrin receptor, Her-2 / neu, telomerase inhibitor, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. Further target proteins include acetyl-CoA carboxylase, adenylate succinate synthase, protoporphyrinogen oxidase, and enolpyruvate-shikimate-phosphate synthase.

[0430] In some embodiments, the target protein is derived from a kinase that the targeting ligand can bind to or bind to, including but not limited to tyrosine kinases (e.g., AATK, ABL, ABL2, ALK, AXL, BLK, BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, I LK, INSR, INSRR, IRAK4, ITK, JAK1, JAK2, JAK3, KDR, KIT, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MET, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA, PDGF RB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1 or ZAP70).

[0431] In some embodiments, the target protein is derived from a kinase that the targeting ligand can bind to or bind to, 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-β, TLK2, TSSK1, TSSK2, ULK1 or ULK2).

[0432] In some implementations, the target protein is derived from a kinase that the target ligand can bind to or bind to, including but not limited to cyclin-dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.

[0433] In some implementations, the target protein is derived from a kinase that the target ligand can bind to or bind to, including but not limited to leucine-rich repeat kinases (e.g., LRRK2).

[0434] In some embodiments, the target protein is derived from a kinase that the target ligand can bind to or bind to, including but not limited to lipid kinases (e.g., PIK3CA, PIK3CB) or sphingosine kinases (e.g., S1P).

[0435] In some embodiments, the target protein is derived from a bromine-containing BET protein that the targeting ligand can bind to or bind to, 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 some implementations, the bromine-containing domain BET protein is BRD4.

[0436] In some embodiments, the target protein is derived from nuclear proteins that the targeting ligand can bind to or bind to, including but not limited to BRD2, BRD3, BRD4, antennal foot homologous domain proteins, BRCA1, BRCA2, CCAAT-enhancing binding proteins, histones, polycomb family proteins, high-mobility group proteins, telomere-binding proteins, 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.

[0437] In one embodiment, the target protein is a protein or its precursor, variant (e.g., splice variant), mutant (e.g., substitution, deletion, replication, insertion, insertion / deletion, extension, etc.), homolog, chimera, polymorph, isotype, modified (e.g., post-translational modification via glycosylation, phosphorylation, proteolysis, etc.), or recombinant.

[0438] In some embodiments, the target protein is a member of the retinol X receptor (RXR) family, and the condition being treated is a neuropsychiatric or neurodegenerative disorder. In some embodiments, the target protein is a member of the retinol X receptor (RXR) family, and the condition being treated is schizophrenia.

[0439] In some embodiments, the target protein is dihydrofolate reductase (DHFR), and the condition being treated is cancer. In some embodiments, the target protein is dihydrofolate reductase (DHFR), and the condition being treated is caused by microorganisms.

[0440] In some implementations, the target protein is dihydrofolate reductase (BaDHFR) from Bacillus anthracis, and the condition being treated is anthrax.

[0441] In some implementations, the target protein is heat shock protein 90 (HSP90), and the condition being treated is cancer.

[0442] In some implementations, the target protein is a kinase or phosphatase, and the condition being treated is cancer.

[0443] In some implementations, the target protein is HDM2 and / or MDM2, and the condition being treated is cancer.

[0444] In some implementations, the target protein is a BET protein containing a bromine domain, and the condition being treated is cancer.

[0445] In some implementations, the target protein is a lysine methyltransferase, and the condition being treated is cancer.

[0446] In some implementations, the target protein belongs to the RAF family, and the condition being treated is cancer.

[0447] In some embodiments, the target protein belongs to the FKBP family, and the condition treated is an autoimmune disease. In some embodiments, the target protein belongs to the FKBP family, and the condition treated is organ rejection. In some embodiments, the target protein belongs to the FKBP family, and the compound is administered prophylactically to prevent organ failure.

[0448] In some implementations, the target protein is an androgen receptor, and the condition being treated is cancer.

[0449] In some implementations, the target protein is an estrogen receptor, and the condition being treated is cancer.

[0450] In some embodiments, the target protein is a viral protein, and the condition treated is a viral infection. In some embodiments, the target protein is a viral protein, and the condition treated is HIV, HPV, or HCV.

[0451] In some implementations, the target protein is the AP-1 or AP-2 transcription factor, and the condition being treated is cancer.

[0452] In some embodiments, the target protein is an HIV protease, and the condition treated is HIV infection. In some embodiments, the target protein is an HIV integrase, and the condition treated is HIV infection. In some embodiments, the target protein is an HCV protease, and the condition treated is HCV infection. In some embodiments, the treatment is preventative, and the target protein is a viral protein.

[0453] In some embodiments, the target protein is a member of the histone deacetylase (HDAC) family, and the condition is a neurodegenerative disease. In some embodiments, the target protein is a member of the histone deacetylase (HDAC) family, and the condition is Huntington's disease, Parkinson's disease, Kennedy's disease, amyotrophic lateral sclerosis (ALS), Rubinstein-Taybi syndrome, or stroke.

[0454] In some embodiments, the target protein, as mentioned herein, is named after the gene that expresses it. Those skilled in the art will recognize that when a gene is referred to as a target protein, the protein encoded by that gene is the target protein. For example, the ligand of the protein SMCA2 encoded by SMRCA2 is referred to as the SMRCA2 targeting ligand.

[0455] Figure 9 This is a dendrogram of the human bromine domain family of proteins organized into eight subfamilies, which relates to epigenetic signaling and chromatin biology. (Optional) Figure 9 Any protein of the bromine domain family may be used as a target protein according to the present invention.

[0456] Targeted ligands In some respects, the targeting ligand is a ligand that covalently or nonvalently binds to a target protein that has been selected for proteasomal degradation via a chosen degradation determinant. Figure 1A-8JJJJJ Targeting ligands for various proteins are described, where R is the linker site. While specific targeting ligands are illustrated in the figures, other ligands and examples can be found in the references cited in the figure summary or are generally known in the art.

[0457] In one implementation, a targeting ligand binds to an endogenous protein that has been selected for degradation as a means of achieving a therapeutic effect on the host. Illustrative targeting ligands include: RXR ligands, DHFR ligands, Hsp90 inhibitors, kinase inhibitors, HDM2 and MDM2 inhibitors, compounds targeting the bromine-containing human BET protein, HDAC inhibitors, MerTK ligands, IDH1 ligands, Mcl-1 ligands, SMRCA2 ligands, EGFR ligands, RAF ligands, cRAF ligands, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHR), etc. Targeting ligands are also considered to include their pharmaceutically acceptable salts, prodrugs, and isotope derivatives.

[0458] In some respects, the targeting ligand binds to a dehalogenase in a patient or subject or diagnostic assay, and is a haloalkane (preferably C1-C). 10The alkyl group is substituted with at least one halogen group, preferably a halogen group distal to the alkyl group (i.e., away from the linker). In other embodiments, the targeting ligand is a haloalkyl group, wherein the size range of said alkyl group is typically from about 1 or 2 carbons to about 12 carbons, typically from about 2 to 10 carbons, typically from about 3 carbons to about 8 carbons, and more typically from about 4 carbons to about 6 carbons. The haloalkyl group is typically linear (although branched alkyl groups may also be used) and is capped with at least one halogen group (preferably a single halogen group, typically a single chlorine group). The haloalkyl PT group used in this invention preferably has the chemical structure —(CH2). v - Halogen is indicated, where v is any integer from 2 to 12, typically from about 3 to about 8, and more typically from about 4 to about 6. The halogen can be any halogen, but is preferably Cl or Br, and more typically Cl.

[0459] In some embodiments, the targeting ligand is a retinoid X receptor (RXR) agonist or antagonist. Non-limiting examples include retinol, retinoic acid, besalodin, docosahexaenoic acid, WO 9929324, Canan Koch et al., in their publication entitled “Identification of the First Retinoid X Receptor Homodimer Antagonist” (J. Med. Chem. 1996, 39, 3229-3234), WO 9712853, EP 0947496A1, WO 2016002968, and compounds and their analogues.

[0460] In some implementations, the targeting ligand is a DHFR agonist or antagonist. Non-limiting examples include folic acid, methotrexate, 8,10-dideazatetrahydrofolate, compounds disclosed by Tian et al. (Chem. Biol. Drug Des. 2016, 87, 444-454) entitled "Synthesis, Antifolate and Anticancer Activities of N5-Substituted 8,10-Dideazatetrahydrofolate Analogues", compounds prepared by Kaur et al. (Biorg. Med. Chem. Lett. 2016, 26, 1936-1940) entitled "Rational Modification of the Lead Molecule: Enhancement in the Anticancer and Dihydrofolate Reductase Inhibitory Activity", WO 2016022890, and Zhang et al. (Int. J. Antimicrob. Agents 46, 174-182) entitled "New The compounds disclosed in "Small-Molecule Inhibitors of Dihydrofolate Reductase Inhibit Streptococcus Mutans", the modified trimethoprim analog developed by Singh et al. (J. Med. Chem. 2012, 55, 6381-6390) entitled "Mechanism Inspired Development of Rationally Designed Dihydrofolate Reductase Inhibitors as Anticancer Agents", WO20111153310 / and its analogs.

[0461] In some implementations, the targeting ligand is derived from estrogen, estrogen analogues, SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or another form of partial or complete estrogen antagonist or agonist. Examples are the partially anti-estrogens raloxifene and tamoxifen, and the fully anti-estrogens fulvestrant. Non-limiting examples of anti-estrogenic compounds are provided in WO 2014 / 19176, WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132 assigned to Astra Zeneca, and US 2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patents 9,078,871, 8,853,423 and 8,703,810, as well as US 2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205138. Other non-limiting examples of anti-estrogenic compounds include: SERMS such as aordrin, bardoxifen, broparestriol, chlorotrianisene, clomiphene citrate, cyclofennig, lasoxifene, olmexifen, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testosterone, anastrozole, exemestane, faldazole, formestan, and letrozole; and anti-gonadotropic hormones such as leuprorelin, cetrorexone, allylestradiol, chlormedrone acetate, cyproterone acetate, dimagestrol acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, norethindrone acetate, progesterone, and spironolactone.Other estrogen ligands that may be used according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US 2016 / 0175289, US 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO2006 / 078834; US 6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US ​​2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US5880137, WO 2012 / 048058 and WO 2007 / 087684.

[0462] In some implementations, the targeting ligand is Vallee et al. ( J. Med. Chem. 2011, 54 HSP90 inhibitors identified in the article "Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone" (7206-7219), including YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluorene-9-yl]-succinamide), Brough et al. (J. Med. Chem. 2008, 51 HSP90 inhibitors (modified) identified in the article titled "4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer" (pp. 196-218), including compound 2GJ (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide), HSP90 inhibitor geldemycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1](derivatively) or any derivative thereof (e.g. 17-alkylamino-17-demethoxygeldemycin (“17-AAG”) or 17-(2-dimethylaminoethyl)amino-17-demethoxygeldemycin (“17-DMAG”)), or Wright et al. ( Chem. Biol. 2004, 11 HSP90 inhibitors (modified) identified in the paper "Structure-Activity Relationships in Purine-Based Inhibitor Binding to Hsp90 Isoforms" (pp. 775-785), including the HSP90 inhibitor PU3, are mentioned. Other non-limiting examples of Hsp90-targeting ligands include SNX5422, currently in Phase I clinical trials, and Reddy et al. (pp. 775-785). Clin. Lymphoma Myeloma Leuk. 2013, 13 , 385-391), titled "Phase I Trial of the Hsp90 Inhibitor Pf-04929113 (Snx5422) in Adult Patients with Recurrent, Refractory Hematologic Malignancies", or NVP-AUY922, whose anticancer activity was described by Jensen et al. ( Breast Cancer Research : BCR 2008, 10An evaluation was conducted (R33-R33) entitled "Nvp-Auy922: ASmall Molecule Hsp90 Inhibitor with Potent Antitumor Activity in PreclinicalBreast Cancer Models".

[0463] In some implementations, the targeting ligand is Millan et al. ( J. Med. Chem. 2011, 54 The kinase inhibitors identified in the study, 7797-7814, entitled "Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease," include kinase inhibitors Y1W and Y1X, as described by Schenkel et al. ( , 7797-7814). J. Med. Chem. 2011, 54 The kinase inhibitors identified in the study, 8440-8450, entitled "Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors," include compounds 6TP and OTP, as described by van Eis et al. ( ). Biorg. Med. Chem. Lett. 2011, 21 The kinase inhibitors identified in the paper "2,6-Naphthyridines as Potent and Selective Inhibitors of the Novel Protein Kinase C Isozymes" (7367-7372) include kinase inhibitors O7U and YCF, as described by Lountos et al. J. Struct. Biol. 2011, 176The kinase inhibitors identified in the article 292-301, entitled "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", include kinase inhibitors XK9 and NXP, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib, Gleevec, pazopanib, AT-9283, TAE684, nilotanib, NVP-BSK805, crizotinib, JNJ FMS, foretinib, OSI-027, OSI-930, or OSI-906.

[0464] In some implementations, the targeting ligand is Vassilev et al. ( Science 2004, 303 , 844-848), titled "In Vivo Activation of the P53 Pathway by Small-Molecule Antagonists of Mdm2" and Schneekloth et al. ( Bioorg. Med. Chem. Lett. 2008, 18 The HDM2 / MDM2 inhibitors identified in the paper titled "Targeted Intracellular Protein Degradation Induced by a Small Molecule: EnRoute to Chemical Proteomics" (5904-5908) include compounds nutlin-3, nutlin-2, and nutlin-1.

[0465] In some implementations, the targeting ligand is Filippakopoulos et al. ( Nature 2010, 468 Human BET bromodomain-targeting ligands identified in the study, 1067-1073, entitled "Selective Inhibition of Bet Bromodomains," include, for example, JQ1; Nicodeme et al. ( Nature 2010, 468 , 1119-1123), titled "Suppression of Inflammation by a Synthetic Histone Mimic"; Chung et al. ( J. Med. Chem. 2011, 54The ligands identified in the paper "Discovery and Characterization of Small Molecule Inhibitors of the Bet Family Bromodomains" (3827-3838); Hewings et al. ( J. Med. Chem. 2011, 54 Compounds disclosed in ,6761-6770, entitled "3,5-Dimethylisoxazoles Act as Acetyl-Lysine-MimeticBromodomain Ligands"; Dawson et al. ( Nature 2011, 478 The ligand identified in patent application 529-533, entitled "Inhibition of Bet Recruitment to Chromatin as an Effective Treatment for MLL-Fusion Leukaemia"; or the ligand identified in the following patent applications: US 2015 / 0256700, US 2015 / 0148342, WO 2015 / 074064, WO 2015 / 067770, WO 2015 / 022332, WO 2015 / 015318 and WO 2015 / 011084.

[0466] In some implementations, the targeting ligand is Finnin et al. ( Nature 1999, 401 The HDAC targeting ligand identified in the article titled "Structures of a Histone Deacetylase Homologue Bound to the Tsa and SahaInhibitors" (188-193) or the ligand of formula (I) identified in PCT WO0222577.

[0467] In some implementations, the targeting ligand is Chang et al. ( Nat Struct Mol Biol 2009, 16 The human lysine methyltransferase ligand identified in the paper titled "Structural Basis for G9a-Like Protein Lysine Methyltransferase Inhibition by Bix-01294" (pp. 312-317), by Liu et al. J Med Chem 2009, 52The ligands identified in the article "Discovery of a 2,4-Diamino-7-Aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a", 7950-7953, azacitidine, decitabine, or analogues thereof.

[0468] In some embodiments, the targeting ligand is an angiogenesis inhibitor. Non-limiting examples of angiogenesis inhibitors include GA-1, estradiol, testosterone, ovasin, nicotinic acid, and analogues thereof.

[0469] In some embodiments, the targeting ligand is an immunosuppressive compound. Non-limiting examples of immunosuppressive compounds include: AP21998, hydrocortisone, prednisone, prednisolone, methylprednisolone, beclomethasone dipropionate, methotrexate, cyclosporine, tacrolimus, actinomycin, and analogues thereof.

[0470] In some embodiments, the targeting ligand is an aryl hydrocarbon receptor (AHR) ligand. Non-limiting examples of AHR ligands include apigenin, SR1, LGC006, and analogues thereof.

[0471] In some implementations, the targeting ligand is MerTK or Mer-targeting ligand. Non-limiting examples of MerTK-targeting ligands are included in WO2013 / 177168 and WO2014 / 085225, both entitled “Pyrimidine Compounds for the Treatment of Cancer”, filed by Wang et al.

[0472] In some embodiments, the targeting ligand is an EGFR ligand. In some embodiments, the targeting ligand is an EGRF ligand selected from afatinib, dacomitinib, neratinib, poziotinib, and canatinib, or derivatives thereof.

[0473] In some embodiments, the targeting ligand is an FLT3 ligand. In some embodiments, the targeting ligand is an FLT3 ligand selected from tandotinib, letatinib, sorafenib, midotutolin, quezatinib, and crenolanib.

[0474] In some embodiments, the targeting ligand is a RAF inhibitor. In some embodiments, the targeting ligand is a RAF inhibitor selected from dabrafenib, regorafenib, and vemurafenib. In some embodiments, the targeting ligand is a cRAF inhibitor.

[0475] In some embodiments, the targeting ligand is the Ubc9 SUMO E2 ligase 5F6D targeting ligand, including but not limited to those described in “Insights Into the Allosteric Inhibition of the SUMO E2 Enzyme Ubc9.” Hewitt, WM, et al. (2016) Angew. Chem. Int. Ed. Engl. 55: 5703-5707.

[0476] In another embodiment, the targeting ligand is a Tank1 targeting ligand, which includes, but is not limited to, those described in “Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939.” Kirby, CA, Cheung, A., Fazal, A., Shultz, MD, Stams, T, (2012) Acta Crystallogr., Sect. F 68: 115-118; and “Structure-Efficiency Relationship of [1,2,4]Triazol-3-ylamines as Novel Nicotinamide Isosteres that Inhibit Tankyrases.” Shultz, MD et al. (2013) J. Med. Chem. 56: 7049-7059.

[0477] In another embodiment, the targeting ligand is an SH2 domain targeting ligand of pp60 Src, including but not limited to those described in “Requirements for Specific Binding of Low Affinity Inhibitor Fragments to the SH2 Domain of pp60Src Are Identical to Those for High Affinity Binding of Full Length Inhibitors,” Gudrun Lange et al., J. Med. Chem. 2003, 46, 5184-5195.

[0478] In another embodiment, the targeting ligand is a Sec7 domain targeting ligand, including but not limited to those described in “The Lysosomal Protein Saposin B Binds Chloroquine,” Huta, BP et al. (2016) Chemmedchem 11: 277.

[0479] In another embodiment, the targeting ligand is an activator protein-B targeting ligand, including but not limited to those described in “The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding” I. Nemcovicova and DM Zajonc ActaCryst. (2014). D70, 851-862.

[0480] In another embodiment, the targeting ligand is a protein S100-A7 2OWS targeting ligand, including but not limited to those described in “2WOS STRUCTURE OF HUMAN S100A7 IN COMPLEX WITH 2,6 ANS” DOI: 10.2210 / pdb2wos / pdb; and “Identification and Characterization of Binding Sites on S100A7, a Participant in Cancer and Inflammation Pathways.” Leon, R., Murray et al. (2009) Biochemistry 48: 10591-10600.

[0481] In another embodiment, the targeting ligand is a phospholipase A2 targeting ligand, including but not limited to those described in “Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2”, Schevitz, RW et al., Nat. Struct. Biol. 1995, 2, 458-465.

[0482] In another embodiment, the targeting ligand is a PHIP targeting ligand, including but not limited to those described in “A Poised Fragment Library Enables Rapid Synthetic Expansion Yielding the First Reported Inhibitors of PHIP(2), an Atypical Bromodomain” Krojer, T.; et al. Chem. Sci. 2016, 7, 2322–2330.

[0483] In another implementation, the targeting ligand is a PDZ targeting ligand, including but not limited to those described in “Discovery of Low-Molecular-Weight Ligands for the AF6 PDZ Domain”, Mangesh Joshi et al., Angew. Chem. Int. Ed. 2006, 45, 3790-3795.

[0484] In another embodiment, the targeting ligand is a PARP15 targeting ligand, including but not limited to those described in “Structural Basis for Lack of ADP-ribosyltransferase Activity in Poly(ADP-ribose)Polymerase-13 / Zinc Finger Antiviral Protein.” Karlberg, T. et al., (2015) J. Biol. Chem. 290: 7336-7344.

[0485] In another embodiment, the targeting ligand is a PARP14 targeting ligand, which includes, but is not limited to, those described in “Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening.” Andersson, CD et al., (2012) J.Med.Chem. 55: 7706-7718.; “Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors.” Wahlberg, E. et al., (2012) Nat. Biotechnol. 30: 283-288.; “Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening.” Andersson, CD et al., (2012) J.Med.Chem. 55: 7706-7718.

[0486] In another embodiment, the targeting ligand is an MTH1 targeting ligand, including but not limited to those described in Helge Gad et al., Nature, 2014, 508, 215-221, “MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool”.

[0487] In another embodiment, the targeting ligand is an mPGES-1 targeting ligand, including but not limited to those described in “Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics.” Luz, JG et al., (2015) J.Med.Chem. 58: 4727-4737.

[0488] In another embodiment, the targeting ligand is a FLAP-5-lipoxygenase-activating protein targeting ligand, including but not limited to those described in “Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein,” Ferguson, AD, McKeever, BM, Xu, S., Wisniewski, D., Miller, DK, Yamin, TT, Spencer, RH, Chu, L., Ujjainwalla, F., Cunningham, BR, Evans, JF, Becker, JW (2007) Science 317: 510-512.

[0489] In another embodiment, the targeting ligand is an FA-binding protein targeting ligand, including but not limited to those described in “AReal-World Perspective on Molecular Design.” Kuhn, B. et al. J. Med. Chem. 2016, 59, 4087–4102.

[0490] In another embodiment, the targeting ligand is a BCL2 targeting ligand, including but not limited to those described in “ABT-199, apotent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.” Souers, AJ et al. (2013) NAT.MED. (NY) 19: 202-208.

[0491] In another implementation, the targeting ligand is an NF2L2 targeting ligand.

[0492] In another implementation, the targeting ligand is the CTNNB1 targeting ligand.

[0493] In another implementation, the targeting ligand is the CBLB targeting ligand.

[0494] In another implementation, the targeting ligand is the BCL6 targeting ligand.

[0495] In another implementation, the targeting ligand is the RASK targeting ligand.

[0496] In another implementation, the targeting ligand is a TNIK targeting ligand.

[0497] In another implementation, the targeting ligand is the MEN1 targeting ligand.

[0498] In another implementation, the targeting ligand is the PI3Ka targeting ligand.

[0499] In another implementation, the targeting ligand is the IDO1 targeting ligand.

[0500] In another implementation, the targeting ligand is the MCL1 targeting ligand.

[0501] In another implementation, the targeting ligand is the PTPN2 targeting ligand.

[0502] In another implementation, the targeting ligand is the HER2 targeting ligand.

[0503] In another embodiment, the targeting ligand is an EGFR-targeting ligand. In one embodiment, the targeting ligand is selected from erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), lozitinib (CO-1686), osimertinib (Tagrisso), omamotinib (Olita), natratinib (ASP8273), nazatinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer). Linkers can be placed on these targeting ligands at any location without interfering with ligand binding to EGFR. Non-limiting examples of linker binding sites are provided in the table below. In one embodiment, the EGFR targeting ligand binds to the L858R mutant of EGFR. In another embodiment, the EGFR targeting ligand binds to the T790M mutant of EGFR. In yet another embodiment, the EGFR targeting ligand binds to the C797G or C797S mutant of EGFR. In one embodiment, the EGFR targeting ligand is selected from erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, and binds to the L858R mutant of EGFR. In another embodiment, the EGFR-targeting ligand is selected from osimertinib, loczitinib, omamotinib, natratinib, nazatinib, PF-06747775, icotinib, neratinib, avitinib, tarloxotinib, PF-0645998, tesevatinib, transtinib, WZ-3146, WZ8040, and CNX-2006, and binds to the T790M mutant of EGFR. In another embodiment, the EGFR-targeting ligand is EAI045 and binds to the C797G or C797S mutant of EGFR.

[0504] In one implementation, protein targets and targeting ligand pairs are selected by screening a ligand library. Such screening is illustrated in Duong-Ly et al., “Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases”; Cell Reports 14, 772-781, February 2, 2016.

[0505] In one implementation, protein targets and target ligand pairs are identified by screening for mixed kinase-binding ligands that are specifically degraded in the background. Non-limiting examples of target ligands are shown below and can be found in “Optimized Chemical Proteomics Assay for Kinase Inhibitor Profiling”, Guillaume Médard, Fiona Pachl, Benjamin Ruprecht, Susan Klaeger, Stephanie Heinzlmeir, Dominic Helm, Huichao Qiao, Xin Ku, Mathias Wilhelm, Thomas Kuehne, Zhixiang Wu, Antje Dittmann, Carsten Hopf, Karl Kramer, and Bernhard Kuster J. Proteome Res., 2015, 14(3), pp 1574–1586: These ligands can be linked to connectors as shown below: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; in: R is the connection point of the connector.

[0506] According to the present invention, the targeting ligand can be covalently bound to the linker in any manner to achieve the desired result of the degradation determinant being used for therapeutic purposes. In some non-limiting embodiments, the targeting ligand binds to a linker having functional groups that do not adversely affect the binding of the ligand to the target protein. The following linker points are exemplary in nature, and those skilled in the art will be able to identify different suitable linker points.

[0507] The non-limiting compounds described below exemplify some members of these types of small molecule targeting ligands. In the table below, R is the connection point between the linker and the targeting ligand.

[0508] In some implementations, the targeting ligand is a compound of formula TL-I: (TL-I), Or its pharmaceutically acceptable salt, wherein: for or ; A 1 For S or C=C; A 2 For NRa 5 Or O; nn1 is 0, 1, or 2; Each Ra 1 Independently C1-C3 alkyl, (CH2) 0-3 -CN、(CH2) 0-3 -Halogen, (CH2) 0-3 -OH, (CH2) 0-3 -C1-C3 alkoxy or R; Ra 2 It can be H, C1-C6 alkyl, or (CH2). 0-3 -Heterocyclic group, (CH2) 0-3 -Phenyl or R, wherein the heterocyclic group comprises a saturated 5 or 6-membered ring and 1-2 heteroatoms selected from N, O and S, and is optionally substituted with a C1-C3 alkyl group, and wherein the phenyl group is optionally substituted with a C1-C3 alkyl group, CN, halogen, OH, or C1-C3 alkoxy group; nn2 can be 0, 1, 2, or 3; Each Ra 3 Independently C1-C3 alkyl, (CH2) 0-3 -CN、(CH2) 0-3 - Halogen or R; Ra 4 It is a C1-C3 alkyl group; Ra 5 It is H or C1-C3 alkyl; and R is the connection point of the connector.

[0509] In the case of compounds of formula TL-I, only one R is substituted.

[0510] In some implementations, the targeting ligand is a compound of formula TL-VIII or TL-IX: (TL-VIII) (TL-IX) (TL-X) or (TL-XI), In which compounds of formula TL-VIII or TL-IX are substituted by only one R.

[0511] In some implementations, for .

[0512] In some implementations, for .

[0513] In some implementations, A 1 Let it be S.

[0514] In some implementations, A 1 C=C.

[0515] In some implementations, A 2 For NRa 5 In a further embodiment, Ra 5 For H. In other embodiments, Ra 5 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, Ra 5 It is a methyl group.

[0516] In some implementations, A 2 It is O.

[0517] In some implementations, nn1 is 0.

[0518] In some implementations, nn1 is 1.

[0519] In some implementations, nn1 is 2.

[0520] In some implementations, at least one Ra 1 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, at least one Ra 1 It is a methyl group. In a further embodiment, the two Ra... 1 It is a methyl group.

[0521] In some implementations, at least one Ra 1 It is CN, (CH2)-CN, (CH2)2-CN, or (CH2)3-CN. In a further embodiment, at least one Ra 1 It is (CH2)-CN.

[0522] In some implementations, at least one Ra1 It is a halogen (e.g., F, Cl, or Br), (CH2)-halogen, (CH2)2-halogen, or (CH2)3-halogen. In a further embodiment, at least one Ra 1 It can be Cl, (CH2)-Cl, (CH2)2-Cl or (CH2)3-Cl.

[0523] In some implementations, at least one Ra 1 It can be OH, (CH2)-OH, (CH2)2-OH or (CH2)3-OH.

[0524] In some implementations, at least one Ra 1 It is a C1-C3 alkoxy group (e.g., methoxy, ethoxy, or propoxy), (CH2)-C1-C3 alkoxy, (CH2)2-C1-C3 alkoxy, or (CH2)3-C1-C3 alkoxy. In some embodiments, at least one Ra 1 It is a methoxy group.

[0525] In a further implementation, Ra 5 For H. In other embodiments, Ra 5 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl or isopropyl).

[0526] In a further implementation, Ra 5 For H. In other embodiments, Ra 5 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In other embodiments, Ra 5 It is a methyl group.

[0527] In some implementations, a Ra 1 Let R be the value.

[0528] In some implementations, Ra 2 For H.

[0529] In some implementations, Ra 2 It is a straight-chain C1-C6 or branched C3-C6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl). In a further embodiment, Ra 2 It is methyl, ethyl or tert-butyl.

[0530] In some implementations, Ra 2 It is a heterocyclic group, (CH2)-heterocyclic group, (CH2)2-heterocyclic group, or (CH2)3-heterocyclic group. In a further embodiment, Ra 2The heterocyclic group is (CH2)3-heterocyclic. In other embodiments, the heterocyclic group is selected from pyrrolidinyl, pyrazolylyl, imidazoalkyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, and thiomorpholinyl. In other embodiments, the heterocycle is piperazinyl.

[0531] In some embodiments, the heterocyclic group is replaced by a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl).

[0532] In some implementations, Ra 2 It is phenyl, (CH2)-phenyl, (CH2)2-phenyl, or (CH2)3-phenyl. In a further embodiment, Ra 2 It is a phenyl group.

[0533] In some embodiments, the phenyl group is substituted with a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, the phenyl group is substituted with CN. In some embodiments, the phenyl group is substituted with a halogen (e.g., F, Cl, or Br). In some embodiments, the phenyl group is substituted with OH. In some embodiments, the phenyl group is substituted with a C1-C3 alkoxy group (e.g., methoxy, ethoxy, or propoxy).

[0534] In some implementations, Ra 2 Let R be the value.

[0535] In some implementations, nn2 is 0.

[0536] In some implementations, nn2 is 1.

[0537] In some implementations, nn2 is 2.

[0538] In some implementations, nn2 is 3.

[0539] In some implementations, at least one Ra 3 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, at least one Ra 3 It is a methyl group.

[0540] In some implementations, at least one Ra 3 It is CN, (CH2)-CN, (CH2)2-CN, or (CH2)3-CN. In a further embodiment, at least one Ra 3 For CN.

[0541] In some implementations, at least one Ra 3It is a halogen (e.g., F, Cl, or Br), (CH2)-halogen, (CH2)2-halogen, or (CH2)3-halogen. In a further embodiment, at least one Ra 3 It is Cl, (CH2)-Cl, (CH2)2-Cl, or (CH2)3-Cl. In a further embodiment, at least one Ra 3 It is Cl.

[0542] In some implementations, a Ra 3 Let R be the value.

[0543] In other embodiments, Ra 5 For H. In other embodiments, Ra 5 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl or isopropyl).

[0544] In some implementations, Ra 4 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, Ra 4 It is a methyl group.

[0545] In some implementations, Ra 5 For H.

[0546] In some implementations, Ra 5 It is a C1-C3 alkyl group (e.g., methyl, ethyl, propyl, or isopropyl). In a further embodiment, Ra 5 It is a methyl group.

[0547] In some implementations, for And A 1 Let it be S.

[0548] In some implementations, for And A 1 The expression is C=C.

[0549] In some implementations, for And A 1 The expression is C=C.

[0550] In some implementations, A 2 It is NH, and Ra 2 (CH2) 0-3 - Heterocyclic group. In a further embodiment, Ra 2 It is (CH2)3-heterocyclic group.

[0551] In some implementations, A 2 It is NH, and Ra2 (CH2) 0-3 -Phenyl. In a further embodiment, Ra 2 The phenyl group is substituted with OH in a further embodiment.

[0552] In some implementations, A 2 It is NH, and Ra 2 Let R be the value.

[0553] In some implementations, A 2 It is NH, and Ra 2 It is H or a C1-C6 alkyl group. In a further embodiment, Ra 2 It is a C1-C4 alkyl group.

[0554] In some implementations, A 2 It is O, and Ra 2 It is H or a C1-C6 alkyl group. In a further embodiment, Ra 2 It is a C1-C4 alkyl group.

[0555] III. Treatment Methods Compounds of formulas I, II, III, IV, V, and VI may be used in effective amounts to treat a host (including humans) suffering from any of the conditions described herein, wherein the compounds are optionally in a pharmaceutically acceptable carrier. In some embodiments, the method comprises administering an effective amount of an active compound as described herein or a salt thereof, which optionally includes a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, which is optionally combined with or alternates with another bioactive agent or pharmaceutical combination.

[0556] Compounds of Formulas I, II, and III as described herein, or pharmaceutically acceptable salts thereof, can be used to degrade target proteins that are mediators of a patient's (e.g., a human) condition. The reduction in the level of a protein determined by the degradation of a daughter body of Formulas I, II, or III of the present invention provides treatment for the disease state or condition in question, which is regulated by the target protein through a reduction in the level of that protein in cells (e.g., the patient's cells). When used in conjunction with Formulas I, II, or III, the term "disease state or condition" is intended to refer to any disease state or condition in which a protein dysregulation involving a selected target protein occurs, and in which the degradation of such a protein in a patient can provide beneficial treatment or symptom relief to the patient in need. In some cases, the disease state or condition can be cured.

[0557] When administered to a host (including humans) in an effective amount, compounds of formula I, II, or III may be used as therapeutic agents to treat tumors, cancers (solid, non-solid, diffuse, hematologic, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, hematologic disorders, myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Woldanström macroglobulinemia, Wescott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; autoimmune disorders such as lupus, Crohn's disease, Addison's disease, and celiac disease. Diseases including: dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

[0558] For example, when used in combination with formulas IV, V, and VI, the term "disease state or condition" refers to any therapeutic indication that can be treated by reducing the activity of cereblon or an E3 ligase containing cereblon, including but not limited to the known uses of cereblon binders thalidomide, pomalidomide, or lenalidomide. Compounds of formulas IV, V, or VI may increase, decrease, or modify the activity of cereblon through binding. Non-limiting examples of the use of cereblon binders include multiple myeloma, hematologic disorders such as myelodysplastic syndromes, cancer, tumors, abnormal cell proliferation, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, HIV / AIDS, HBV, HCV, hepatitis, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behçet's disease, tuberculosis, and myelofibrosis. Other indications include myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, Woldanstrom macroglobulinemia, Wiscot-Aldridge syndrome, or post-transplant lymphoproliferative disorders; immune disorders, including autoimmune disorders such as lupus, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis (especially rheumatoid arthritis), or type I diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections, as generally described herein; and inflammatory conditions, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, and ulcerative colitis.

[0559] In some embodiments, the present invention provides the administration of an effective amount of the compound to treat a patient (e.g., a human) suffering from an infectious disease, wherein the treatment targets a target protein of the infectious agent or the host (Formula I, II, III), or works by binding to cereblon or its E3 ligase (Formula IV, V, or VI) (optionally in combination with another bioactive agent). Disease states or conditions can be caused by the following: microbial agents or other exogenous agents such as viruses (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, influenza, coronavirus, EBV, viral pneumonia, drug-resistant viruses, avian influenza, RNA viruses, DNA viruses, adenovirus, poxvirus, microRNA virus, capsular virus, orthomyxovirus, retrovirus, or hepatotropic DNA virus), 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, intestinal worms, worms, prions, parasites, or other microorganisms.

[0560] In some embodiments, the symptoms treated with the compounds of the present invention are those related to abnormal cell proliferation. Abnormal cell proliferation, particularly excessive proliferation, can be caused by a variety of factors, including gene mutations, infections, exposure to toxins, autoimmune diseases, and benign or malignant tumors.

[0561] Many skin conditions are associated with excessive cell proliferation. For example, psoriasis is a benign skin disease typically characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells for unknown reasons. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0562] Other proliferative cell disorders include angiogenesis disorders, fibrosis disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0563] Angiogenic disorders include both angiogenesis and vascularization. The proliferation of smooth muscle cells during plaque development in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0564] Fibrotic disorders are typically caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis of the liver and mesangial proliferative cell disease of the glomeruli. Cirrhosis is characterized by an increase in extracellular matrix components, leading to liver scarring. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

[0565] Glomerular mesangial disorders are caused by the abnormal proliferation of glomerular mesangial cells. Glomerular mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerular diseases.

[0566] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, thought to be related to the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0567] Other diseases that may include abnormal cell proliferation components include Bechtel syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipohistiocytosis, septic shock, and general inflammation.

[0568] Skin contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity. Other examples include atopic dermatitis, eczema, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0569] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin plays a crucial role in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites outside the skin, such as the airways of asthma and the tear-producing ocular glands of dry keratoconjunctivitis.

[0570] In one non-limiting embodiment, the compounds of the present invention are used as topical agents to treat the following conditions: contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel approach can also be used to reduce the infiltration of malignant leukocytes into the skin in diseases such as mycosis fungoides. By applying the compounds topically to the eyes, these compounds can also be used to treat aqueous defective dry eye conditions (e.g., immune-mediated keratoconjunctivitis) in patients suffering from these conditions.

[0571] The disease conditions treatable according to the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliary diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Shama-Tuscan disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Cranfield syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Parfum-Weil syndrome, sickle cell disease, Ty-Sachs disease, and Turner syndrome.

[0572] Other disease states or conditions that can be treated with the compounds disclosed according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Gurney's-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, ADHD, and vasculitis.

[0573] Other disease states or conditions that can be treated with the compounds disclosed according to the present invention include ceruloplasmin deficiency, type II chondrodysplasia, chondrodysplasia, cusp, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenosylsuccinate lyase deficiency, adrenocorticotropic syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria, α1-antitrypsin deficiency, α-1 protease inhibitors, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, enamel hypoplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse somatic angiokeratoma, and retinal angiomatosis (von Hippel-Lin). Acoustic telangiectasia, Appel syndrome, arachnoid fingers (Marfan syndrome), Stickler syndrome, congenital multiple chorioarthritis (Ehlers-Donlow syndrome # chorioarthritis type), ataxia-telangiectasia, Ritter syndrome, essential pulmonary hypertension, Sandhof disease, neurofibromatosis type II, Bill-Stevenson cutaneous swirl syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombotic tendency, Bloch-Sulzberger syndrome (chromosomal disorder), Bloom syndrome, X-linked sideroblastic anemia, Bonavir-Ulrich syndrome (Turner syndrome), Burnaway disease (tuberous sclerosis), prions, Bert-Hogg-Dub syndrome, osteogenesis imperfecta, Broad Thumb-Hallux syndrome Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), bending limb dysplasia, biotinylate deficiency, cardiomyopathy (Noonan syndrome), Cri-du-chat syndrome, CAVD (congenital absence of vas deferens), Caylor's heart-face syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (chondrodystrophy). Incomplete development of the vertebral epiphysis, Lesch-Niehan syndrome, galactosemia, Ehlers-Donnell syndrome, lethal developmental dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, familial adenomatous polyposis, congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disorders, cone aberrant syndrome, Wenkuli's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menx's disease), hereditary coprophytinosis, Cowden syndrome,Craniofacial joint deformities (Kruzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Koshman-Barten-Stenet syndrome (myotrophic lateral dystrophy), Bill Stevenson cutaneous swirl syndrome, primary hyperoxaluria, vertebral epiphyseal dysplasia (Stratwick type), Duchenne & Becker muscular dystrophy (DBMD), Usher syndrome, degenerative neurological disorders (including Degrowsley syndrome and Degerina-Sotas syndrome), developmental disorders, type V distal spinal muscular atrophy, androgen insensitivity syndrome, diffuse spheroid sclerosis (Clapey disease), DeGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoiesis... Porphyria, Erythrocyte 5-aminolevulinic acid synthase deficiency, Erythropoietic porphyria, Erythropoietic protoporphyria, Erythropoietic uroporphyria, Friedreich ataxia-familial paroxysmal polyserositis, Tardive cutaneous porphyria, Familial barosensitive neuropathy, Primary pulmonary hypertension (PPH), Pancreatic cystic fibrosis, Fragile X syndrome, Galactosemia, Hereditary brain disorders, Giant cell hepatitis (neonatal hemochromatosis), Glennblad-Standberg syndrome (pseudomyxanthomas elastica), Gendar disease (congenital erythropoietic porphyria), Hemochromatosis, Holgren's syndrome, Sickle cell anemia, Hemophilia, Hepatic erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau) Diseases including: Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, achondroplasia, hypochromic anemia, immune system disorders (including X-linked severe combined immunodeficiency), Inslee-Asterley syndrome, Jackson-Wes syndrome, Jubert syndrome, Lesch-Niehan syndrome, Jackson-Wes syndrome, nephropathy (including hyperoxaluria), Kleinfeld syndrome, Knister dysplasia, intermittent dementia, Lange-Saldino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysylhydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knister dysplasia), Marfan syndrome, movement disorders, Mowert-Wilson syndrome, and cystic fibrosis. Mink syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landy disease, Piotrs-Jegers syndrome, polycystic kidney disease, multiple osteofibrous dysplasia (McChune-Albright syndrome), Piotrs-Jegers syndrome, Pride-Rabat-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Niehan syndrome), essential pulmonary hypertension, primary senile dementia, prion diseases, premature aging (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia.Protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthomas elastica), Rb (retinoblastoma), Racklinghausen disease (neurofibromatosis type I), relapsing polyserositis, retinopathy, retinoblastoma, Ritter syndrome, RFALS type 3, Rack syndrome, Riley-Day syndrome, Lucy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fomery syndrome, breast sarcoma, leukemia and adrenal gland (SBLA) syndrome, tuberous sclerosis, SDAT, congenital SED (congenital vertebral epiphyseal dysplasia), Stradwick SED (Strardwick type vertebral epiphyseal dysplasia), SEDc (congenital vertebral epiphyseal dysplasia), SEMD, Stradwick type (Strardwick type vertebral epiphyseal dysplasia) The following are listed as examples of genetic disorders: vertebral epiphyseal dysplasia, Shprintzen syndrome, skin pigmentation disorders, Smith-Limeley-Oppitz syndrome, South African hereditary porphyria (variant porphyria), infantile-ascending hereditary spastic paralysis, lang...

Claims

1. Compounds of Formula I or Formula II: (AND) (II) Or pharmaceutically acceptable salts, N-oxides, or isotope derivatives; in: A is CR 8 R 9 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A' is CR 1 R 2 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; A'' is CR 3 R 4 C═O, C═S, C═CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2; X is independently NH, NR 11 CH2, CHR 12 C(R) 12 2. O or S; Z represents O, S, CH2, CH(C1-C4 alkyl) and C(C1-C4 alkyl)2; n is 0, 1, 2, or 3; Is it a single bond or a double bond? R 1 R 2 R 3 R 4 R 6 R 7 R 8 R 9 and R 13 Independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, -NH (aliphatic) and -Nalkyl; Or R 1 and R 2 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 3 and R 4 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 6 and R 7 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 8 and R 9 Forming 3-, 4-, 5- or 6-membered spirocarbocyclic rings, or 4-, 5- or 6-membered spiroheterocyclic rings containing one or two heteroatoms selected from N and O; Or R 1 and R 3 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 1 and R 7 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 3 and R 7 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 13 and R 1 Forming 3, 4, 5, or 6 carbon fused rings; Or R 13 and R 6 Forming 3, 4, 5, or 6 carbon fused rings; Or R 13 and R 4 Forming 1, 2, 3, or 4 carbon bridged rings; Or R 13 and R 5 Forming 3, 4, 5 or 6 carbon fused rings, where R 5 In R 13 On the α carbon, or a 1, 2, 3, or 4 carbon bridge ring, where R 5 Not in R 13 On the α-carbon; R 5 In each case, it is selected from: alkyl, olefin, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -NH (aliphatic), -N (aliphatic)2, -NHSO2 (aliphatic), -N (alkyl)SO2 (aliphatic), -NHSO 2( Aryl or heteroaryl), -N(aliphatic)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2ynyl, -N(alkyl)SO2ynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and haloalkyl; Or two Rs 5 Substituents, together with the carbon atoms they are bonded to, can form 3, 4, 5, or 6-membered rings; R 10 It is a linker-targeting ligand; Q 1 Q 2 Q 3 and Q 4 Independently selected from CH and CR 12 N, and in some embodiments, the number of nitrogen atoms in the ring is 0, 1, 2 or 3, and when Q is in a six-membered ring (unfused or fused) and at least one is nitrogen, the ring may be pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine or tetraazine. R 11 It is independently selected from alkyl, alkenyl, alkynyl, C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic; R 12 Independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, azide, amino, -C(O)H, -C(O)OH, -C(O) (aliphatic group), -C(O)O (aliphatic group), -NH (aliphatic group), -N (aliphatic group)2, -NHSO2 (aliphatic group), -N (aliphatic group)SO2 (aliphatic group), -NHSO 2( Aryl or heteroaryl), -N(aliphatic)SO2aryl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2ynyl, -N(alkyl)SO2ynyl, cyano, nitro, nitroso, -SH, -Salkyl, and haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl and heterocyclic; Linkers are chemical groups that connect degradation determinants to target ligands; A targeting ligand is a portion of a target protein that can bind to or bind to the target protein, and the target protein is selected from those in Figures 1A to 8PPPPP; The compound wherein the compound satisfies at least one of a, b, c, d, e, f, g, h, i, j, k, l, or m: n. R 1 and R 3 Forming 1 or 2 carbon bridged rings; o. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; p. R 4 and R 13 Forming 1 or 2 carbon bridged rings; q. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; r. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; or s. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

2. The compound of claim 1, wherein the compound is selected from: ， ， ， , ,and .

3. Compounds of Formula III: (III) Or pharmaceutically acceptable salts, N-oxides, or isotope derivatives. Where m is 1 or 3, and the other variables are as described in claim 1.

4. Compounds of formula IV or V: (IV) (V) Or pharmaceutically acceptable salts, N-oxides, or isotope derivatives; in: The variable is as described in claim 1, and requires that at least one of a, b, c, d, e, f, g, h, i, or j is: k. R 1 and R 2 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; l. R 3 and R 4 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; m. R 6 and R 7 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; n. R 8 and R 9 Forming 4, 5, or 6-membered spiroheterocyclic rings or 3, 4, 5, or 6-membered spirocarbon rings; o. R 1 and R 3 Forming 1 or 2 carbon bridged rings; p. R 1 and R 13 Forming 3, 4, 5, or 6-membered fused rings; q. R 4 and R 13 Forming 1 or 2 carbon bridged rings; r. A is P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; s. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; or t. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

5. Compounds of formula III, selected from: , , , , , , ,and .

6. Compounds of Formula VI: (WE) Or pharmaceutically acceptable salts, N-oxides, or isotope derivatives; The variable is as described in claim 1, and in some embodiments, it is required that at least one of a, b, c, d, e, f, g, h, i, j, k, l, or m is: n. m is 3 and n is not 0; o. R 1 and R 2 Forming a spiral ring; p. R 3 and R 4 Forming a spiral ring; q. R 6 and R 7 Forming a spiral ring; r. R 8 and R 9 Forming a spiral ring; s. R 1 and R 3 Forming 1 or 2 carbon bridged rings; t. R 1 and R 13 Forming 3, 4, 5, or 6 carbon fused rings; u. R 4 and R 13 Forming 1 or 2 carbon bridged rings; v. R 13 and R 5 Forming 3, 4, 5, or 6 carbon fused rings; w. R 13 and R 5 Forming 1 or 2 carbon bridged rings; x. A is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; y. A' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2; or z. A'' is SO2, S(O), P(O)O alkyl, P(O)NH alkyl, P(O)N(alkyl)2, P(O) alkyl, P(O)OH or P(O)NH2.

7. The compounds of claims 1-6, wherein the linker has a chain of 2 to 20 carbon atoms, wherein one or more carbon atoms may be replaced by heteroatoms such as O, N, S or P or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.

8. The compound according to claims 1-6, wherein the linker is selected from the formulas L1, L1I, LIII, LIV, LV, LVI, and LVII: in: X 1 and X 2 Independently selected from bonds, NH, NR 25 CH2, CHR 25 C(R) 25 2. O and S; R 20 R 21 R 22 R 23 and R 24 Independently selected from bonds, alkyl groups, -C(O)-, -C(O)O-, -OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, -N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-OR) 26 )-、-CH(-NHR 25 -CH(-NH2)-, -CH(-NR) 25 2) -、-C(-OR 26 )alkyl, -C(-NHR) 25 )alkyl-, -C(-NH2)alkyl-, -C(-NR 25 2) Alkyl-, -C(R) 4 R 4 )-, -alkyl (R 27 )-alkyl(R 28 )-、-C(R 27 R 28 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 -NHC(O)NH- -N(R) 25 )C(O)N(R 25 )-、-N(H)C(O)N(R 25 ), polyethylene glycol, poly(lactic acid-co-glycolic acid), olefin, haloalkyl, alkoxy, alkyne, heteroarylalkyl, aryl, arylalkyl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocyclic, or -O-(CH2). 1-12 -O-, -NH-(CH2) 1-12 -NH-, -NH-(CH2) 1-12 -O-, or -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- or -NH-(CH2) 1-12 -S-; R 25 In each case, it is selected from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic; R 26 It includes hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic groups; and R 27 and R 28 It is independently selected from hydrogen, alkyl, amine, or together with the carbon atoms to which they are attached, to form C(O), C(S), C=CH2, C3-C6 spirocarbocycles, or 4-, 5-, or 6-membered spiroheterocycles containing one or two heteroatoms selected from N and O, or to form one or two carbon-bridged rings.

9. The compound according to claims 1-6, wherein the linker is a portion selected from formula LVIII, LIX, and LX: Each of the variables is defined as described in claim 8.

10. The compound of claims 1-6, wherein the linker is selected from... ， ， , , , , , , , , , , , , , , , , , , ,and The variables mentioned therein are defined as in claim 8.

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