Tricyclic heterobifunctional compounds for degrading target proteins

Abstract

Provided are heterobifunctional compounds for targeted protein degradation comprising a tricyclic hypochromate binder linked to an appropriate protein targeting ligand to degrade a protein of interest that mediates a targeted disease.

Description

[0001] This invention is a divisional application of the invention patent application filed on October 14, 2021, with application number 202180080906.7 and invention title "Tricyclic Heterofunctional Compounds for Degrading Target Proteins". Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 091,897, filed October 14, 2020, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0003] The disclosed invention provides a catalytic drug protein degrader comprising a tricyclic hydroxycerebroside binder linked to a suitable protein-targeting ligand to degrade a target protein mediating a target disease.

[0004] By incorporating references The text file named “16010-050WO1_SequenceListing_ST25.txt” was created on October 14, 2021, and is 3.94 KB in size. Its entire contents are incorporated herein by reference. Background Technology

[0005] Proteins are large and complex molecules that play many crucial roles in the human body. Protein-protein interaction mechanisms are involved in health and disease states. Many diseases are caused by mutations, alterations, or overexpression of proteins, often leading to abnormal cell proliferation or other functional disorders.

[0006] The human body possesses a highly conserved homeostasis system that maintains a stable balance of proteins. This system relies on a complex protein degradation mechanism to identify proteins and break them down into their constituent amino acids. This process is partly mediated by E3 ligases, which act as quality control inspectors, identifying aged, damaged, misfolded, or otherwise prepared-for-degradation proteins. E3 ligases attach a series of molecular tags called ubiquitins to proteins in a process called ubiquitination. Once a protein is polyubiquitinated, it is released by E3 ligases and rapidly recognized by the proteasome, the cell's recycling plant. The proteasome degrades the ubiquitinated protein into amino acids, which are then recycled into new proteins.

[0007] This protein degradation system is sometimes referred to as the ubiquitin-proteasome pathway (UPP). The UPP is 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. Insufficient or defective proteasome degradation is associated with a variety of clinical diseases, including abnormal cell proliferation, including cancer, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, and cardiovascular disease.

[0008] Historically, disease-mediating proteins have been targeted for drug therapy using inhibitors that fit within the enzyme pocket and interfere with protein activity, or by binding to the protein to disrupt its activity. However, many proteins are "undruggable" because they are not enzymes, lack an active pocket, or do not readily bind to interfering molecules in the body. Inhibitory mechanisms often require high doses of drug to adequately and sustainably occupy the target. Since pharmacological action is driven by drug exposure, the overall time and duration of drug action depend on drug absorption, distribution, and elimination. These drug levels can be difficult to achieve and may lead to significant off-target effects. Identifying proteins with specific active sites and inhibitory approaches that inhibit these sites in a benign manner is challenging.

[0009] Recently, efforts have been made to utilize the body's proteasome protein degradation system to degrade rather than inhibit disease-mediating proteins.

[0010] C4 Therapeutics, Inc. has filed patent applications describing compounds capable of binding to E3 ubiquitin ligases and for degrading target proteins, including: WO 2021 / 178920, entitled "Compounds for Targeted Degradation of BRD9"; WO 2021 / 127561, entitled "Isoindolinone and Indazole Compounds for the Degradation of EGFR"; WO 2021 / 086785, entitled "Bifunctional Compounds"; WO 2021 / 083949, entitled "Bifunctional Compounds for the Treatment of Cancer"; WO 2020 / 132561, entitled "Targeted Protein Degradation"; WO 2019 / 236483, entitled "Spirocyclic Compounds"; WO 2020 / 051235, entitled "Compounds for the Degradation of BRD9 or MTH1"; WO WO 2019 / 191112, titled "Cereblon Binders for the Degradation of Ikaros"; WO 2019 / 204354, titled "Spirocyclic Compounds"; WO 2019 / 099868, titled "Degraders and Degrons for Targeted Protein Degradation"; WO 2018 / 237026, titled "N / O-Linked Degrons and Degronimers for Protein Degradation"; WO 2017 / 197051, titled "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation"; WO 2017 / 197055, titled "Heterocyclic Degronimers for Target Protein Degradation"; WO 2017 / 197036, titled "Spirocyclic Degronimers for Target Protein Degradation".WO 2017 / 197046, entitled "C3-CarbonLinked Glutarimide Degronimers for Target Protein Degradation"; and WO 2017 / 197056, entitled "Bromodomain Targeting Degronimers for Target Protein Degradation."; C4 Therapeutics Inc.'s WO 2020 / 210630 describes tricyclic compounds. Calico LifeSciences LLC and AbbVie Inc.'s WO 2021 / 127586 describes PTPN1 and PTPN2 ligands covalently bound to various hydroxycerebroside ligands.

[0011] Other examples of protein degradation applications include WO 2021 / 041664, WO 2021 / 143822, WO 2021 / 143816, WO 2020 / 010227, WO 2020 / 006262 and WO 2019 / 148055.

[0012] Despite these efforts, there remains a need for new compounds and pharmaceutical compositions capable of degrading disease-mediating proteins, their methods of use, and their preparation methods. Summary of the Invention

[0013] Compounds, their uses, and preparation methods are provided, said compounds mediating disease target proteins via the ubiquitin-proteasome pathway (UPP) for the treatment of diseases in hosts (typically humans) that respond to protein degradation. The invention provides compounds of formula I, II, or III, or pharmaceutically acceptable salts thereof, comprising a targeting ligand binding to a target protein, an E3 ligase-binding moiety (a tricyclic hydroxycerebroside ligand), a linker covalently linking the targeting ligand to a spacer, and a spacer covalently linking the linker to the E3 ligase-binding moiety.

[0014] The compounds of the present invention provided herein, or pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable compositions thereof, may be used to treat conditions mediated by target proteins. Target proteins are typically mutated, altered, or overexpressed proteins, wherein the mutation, alteration, or overexpression transforms their normal function into a dysfunction that causes or contributes to disease. In some aspects, disease is abnormal cell proliferation, such as cancer or tumor. In some embodiments, a method of treating a patient suffering from a condition mediated by target proteins is provided, comprising administering an effective amount of one or more compounds as described herein, or pharmaceutically acceptable salts thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition. In some embodiments, a tricyclic heterobifunctional compound bound to hydroxycerebroside is administered in combination with another drug or biological agent (which may be standard care for the disease to be treated) to a host in need, typically a human.

[0015] The tricyclic hydroxycerebroside-binding heterobifunctional compound presented in this article is catalytic. Targeted protein degradation mediated by this compound typically occurs rapidly, taking only milliseconds from initial target ligase encounter to polyubiquitination and release for proteasome degradation. Once a molecule of the target protein undergoes targeted protein degradation, the degrading agent is released, and the process is repeated using the same degrading agent molecule. This recursive process of target protein binding, ternary complex formation with E3 ligase, ubiquitination, and degradation release can occur thousands of times in the case of a single degradation molecule.

[0016] In one respect, the tricyclic cerebellar heterocyclic degraders described herein are orally bioavailable and can be provided in effective amounts in convenient solid dosage forms, including but not limited to pills, tablets, capsules, or liquids. Alternatively, the degraders can be administered parenterally, including via intravenous delivery, or topically, or in other ways as further described herein.

[0017] In one respect, compounds of formula I are provided: Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0018] Tricyclic hydroxycerebroside ligands are selected from one of the following portions, where the bond in parentheses indicates that the tricyclic portion is connected to the spacer / connector in a manner that achieves the desired potency and catalytic degradation spectrum via covalent bonds on ring-A, ring-B, ring-C, or ring-D.

[0019] ; n is 0, 1, or 2; X is NR 10 NR 6 , O or S; X' is NR 10 O, CH2 or S; Q is CR 7 Or N; Q' and Q'' are independently selected from CR 1 and N.

[0020] Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring-A is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 1 Substituents are substituted.

[0021] Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring -B is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 2 Substituents are substituted.

[0022] In some embodiments, ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein ring-A is optionally composed of one, two, or three independently selected from R, as permitted by valence. 1 Substituents are substituted.

[0023] In some embodiments, ring-B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein ring-B is optionally composed of one, two, or three independently selected from R, as permitted by valence. 2 Substituents are substituted.

[0024] The ring -C is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein each ring -C is optionally composed of 1, 2, or 3 independently selected from R, as permitted by the valence. 1 Substituents are substituted.

[0025] Ring-D is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein each ring-D is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 2 Substituents are substituted.

[0026] R 1 and R 2 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or alternatively, if valence and stability permit, R 1 Or R 2 It can be a divalent part, such as =O, =S, or =NR. 41 ; and R 1 The group can optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings, which can bridge ring-A and ring-B or ring-C and ring-D, depending on the situation and need.

[0027] R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 Combining to form 1 or 2 carbon connections, for example when R 3 and R 6 When forming a 1-carbon bond yes ; Or R 3 and R 4 Combinations form 1, 2, 3, or 4 carbon connections, for example, when R 3 and R 4 When forming a 1-carbon bond yes ; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds.

[0028] R 4 and R 5 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 6 and R 7 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 ; R 6 It is hydrogen, alkyl, or haloalkyl; Or R 3 and R 6 'Combined to form 1 or 2 carbon connections.'

[0029] R 10 and R 11 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; And R 13 and R 14 Each instance is independently selected from hydrogen, alkyl, and haloalkyl.

[0030] Spacers are bivalent connections that can have the following structure: X 3 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 The divalent moiety of -, -C(S)-, -S(O)-, -S(O)2-, and -S-; or it can be an arylalkyl, heterocyclic alkyl, or heteroarylalkyl (in any orientation), wherein each of the heterocycle, aryl, heteroaryl, and bicyclic can be independently selected from R by 1, 2, 3, or 4. 40 Substituents of the substituents; R 15 R 16 R 17 and R18 Each occurrence is independently selected from bonds, alkyl groups (which in some embodiments are carbocyclic), -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; Where X 3 and R 15-18 Together, a tricyclic hydroxycerebroside ligand is covalently attached to the stable portion of the linker, and in some embodiments, the spacer is a covalent bond; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R 27 Each time it appears, it is independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic or heteroaryl), olefin and alkyne; R 40 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)2, -NHSO2 (aliphatic, including alkyl), -N (aliphatic, including alkyl)SO2alkyl, -NHSO2 (aryl, heteroaryl or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl or heterocyclic), -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl; R 41 It is aliphatic (including alkyl), aryl, heteroaryl, or hydrogen; The targeting ligand is the part that binds to the target protein and is covalently linked to the tricyclic hydroxycerebroside ligand via a linker-spacer. Target proteins are selected proteins in the body that cause or contribute to the disease to be treated. The connector is a divalent linker, such as the divalent linker of formula LI.

[0031] In some implementations, the connector has the following formula: (LI).

[0032] in, X 1 and X 2 Each time it appears, it is independently selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, alkyl groups, aliphatic groups, heteroaliphatic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 )-, -C(S)-, -S(O)-, -S(O)2- and -S-; wherein each of the heterocyclic, aryl, heteroaryl and bicyclic is optionally selected independently by 1, 2, 3 or 4 from R 40 Substituents of the substituents; R 20 R 21 R 22 R 23 and R 24 Each time it appears, it is independently selected from bonds, alkyl groups, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -, alkylene oxide, -C(R) 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefinic, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocyclic; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R 27Each time it appears, it is independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic or heteroaryl), olefin and alkyne; R 40 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl)2, -NHSO2 (aliphatic, including alkyl), -N (aliphatic, including alkyl)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2 alkenyl, -N (alkyl)SO2 alkenyl, -NHSO2 ynyl, -N (alkyl)SO2 ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo and cycloalkyl; and R 41 It is aliphatic, aryl, heteroaryl, or hydrogen.

[0033] In some respects, compounds of formula II are provided: (II) Or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; For equation II: The targeting ligand is the portion that binds to the target protein and is covalently linked to the tricyclic hydroxycerebroside ligand via a linker-spacer. The targeting ligand does not include the following substructures. or Target proteins are selected proteins in the body that cause or contribute to the disease to be treated, wherein the target protein is not a PTP enzyme (e.g., PTPN1 or PTPN2). And all other variables as defined in Equation I or in the implementation scheme described herein.

[0034] In some respects, compounds of formula III are provided: (III).

[0035] Alternatively, a pharmaceutically acceptable salt, N-oxide, isotope derivative, or prodrug thereof may be disposed in a pharmaceutically acceptable carrier to form a composition.

[0036] For equation III: Tricyclic hydroxycerebroside ligands were selected from: and ; R 1 'and R 2 'In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic, wherein if R 1 If it is hydrogen, then R 2 'Not hydrogen, and if R 2 'If it is hydrogen, then R' 1 It's not hydrogen; And all other variables as defined in Equation I or in the implementation scheme described herein.

[0037] In some embodiments, the tricyclic hydroxycerebroside ligand having the linkage as described above is selected from: and .

[0038] In some other embodiments, the tricyclic hydroxycerebroside-binding moiety having the linkage as described above is selected from: and .

[0039] The variables, substituents, embodiments, and each combination of compounds resulting from these combinations are considered specific and individually disclosed, because such descriptions are for spatial convenience only and are not intended to describe only the class or even subclass of compounds.

[0040] In some embodiments, the compounds of the present invention are selected from formulas IIa-1 and IIb-1: IIa-1 IIb-1; Or its pharmaceutically acceptable salt.

[0041] In some embodiments, the compounds of the present invention are selected from formulas IIa-2 and IIb-2: IIa-2 IIb-2; Or its pharmaceutically acceptable salt.

[0042] In some embodiments, the compounds of the present invention are selected from formulas IIa-3 and IIb-3: IIa-3 IIb-3 Or its pharmaceutically acceptable salt; in: Q 1 Q 2 Q 3 Independently selected from CH and CR 1 N; and all other variables as defined in this document.

[0043] In some embodiments, the compounds of the present invention are selected from formulas IIa-4 and IIb-4: IIa-4 IIb-4 Or its pharmaceutically acceptable salt.

[0044] In some embodiments, the compounds of the present invention are selected from formulas IIa-5 and IIb-5: IIa-5 IIb-5 Or its pharmaceutically acceptable salt.

[0045] In some embodiments, the compounds of the present invention are selected from formulas IIa-6 and IIb-6: IIa-6 IIb-6 Or its pharmaceutically acceptable salt.

[0046] In some embodiments, the compounds of the present invention are selected from formulas IIa-7 and IIb-7: IIa-7 IIb-7 Or its pharmaceutically acceptable salt.

[0047] Non-limiting examples of compounds of the present invention include: In some embodiments, a treatment method is provided, comprising administering to a patient in need, such as a human, an effective amount of a compound of formula I, II, or III, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. For example, in some embodiments, a compound of formula I, II, or III is administered to a human to treat abnormal cell proliferation or cancer.

[0048] In some embodiments, the compounds of the present invention are used to degrade target proteins having allosteric ligands as targeting ligands. In some embodiments, the compounds of the present invention are used to degrade target proteins having ortho-ligands as targeting ligands. In some embodiments, the compounds of the present invention are used to degrade target proteins that have not been recruited to the E3 ubiquitin ligase complex via targeting ligands.

[0049] In some embodiments, the compounds of the present invention offer one or more, and often more, advantages over conventional protein inhibition therapies. For example, the tricyclic hydroxycerebroside heterobifunctional protein-degrading compounds of the present invention can a) overcome conventional resistance; b) prolong the kinetics of targeting ligand action by disrupting the protein, thus requiring protein resynthesis even after the compound is metabolized; c) target all functions of the target protein at once, rather than specific activities or binding events; d) have higher potency than inhibitors due to their catalytic activity; and / or e) require lower doses than conventional protein inhibitors, thereby reducing the likelihood of toxicity.

[0050] In some embodiments, the compounds of the present invention are used to treat cancers with mutated target proteins. In some embodiments, the targeting ligand selectively binds to the mutated protein without significantly binding to the wild-type protein.

[0051] In some embodiments, the compounds of the present invention are used to treat cancers that are resistant to treatment with the targeted ligand alone.

[0052] In some embodiments, the compounds of the present invention provide an improved efficacy and / or safety profile relative to individual targeting ligands.

[0053] In some implementations, treatment of conditions mediated by the target protein requires lower concentrations of the tricyclic cerebellar bifunctional protein described herein, compared to targeting ligands alone.

[0054] In some embodiments, an effective amount of the compound of the present invention has fewer at least one side effect in treating conditions mediated by the target protein than an effective amount of the target ligand alone.

[0055] In some implementations, effective treatment of conditions mediated by target proteins requires doses of the selected compounds described herein at a lower frequency compared to effective treatment with a single targeting ligand.

[0056] Another aspect of the invention provides compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or their pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for use in the preparation of medicaments for inhibiting or preventing disease mediated by target proteins or for regulating or reducing the amount of target proteins.

[0057] Another aspect of the invention provides compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or their pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for use in the preparation of medicaments for the treatment or prevention of diseases mediated by target proteins.

[0058] In some embodiments, the selected compounds described herein can be used to treat conditions involving abnormal cell proliferation, such as tumors or cancer, wherein the target protein is an oncogenic protein or a signaling mediator of an abnormal cell proliferation pathway, the degradation of which reduces abnormal cell growth.

[0059] In some embodiments, the selected compound of Formula I, Formula II or Formula III, or its pharmaceutically acceptable salt, has at least one desired atomic isotopic substitution in an amount higher than the natural abundance of the isotope, i.e., it is enriched.

[0060] In some embodiments, the compound of formula I, formula II or formula III or its pharmaceutically acceptable salt comprises one or more deuterium atoms.

[0061] Other features and advantages of this application will be apparent from the following detailed description.

[0062] Therefore, the present invention includes at least the following features: (a) A compound of formula I, II or III as described herein, or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives) or a pharmaceutically acceptable composition thereof; (b) A method for treating a condition mediated by a target protein, such as abnormal cell proliferation, including cancer, said method comprising administering to a patient, such as a human, an effective amount of a compound of formula I, II or III as described herein, or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutically acceptable composition. (c) A compound of formula I, II or III or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives) for the treatment of conditions mediated by target proteins, such as abnormal cell proliferation, such as tumors or cancers, inflammatory diseases, autoimmune diseases or fibrotic diseases.

[0063] (d) Use in effective amounts of a compound of formula I, II or III or a pharmaceutically acceptable salt thereof in the treatment of patients in need of treatment for conditions mediated by target proteins, such as abnormal cell proliferation, such as tumors or cancers, typically in humans. (e) Use of a compound of formula I, II or III or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives) in the preparation of a medicament for treating a condition mediated by a target protein, such as abnormal cell proliferation, such as tumors or cancer. (f) A pharmaceutical composition comprising a patient-effective therapeutic amount of a compound of formula I, II or III or a pharmaceutically acceptable salt or isotopic derivative thereof; and optionally a pharmaceutically acceptable carrier or diluent; (g) The compounds of formula I, II or III as described herein are enantiomers or mixtures of diastereomers (related), including racemates; (h) Compounds of Formula I, II, or III as described herein, in enantiomerically or diastereomerically (as relevant), including isolated enantiomers or diastereomers (i.e., with a purity of about 85, 90, 95, 97, or 99%); and (i) A method for preparing a therapeutic product containing an effective amount of a compound of formula I, II or III as described herein, or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0064] Figure 1A-1CNon-limiting examples of retinoid X receptor (RXR) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0065] Figure 1D-1F Non-limiting examples of universal dihydrofolate reductase (DHFR) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0066] Figure 1G Non-limiting examples of anthrax bacillus dihydrofolate reductase (BaDHFR) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0067] Figure 1H-1J Non-limiting examples of heat shock protein 90 (HSP90) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0068] Figure 1K-1Q Non-limiting examples of universal kinase and phosphatase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0069] Figure 1R-1S Non-limiting examples of tyrosine kinase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0070] Figure 1T Non-limiting examples of aurora kinase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0071] Figure 1U Non-limiting examples of protein tyrosine phosphatase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0072] Figure 1V Non-limiting examples of ALK-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0073] Figure 1W Non-limiting examples of ABL-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0074] Figure 1X Non-limiting examples of JAK2-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0075] Figure 1Y-1Z Non-limiting examples of MET-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0076] Figure 1AA Non-limiting examples of mTORC1 and / or mTORC2 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0077] Figure 1BB-1CC Non-limiting examples of targeting ligands for the hypertrophic / stem cell growth factor receptor (SCFR), also known as the c-KIT receptor, are provided, where R denotes an exemplary point connecting spacers.

[0078] Figure 1DD Non-limiting examples of IGF1R and / or IR targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0079] Figure 1EE-1FF Non-limiting examples of HDM2 and / or MDM2 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0080] Figure 1GG-1MM Non-limiting examples of protein-targeting ligands with BET bromo domains are provided, where R denotes an exemplary point connecting spacers.

[0081] Figure 1NN Non-limiting examples of HDAC-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0082] Figure 100 Non-limiting examples of RAF receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0083] Figure 1PP Non-limiting examples of FKBP receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0084] Figure 1 QQ-1TT Non-limiting examples of androgen receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0085] Figure 1UU Non-limiting examples of estrogen receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0086] Figure 1VV-1WW Non-limiting examples of thyroid hormone receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0087] Figure 1XX Non-limiting examples of HIV protease-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0088] Figure 1YY Non-limiting examples of HIV integrase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0089] Figure 1ZZNon-limiting examples of HCV protease targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0090] Figure 1AAA Non-limiting examples of AP1 and / or AP2 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0091] Figure 1BBB-1CCC Non-limiting examples of MCL-1 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0092] Figure 1DDD Non-limiting examples of IDH1 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0093] Figure 1EEE-1FFF Non-limiting examples of RAS or RASK targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0094] Figure 1GGG Non-limiting examples of MERTK or MER targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0095] Figure 1 HHH-1III Non-limiting examples of EGFR-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0096] Figure 1JJJ-1KKK Non-limiting examples of FLT3-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0097] Figure 1 LLL Non-limiting examples of SMARCA2 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0098] Figure 2A Non-limiting examples of kinase inhibitor targeting ligands U09-CX-5279 (derived) are provided, where R denotes an exemplary point connecting spacers.

[0099] Figure 2B-2C Non-limiting examples of kinase inhibitor targeting ligands are provided, including kinase inhibitor compounds Y1W and Y1X (derived), where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the kinase inhibitors identified in: Millan et al., “Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease”. J. Med. Chem.,54:7797 (2011).

[0100] Figure 2D Non-limiting examples of kinase inhibitor targeting ligands are provided, including the kinase inhibitor compounds 6TP and OTP (derived), where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the kinase inhibitors identified in: Schenkel et al., “Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors”. J. Med. Chem. , 54 (24): 8440-8450(2011).

[0101] Figure 2E Non-limiting examples of kinase inhibitor targeting ligands are provided, including the kinase inhibitor compound 07U, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the kinase inhibitor identified in: Van Eis et al., “2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes”. Biorg. Med. Chem. Lett., 21(24): 7367-72(2011).

[0102] Figure 2F Non-limiting examples of kinase inhibitor targeting ligands are provided, including the kinase inhibitor compound YCF, where R denotes an exemplary site connecting a spacer. For other examples and related ligands, see the kinase inhibitor identified in: Lountos et al., “Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy”. J. Struct. Biol. ,176: 292 (2011).

[0103] Figure 2G-2HNon-limiting examples of kinase inhibitor-targeting ligands are provided, including the kinase inhibitors XK9 and NXP (derived), where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the kinase inhibitor identified in: Lountos et al., “Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2) a Drug Target for Cancer Therapy”. J. Struct. Biol ., 176: 292 (2011).

[0104] Figure 2I-2J Non-limiting examples of kinase inhibitor targeting ligands are provided, where R denotes an exemplary point connecting spacer r.

[0105] Figure 2K-2M Non-limiting examples of cyclin-dependent kinase 9 (CDK9) targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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. "CDKInhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and ApoptoticCell Death in Neuroblastoma Cells." Genes Cancer, 1: 369-380 (2010); Baumli et al. “Halogen bonds form the basis for selective P-TEFb inhibition by DRB.” Chem.Biol.17: 931-936 (2010); Hole et al. “Comparative Structural and Functional Studies of 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9Inhibitors Suggest the Basis for Isotype Selectivity.” J.Med.Chem . 56: 660 (2013); Lücking et al. “Identification of the potent and highly selective PTEFbinhibitor BAY 1251152 for the treatment of cancer – From po to ivapplication via scaffold hops.” Lücking et al. U. AACR Annual Meeting, April 1–5, 2017 Washington, DC USA.

[0106] Figure 2N-2P Non-limiting examples of cyclin-dependent kinase 4 / 6 (CDK4 / 6) targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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)-pyrimidines as selective inhibitors of cyclin-dependent kinase4 / 6. Cho et al. (2010) J. Med. Chem. 53: 7938-7957; Cho YS et al. "Fragment-BasedDiscovery of 7-Azabenzimidazoles as Potent Highly Selective and Orally ActiveCDK4 / 6 Inhibitors." ACS Med Chem Lett3: 445-449 (2012); Li Z. et al. "Discovery ofAMG 925 a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3." J. Med. Chem. 57: 3430-3449 (2014); Chen P. et al. “Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance.” Mol. Cancer Ther. 15: 2273-2281 (2016).

[0107] Figure 2Q Non-limiting examples of cyclin-dependent kinase 12 and / or cyclin-dependent kinase 13 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0108] Figure 2R-2S Non-limiting examples of glucocorticoid receptor-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0109] Figure 2T-2U Non-limiting examples of RasG12C targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0110] Figure 2V Non-limiting examples of Her3-targeting ligands are provided, where R denotes an exemplary point connecting spacers, and R'' is... or .

[0111] Figure 2W Non-limiting examples of Bcl-2 or Bcl-XL targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0112] Figure 2X-2NNNon-limiting examples of BCL2-targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Toure BB et al., “The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.” ACS Med Chem Lett, 4: 186-190 (2013); Porter J. et al. "Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as Selective Bcl-2Inhibitors" Bioorg. Med. Chem. Lett. 19: 230 (2009); Souers AJ et al. "ABT-199 apotent and selective BCL-2 inhibitor achieves antitumor activity while sparing platelets." Nature Med. 19: 202-208 (2013); Angelo Aguilar et al. "A Potentand 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 InhibitorInducing Complete and Long-Lasting Tumor Regression In Vivo" PLoS ONE 9(6):e99404; Fariba Ne´mati1 et al. "Targeting Bcl-2 / Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts" PLoS ONE9(1): e80836; WO2015011396 is titled "Novel derivatives of indole and pyrrole method for the production thereof and pharmaceutical compositions containing the same"; WO2008060569A1 is titled "Compounds and methods for inhibiting the interaction ofBcl proteins with binding partners"; "Inhibitors of the anti-apoptotic Bcl-2proteins: a patent review" Expert Opinion. Ther. Patents 22(1):2008 (2012); and Porter et al. “Tetrahydroisoquinoline amide substituted phenyl pyrazoles asselective Bcl-2 inhibitors” Bioorg Med Chem Lett. , 19(1):230-3 (2009).

[0113] Figure 200-2UU Non-limiting examples of BCL-XL targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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); Joel D. Leverson et al. "Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy" Science Translational Medicine, 7:279ra40 (2015); and crystal structure PDB3ZK6 (Guillaume Lessene et al., “Structure-guided design of a selective BCL-XL inhibitor”). Nature Chemical Biology 9: 390–397 (2013) Figure 2VV Non-limiting examples of PPAR-γ targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0114] Figure 2WW-2YY Non-limiting examples of EGFR targeting ligands targeting the EGFR L858R mutant are provided, including erlotinib, gefitinib, afatinib, neratinib, and dacomitinib, where R denotes an exemplary point connecting spacers.

[0115] Figure 2ZZ-2FFF Non-limiting examples of EGFR-targeting ligands targeting the EGFR T790M mutant are provided, including osimertinib, roxitinib, omamolinib, nacotinib, nazatinib, PF-06747775, icotinib, neratinib, avitinib, tarotinib, PF-0645998, tervatinib, transtinib, WZ-3146, WZ8040, and CNX-2006, where R denotes an exemplary point connecting a spacer.

[0116] Figure 2GGG Non-limiting examples of EGFR targeting ligands targeting the EGFR C797S mutant are provided, including EAI045, where R denotes an exemplary point connecting spacers.

[0117] Figure 2HHH Non-limiting examples of BCR-ABL targeting ligands targeting the BCR-ABLT315I mutant are provided, including nilotinib and dasatinib, where R denotes an exemplary point connecting a spacer. See, for example, crystal structure PDB3CS9.

[0118] Figure 2III Non-limiting examples of targeting ligands for BCR-ABL are provided, including nilotinib, dasatinib, panatinib, and bosutinib, where R denotes an exemplary point connecting spacers.

[0119] Figure 2JJJ-2KKK Non-limiting examples of ALK-targeting ligands targeting the ALK L1196M mutant are provided, including ceritinib, where R denotes an exemplary point connecting a spacer. See, for example, crystal structure PDB 4MKC.

[0120] Figure 2LLL Non-limiting examples of JAK2 targeting ligands targeting the JAK2V617F mutant are provided, including ruxolitinib, where R denotes an exemplary point connecting spacers.

[0121] Figure 2MMMNon-limiting examples of BRAF-targeting ligands targeting the BRAF V600E mutant are provided, including vemurafenib, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see crystal structure PBD3OG7.

[0122] Figure 2NNN Non-limiting examples of BRAF-targeting ligands are provided, including dabrafenib, where R denotes an exemplary point connecting spacers.

[0123] Figure 2000 Non-limiting examples of LRRK2 targeting ligands targeting the LRRK2 R1441C mutant are provided, where R denotes an exemplary point connecting spacers.

[0124] Figure 2 PPP Non-limiting examples of LRRK2 targeting ligands targeting the LRRK2 G2019S mutant are provided, where R denotes an exemplary point connecting spacers.

[0125] Figure 2 QQQ Non-limiting examples of LRRK2 targeting ligands targeting the LRRK2 I2020T mutant are provided, where R denotes an exemplary point connecting spacers.

[0126] Figure 2RRR-2TTT Non-limiting examples of PDGFRα targeting ligands targeting the PDGFRα T674I mutant are provided, including AG-1478, CHEMBL94431, dovirtinib, erlotinib, gefitinib, imatinib, Janex 1, pazopanib, PD153035, solatinib, sunifenib, and WHI-P180, where R denotes an exemplary point connecting a spacer.

[0127] Figure 2UUU Non-limiting examples of RET targeting ligands targeting RET G691S mutants are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0128] Figure 2VVV Non-limiting examples of RET targeting ligands targeting the RET R749T mutant are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0129] Figure 2 WWW Non-limiting examples of RET targeting ligands targeting RET E762Q mutants are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0130] Figure 2XXXNon-limiting examples of RET targeting ligands targeting the RET Y791F mutant are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0131] Figure 2YYY Non-limiting examples of RET targeting ligands targeting the RET V804M mutant are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0132] Figure 2ZZZ Non-limiting examples of RET targeting ligands targeting the RET M918T mutant are provided, including Tauzasetti, where R denotes an exemplary point connecting spacers.

[0133] Figure 2AAAA Non-limiting examples of fatty acid-binding protein targeting ligands are provided, where R represents an exemplary point connecting spacers.

[0134] Figure 2BBBB Non-limiting examples of 5-lipoxygenase-activating protein (FLAP) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0135] Figure 2CCCC Non-limiting examples of Kringle domain V 4BVV targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0136] Figure 2DDDD Non-limiting examples of lactylglutathione lyase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0137] Figure 2EEEE-2FFFF Non-limiting examples of mPGES-1 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0138] Figure 2GGGG-2JJJJ Non-limiting examples of factor Xa targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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." (to be published); crystal structures PDB 1iqh, 1iqi, 1iqk, and 1iqm; Adler M. et al. "Crystal Structures of Two Potent Nonamidine Inhibitors Bound to Factor Xa." Biochemistry 41: 15514-15523 (2002); Roehrig S. et al. "Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-Oxo-3-[4-(3-Oxomorpholin-4-Yl)Phenyl]-1,3-Oxazolidin-5-Yl}Methyl)Thiophene-2-Carboxamide (Bay 59-7939): An Oral Direct Factor Xa Inhibitor." J. Med. Chem. 48: 5900 (2005); Anselm L. et al. "Discovery of a Factor Xa Inhibitor (3R,4R)-1-(2,2-Difluoro-Ethyl)-Pyrrolidine-3,4-Dicarboxylic Acid 3-[(5-Chloro-Pyridin-2-Yl)-Amide]-4-{[2-Fluoro-4-(2-Oxo-2H-Pyridin-1-Yl)-Phenyl]-Amide} as a Clinical Candidate." Bioorg. Med. Chem.20: 5313 (2010); and Pinto DJ et al. “Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4 56 7-tetrahydro- 1H-pyrazolo[3 4-c]pyridine-3-carboxamide (Apixaban BMS-562247) a Highly Potent Selective Efficacious and Orally BioavailableInhibitor of Blood Coagulation Factor Xa.” J. Med. Chem 50: 5339-5356 (2007).

[0139] Figure 2KKKK Non-limiting examples of kallikrein 7 targeting ligands are provided, where R denotes an exemplary site connecting a spacer. For other examples and related ligands, see Maibaum J. et al., “Small-molecule factor Dinhibitors targeting the alternative complement pathway”. Nat. Chem. Biol. 12:1105-1110 (2016).

[0140] Figure 2LLLL-2MMMM Non-limiting examples of cathepsin K targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Rankovic Z. et al., “Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin kinhibitors”. Bioorg. Med. Chem. Lett. 20: 1524-1527 (2010); and Cai J. et al., “Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.” Bioorg. Med. Chem. Lett. 20: 6890-6894 (2010).

[0141] Figure 2NNNNNon-limiting examples of cathepsin L targeting ligands are provided, where R denotes an exemplary site for linking spacers. 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).

[0142] Figure 20000 Non-limiting examples of cathepsin S targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Jadhav PK et al., “Discovery of CathepsinS Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm”. ACS Med. Chem. Lett. 5: 1138-1142.” (2014).

[0143] Figure 2PPPP-2SSSS Non-limiting examples of MTH1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see Kettle JG et al., “Potent and Selective Inhibitors of Mth1 Probe its Role in Cancer Cell Survival”. J. Med. Chem. 59:2346 (2016); Huber KVM et al. “Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.” Nature 508: 222 (2014); Gad H. et al. "MTH1inhibition eradicates cancer by preventing sanitation of the dNTP pool." Nature 508: 215-221 (2014); Nissink JWM et al. "Mth1 Substrate Recognition--anExample of Specific Promiscuity." Plos One11: 51154 (2016); and Manuel Ellermann et al. “Novel class of potent and selective inhibitors efface MTH1 as broad-spectrum cancer target.” AACR National Meeting Abstract 5226, 2017.

[0144] Figure 2TTTT-2ZZZZ Non-limiting examples of MDM2 and / or MDM4 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see Popowicz GM et al., “Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX / MDM2 antagonist drug discovery.” Cell Cycle, 9 (2010); MiyazakiM. et al. "Synthesis and evaluation of novel orally active p53-MDM2 interactioninhibitors." Bioorg. Med. Chem. 21: 4319-4331 (2013); Miyazaki M. et al. "Discovery of DS-5272 as a promising candidate: A potent and orally activep53-MDM2 interaction inhibitor." Bioorg Med Chem. 23: 2360-7 (2015); Holzer P. et al. “Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A HighlyPotent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials inp53wt Tumors.” J. Med. Chem.58: 6348-6358 (2015); Gonzalez-Lopez de Turiso F. et al. "Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors." J. Med. Chem. 56: 4053-4070 (2013); Gessier F. et al. "Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode." Bioorg. Med. Chem. Lett. 25: 3621-3625 (2015); Fry D.C. et al. "Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor." ACS Med Chem Lett 4: 660-665 (2013); Ding Q. et al. "Discovery of RG7388 a Potent and Selective p53-MDM2 Inhibitor in Clinical Development." J. Med. Chem. 56: 5979-5983 (2013); Wang S. et al. "SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression." Cancer Res. 74: 5855-5865 (2014); Rew Y. et al. "Discovery of AM-7209 a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction." J. Med. Chem.57: 10499-10511(2014); Bogen SL et al. “Discovery of Novel 3 3-Disubstituted Piperidines asOrally 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 PotentSelective and Orally Bioavailable MDM2-p53 Inhibitor in ClinicalDevelopment.” J. Med. Chem. 57: 1454-1472 (2014).

[0145] Figure 2 AAAAA-2EEEEE Non-limiting examples of PARP1, PARP2, and / or PARP3 targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other 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 V.B. et al. "Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose)polymerase (PARP) for the treatment of cancer." Bioorg. Med. Chem. Lett. 20:1023-1026 (2010); Penning T.D. et al. "Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor." J. Med. Chem. 53: 3142-3153 (2010); Ye N. et al. "Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors." J. Med. Chem. 56: 2885-2903 (2013); Patel M.R. et al. "Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors." J. Med. Chem. 57: 5579-5601 (2014); 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 withinhibitor Rucaparib”, Karlberg T. et al.); Papeo GME et al. “Discovery of 2-[1-(44-Difluorocyclohexyl)Piperidin-4-Yl]-6-Fluoro-3-Oxo-2 3-Dihydro-1H-Isoindole-4-Carboxamide (Nms-P118): A Potent Orally Available and Highly SelectiveParp- 1 Inhibitor for Cancer Therapy.” J. Med. Chem. 58: 6875 (2015); Kinoshita T. et al. "Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase." Febs Lett. 556: 43-46 (2004); and Gangloff AR et al. “Discovery of novel benzo[b][1 4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors.” Bioorg. Med. Chem. Lett. 23: 4501-4505 (2013).

[0146] Figure 2FFFFF-2GGGGG Non-limiting examples of PARP14 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0147] Figure 2 HHHHH Non-limiting examples of PARP15 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0148] Figure 2IIIII I provides a non-limiting example of a PDZ domain-targeting ligand, where R represents an exemplary point connecting spacers.

[0149] Figure 2 JJJJJ Non-limiting examples of phospholipase A2 domain-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0150] Figure 2KKKKK Non-limiting examples of protein S100-A7 2WOS targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0151] Figure 2LLLLL-2MMMMM Non-limiting examples of Saposin-B targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0152] Figure 2NNNNN-2OOOOO Non-limiting examples of Sec7-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0153] Figure 2PPPPP-2QQQQQ Non-limiting examples of pp60 Src SH2 domain-targeted ligands are provided, where R denotes an exemplary point connecting spacers.

[0154] Figure 2RRRRR Non-limiting examples of Tank1-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0155] Figure 2SSSSS Non-limiting examples of Ubc9 SUMO E2 ligase SF6D targeting ligands are provided, where R denotes an exemplary point for connecting spacers.

[0156] Figure 2 TTTTT Non-limiting examples of Src-targeting ligands are provided, including AP23464, where R denotes an exemplary point connecting spacers.

[0157] Figure 2 UUUUU-2XXXXX Non-limiting examples of Src-AS1 and / or Src AS2 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0158] Figure 2 YYYYY Non-limiting examples of JAK3-targeting ligands are provided, including tofacitinib, where R denotes an exemplary point connecting spacers.

[0159] Figure 2ZZZZZ Non-limiting examples of ABL-targeting ligands are provided, including tofacitinib and panatinib, where R denotes an exemplary point connecting spacers.

[0160] Figures 3A-3BNon-limiting examples of MEK1-targeting ligands are provided, including PD318088, trametinib, and G-573, where R denotes an exemplary point connecting spacers.

[0161] Figure 3C Non-limiting examples of KIT-targeting ligands are provided, including regorafenib, where R denotes an exemplary point connecting spacers.

[0162] Figure 3D-3E Non-limiting examples of HIV reverse transcriptase targeting ligands are provided, including efavirenz, tenofovir, emtricitabine, ritonavir, raltegravir, and atazanavir, where R denotes an exemplary point connecting spacers.

[0163] Figure 3F-3G Non-limiting examples of HIV protease-targeting ligands are provided, including ritonavir, raltegravir, and atazanavir, where R denotes an exemplary point connecting spacers.

[0164] Figure 3H-3I Non-limiting examples of KSR1-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0165] Figure 3J-3L Non-limiting examples of CTNNB1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For example, --- crystal structures----- and (see “Direct Targeting of b-Catenin by a SmallMolecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt / b-Catenin Signaling” Cell Rep 2016, 16(1), 28; “Rational Design of Small-Molecule Inhibitors for β‐Catenin / T-Cell Factor Protein-Protein Interactions by Bioisostere Replacement” ACS Chem Biol 2013, 8, 524; and “Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in coloncancer” Sci Rep 2020, 10, 8096).

[0166] Figure 3MNon-limiting examples of BCL6-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0167] Figure 3N-3O Non-limiting examples of PAK1 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0168] Figure 3P-3R Non-limiting examples of PAK4 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0169] Figure 3S-3T Non-limiting examples of TNIK-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0170] Figure 3U Non-limiting examples of MEN1-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0171] Figure 3V-3W Non-limiting examples of ERK1-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0172] Figure 3X Non-limiting examples of IDO1 targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0173] Figure 3Y Non-limiting examples of CBP-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0174] Figure 3Z-3SS Non-limiting examples of MCL1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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. wait people “Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.” J. Med. Chem.56: 15-30(2013); Petros A. M. et al. "Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein." Bioorg. Med. Chem. Lett. 24: 1484-1488 (2014); Burke J.P. et al. "Discovery of tricyclic indoles that potently inhibit MCL-1 using fragment-based methods and structure-based design." J. Med. Chem. 58: 3794-3805 (2015); Pelz N.F. et al. "Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (MCL-1) Inhibitors Using Fragment-Based Methods." J. Med. Chem. 59: 2054-2066 (2016); Clifton M.C. et al. "A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1." Plos One 10: e0125010-e0125010 (2015); Kotschy A et al. "The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature538:477-482 (2016); EP 2886545 A1 entitled "New thienopyrimidine derivatives a process for their preparation and pharmaceutical compositions containing them"; Jeffrey W. Johannes et al. "Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors" ACS Med. Chem. Lett. (2017); DOI: 10.1021 / acsmedchemlett.6b00464; Bruncko M. et al. "Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity." J. Med. Chem. 58: 2180-2194 (2015); Taekyu Lee et al. "Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors." FEBS Letters 591: 240–251 (2017); Chen L. et al. "Structure-Based Design of 3-Carboxy-Substituted 1 2 3 4-Tetrahydroquinolines as Inhibitors of Myeloid Cell Leukemia-1 (Mcl-1)." Org. Biomol. Chem.14:5505-5510 (2016); US2016 / 0068545 is titled "Tetrahydronaphthalene derivatives that inhibit mcl-1 protein"; WO 2016207217 A1 is titled "Preparation of new bicyclic derivatives aspro-apoptotic agents"; Gizem Akçay et al. are titled "Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain". Nature Chemical Biology 12:931–936 (2016).

[0175] Figure 3TT Non-limiting examples of ASH1L targeting ligands are provided, where R denotes an exemplary point connecting spacers. See, for example, the crystal structure PDB 4YNM (“Human ASH1L SET domain in complex with S-adenosylmethionine (SAM)” Rogawski DS et al.).

[0176] Figure 3UU-3WW Non-limiting examples of ATAD2-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see Chaikudad A. et al., “Structure-based approaches toward identification of fragments for the low-drugability ATAD2 bromodomain”. Med Chem Comm 5: 1843-1848 (2014); Poncet-Montange G. et al. “Observedbromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.” Biochem. J. 466: 337-346 (2015); Harner MJ et al. "Fragment-Based Screening of the Bromodomain of ATAD2." J. Med. Chem.57: 9687-9692 (2014); Demont EH et al. "Fragment-Based Discovery of Low-Micromolar Atad2Bromodomain Inhibitors." J. Med. Chem . 58: 5649 (2015); and Bamborough P. et al. “Structure-Based Optimization of Naphthyridones into Potent Atad2 BromodomainInhibitors.” J. Med. Chem. 58: 6151 (2015).

[0177] Figure 3XX-3AAA Non-limiting examples of BAZ2A and BAZ2B targeting ligands are provided, where R denotes an exemplary site connecting the spacer. 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.); and Ferguson FM et al., “Targeting low-drugability 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 BAZ2B Bromodomain Ligands: In Silico Discovery and inCrystallo Validation." J. Med. Chem.59: 9919-9927 (2016); Drouin L. et al. "Structure Enabled Design of BAZ2-ICR A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B." J. Med. Chem. 58: 2553-2559 (2015); Chen P. et al. "Discovery and characterization of GSK2801 a selective chemical probe for the bromodomains BAZ2A and BAZ2B." J. Med. Chem. 59:1410-1424 (2016).

[0178] Figure 3BBBNon-limiting examples of BRD1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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).

[0179] Figure 3CCC-3EEE Non-limiting examples of BRD2 Bromo domain 1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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.

[0180] Figure 3FFF-3HHHNon-limiting examples of BRD2 bromodomain-2 targeted ligands are provided, where R denotes an exemplary point connecting the spacer. 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. A bump-and-hole approach to engineercontrolled selectivity of BET bromodomain chemical probes" Science 346: 638-641(2014); Baud MG et al. "New Synthetic Routes to Triazolo-benzodiazepineAnalogues: Expanding the Scope of the Bump-and-Hole Approach for SelectiveBromo and Extra-Terminal (BET) Bromodomain Inhibition" J. Med. Chem. 59: 1492-1500 (2016); Gosmini R. et al. "The Discovery of I-Bet726 (Gsk1324726A) a PotentTetrahydroquinoline Apoa1 Up-Regulator and Selective Bet BromodomainInhibitor" J. Med. Chem.57: 8111 (2014); Crystal structure PDB 5EK9 (“Crystal structure of the second bromodomain of human BRD2 in complex with a hydroquinolinone inhibitor”, Tallant C. et al.); Crystal structure PDB 5BT5; Crystal structure PDB 5dfd; Baud 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).

[0181] Figure 3III-3JJJ Non-limiting examples of BRD4 Bromo domain 1-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures PDB 5WUU and PDB5F5Z.

[0182] Figure 3KKK-3LLL Non-limiting examples of BRD4 bromodomain 2-targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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 Analogues as Potent and Specific BET Bromodomain Inhibitors" J. Med. Chem. 58: 4927-4939 (2015).

[0183] Figure 3MMMNon-limiting examples of BRDT-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures PDB 4flp and PDB 4kcx.

[0184] Figure 3NNN-3QQQ Non-limiting examples of BRD9 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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; PDB 5fp2, (“Structure-Based Design of an Active Selective BRD9 Inhibitor” J Med Chem., 2016, 59(10),4462; and WO2016139361).

[0185] Figure 3RRR Non-limiting examples of SMARCA4 PB1 and / or SMARCA2 targeting ligands are provided, where R represents an exemplary point connecting spacers, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0186] Figure 3SSS-3XXX Additional non-limiting examples of bromodomain-targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Hewings et al., “3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands.” J. Med. Chem. 546761-6770 (2011); Dawson et al. "Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia." Nature 478, 529-533 (2011); US2015 / 0256700; US 2015 / 0148342; WO 2015 / 074064; WO 2015 / 067770; WO 2015 / 022332; WO2015 / 015318; and WO 2015 / 011084.

[0187] Figure 3YYY Non-limiting examples of PB1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures PDB 3mb4, PDB 4q0n, and PDB5fh6.

[0188] Figure 3ZZZ Non-limiting examples of SMARCA4 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures 3uvd and 5dkd.

[0189] Figure 3AAAA Non-limiting examples of SMARCA2 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures 5dkc and 5dkh; and WO2020023657, US20200038378, WO2020010227, WO2020078933, WO2019207538, WO2016138114, WO2020035779, and “Discovery of Orally Active Inhibitors of Brahma Homolog(BRM) / SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1(BRG1) / SMARCA4-Mutant Cancers”. J Med Chem 2018, 61 , 10155.

[0190] Figure 3BBBB Non-limiting examples of TRIM24 (TIF1a) and / or BRPF1 targeting ligands are provided, where R represents an exemplary point connecting spacers, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0191] Figure 3CCCC Non-limiting examples of TRIM24 (TIF1a) targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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).

[0192] Figure 3DDDD-3FFFF Non-limiting examples of BRPF1 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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.

[0193] Figure 3 GGGG Non-limiting examples of CECR2-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0194] Figure 3HHHH-3OOOO Non-limiting examples of CREBBP targeting ligands are provided, where R represents an exemplary point connecting spacers, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For other examples and related ligands, please refer to the 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; and PDB 5tb6.

[0195] Figure 3 PPPP Non-limiting examples of EP300 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structure PDB 5BT3.

[0196] Figure 3 QQQQNon-limiting examples of PCAF-targeting ligands are provided, where R denotes an exemplary point connecting spacers. See, for example, M. Ghizzoni et al. Bioorg. Med. Chem. 18: 5826–5834 (2010).

[0197] Figure 3RRRR Non-limiting examples of PHIP-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, please refer to [link to relevant documentation]. Mol Cancer Ther. 7(9): 2621–2632 (2008).

[0198] Figure 3SSSS Non-limiting examples of TAF1 and TAF1L targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see Picaud S. et al. Sci Adv 2: e1600760-e1600760 (2016).

[0199] Figure 3TTTT Non-limiting examples of histone deacetylase 2 (HDAC2) targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0200] Figure 3 UUUU-3VVVV Non-limiting examples of histone deacetylase 4 (HDAC4) targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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).

[0201] Figure 3 WWWWNon-limiting examples of histone deacetylase 6 targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Harding RJ (to be published); Hai Y. Nat. Chem. Biol. 12: 741-747, (2016); and Miyake Y. Nat. Chem. Biol. 12: 748 (2016).

[0202] Figure 3XXXX-3YYYY Non-limiting examples of histone deacetylase 7 targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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).

[0203] Figure 3ZZZZ-3DDDDD Non-limiting examples of histone deacetylase 8 targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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 Biochemistry 12, 1325-1334 (2004);Decroos C. Biochemistry 54: 2126-2135(2015); Vannini A. Proc. Natl Acad. Sci. 101: 15064 (2004); Vannini A. EMBO Rep. 8:879 (2007); Crystal structure: PDB 5BWZ; Decroos A. ACS Chem. Biol. 9: 2157-2164 (2014); Somoza 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).

[0204] Figure 3 EEEEE Non-limiting examples of histone acetyltransferase (KAT2B) targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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).

[0205] Figure 3FFFFF-3GGGGG Non-limiting examples of histone acetyltransferase (KAT2A) targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see Ringel AE. Acta Crystallogr. D. Struct. Biol. 72: 841-848 (2016).

[0206] Figure 3 HHHHH Non-limiting examples of histone acetyltransferase type B catalytic unit (HAT1) targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see the crystal structure PDB2P0W.

[0207] Figure 3IIIII I provides a non-restrictive example of a cyclic AMP-dependent transcription factor (ATF2) targeting ligand, where R denotes an exemplary point connecting spacers.

[0208] Figure 3 JJJJJ Non-limiting examples of histone acetyltransferase (KAT5) targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0209] Figure 3KKKKK-3MMMMM Non-limiting examples of lysine-specific histone demethylase 1A (KDM1A) targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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).

[0210] Figure 3 NNNNN Non-limiting examples of HDAC6 Zn finger domain-targeted ligands are provided, where R denotes an exemplary point connecting spacers.

[0211] Figure 30000-3PPPPPNon-limiting examples of universal lysine methyltransferase targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0212] Figure 3QQQQQ-3TTTTT Non-limiting examples of DOT1L targeting ligands are provided, where R represents an exemplary point connecting spacers, A is N or CH, and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. For other examples and related ligands, please refer to the crystal structures of PDB 5MVS (“Dot1L in complex with adenosine and inhibitor CPD1” Mobitz, H. et al., ACS Med Chem Lett., 2017, 8: 338-343); PDB 5MW3, 5MW4 (“Dot1L in complex inhibitor CPD7” Be C. et al.); PDB 5DRT (“Dot1L in complex inhibitor CPD2” Chen, C. et al., ACS Med Chem Lett., 2016, 7: 735-740); PDB 5DRY (“Dot1L in complex with CPD3”, Chen, C. et al., ACS Med Chem Lett., 2016, 7: 735-740); and PDB 5DSX (“Dot1L in complex with CPD10”, Chen, C. et al.). ACS Med Chem Lett., 2016, 7: 735-740), crystal structure PDB 5DT2 (“Dot1L in complex with CPD11”, Chen, C., et al., ACS Med Chem Lett., 2016, 7: 735-740), crystal structure PDB 5JUW (“Dot1L in complex with SS148”, Yu W. et al., Structural Genomics Consortium), crystal structure PDB 6TE6 (“Dot1L in complex with an inhibitor, compound3”, Stauffer, F., et al., ACS Med Chem Lett., 2019, 10: 1655-1660).

[0213] Figure 3 UUUUUNon-limiting examples of EHMT1 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 5TUZ (“EHMT1 in complex withinhibitor MS0124”, Babault N. et al.).

[0214] Figure 3 VVVVV Non-limiting examples of EHMT2 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 5TUY (“EHMT2 in complex withinhibitor MS0124”, Babault N. et al.); PDB crystal structure 5TTF (“EHMT2 in complex withinhibitor MS012”, Dong A. et al.); PDB crystal structure 3RJW (Dong A. et al., StructuralGenomics Consortium); PDB crystal structure 3K5K; Liu F. et al. J. Med. Chem. 52: 7950-7953 (2009); and the PDB crystal structure 4NVQ (“EHMT2 in complex with inhibitor A-366” Sweis RF et al.).

[0215] Figure 3 WWWWW Non-limiting examples of SETD2 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0216] Figure 3XXXXX-3YYYYYNon-limiting examples of SETD7 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0217] Figure 3 ZZZZZ Non-limiting examples of SETD8 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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).

[0218] Figures 4A-4B Non-limiting examples of SETDB1 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see PDB crystal structure 5KE2 (“SETDB1 in complex withinhibitor 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., StructuralGenomics Consortium); and PDB crystal structure 5KCO (“SETDB1 in complex with [N]-(4-chlorophenyl)methanesulfonamide”, Walker JR et al.). Figure 4C-4P Non-limiting examples of SMYD2 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, please refer to the following PDB crystal structures: 5KJK (“SMYD2 in complex withinhibitor AZ13450370”, Cowen SD et al.); 5KJM (“SMYD2 in complex with AZ931”, Cowen SD et al.); 5KJN (“SMYD2 in complex with AZ506”, Cowen SD et al.); 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.); and 5ARG (“SMYD2 in complex with BAY598”, Eggert E. et al.). 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.).

[0219] Figure 4Q-4RNon-limiting examples of SMYD3 targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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 GS et al.); crystal structure 5CCL (“SMYD3 in complex with oxindole compound”, Mitchell LH et al.); and crystal structure 5CCM (“Crystal structure of SMYD3 with SAM and EPZ030456”).

[0220] Figure 4S Non-limiting examples of SUV4-20H1 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see PDB crystal structure 5CPR (“SUV4-20H1 in complex withinhibitor A-196”, Bromberg KD et al.).

[0221] Figure 4T-4AA Non-limiting examples of wild-type androgen receptor targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the PDB crystal structures 5T8E and 5T8J (“Androgen Receptor in complex with 4-(pyrrolidin-1-yl)benzonitrile derivatives”, Asano M. et al.); Asano M. et al. Bioorg. Med. Chem. Lett.27: 1897-1901 (2017); PDB crystal structure 5JJM (“Androgen Receptor”, Nadal M. et al.); PDB crystal structure 5CJ6 (“Androgen Receptor in complex with 2-Chloro-4-[[(1R 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile derivatives”, Saeed A. et al.); PDB crystal structure 4QL8 (“Androgen Receptor in complex with 3-alkoxy-pyrrolo[1 2-b]pyrazolines derivatives”, Ullrich T. et al.); PDB crystal structure 4HLW (“Androgen Receptor Binding Function 3 (BF3)Site of the Human Androgen Receptor through Virtual Screening”, Munuganti R.S. et al.); PDB crystal structure 3V49 (“Androgen Receptor lbd with Activator peptide and sarm inhibitor 1” (Nique F. et al.); Nique F. et al. J. Med. Chem. 55: 8225-8235 (2012); PDB crystal structure 2YHD (“Androgen Receptor in complex with AF2 small molecule inhibitor”, Axerio-Cilies P. et al.); PDB crystal structure 3RLJ (“Androgen Receptor ligand binding domain in complex with SARM S-22”, Bohl 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, please refer to [reference needed]. Matias PM et al. “Structural Basis for the Glucocorticoid Response in aMutant Human Androgen Receptor (Ar(Ccr)) Derived from an Androgen-IndependentProstate Cancer. ” J. Med. Chem. 45: 1439 (2002); Sack JS et al. “Crystallographic structures of the ligand-binding domains of the androgen receptor and 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. Cell 16: 425-438 (2004); Pereira de Jesus-Tran K. "Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity." Protein Sci. 15:987-999 (2006); Bohl CE 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 AA 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 CE 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]pyrazolinesas selective androgen receptor modulators with ideal physicochemicalproperties for transdermal administration. ” J. Med. Chem. 57: 7396-7411(2014); Saeed A. et al. “2-Chloro-4-[[(1R 2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile: A Transdermal Selective Androgen ReceptorModulator (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 ReceptorAntagonists for Castration-Resistant Prostate Cancer (CRPC).” J. Med. Chem. 53:2779–2796 (2010).

[0222] Figure 4BB Non-limiting examples of mutant T877A androgen receptor targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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 CE et al.).

[0223] Figure 4CCNon-limiting examples of androgen receptor-targeting ligands for the mutant W741L are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see PDB crystal structure 4OJB (“AndrogenReceptor T877A-AR-LBD”, Hsu CL et al.).

[0224] Figure 4DD-4EE Non-limiting examples of estrogen and / or androgen-targeting ligands are provided, where R denotes an exemplary point connecting spacers.

[0225] Figure 5A Non-limiting examples of afatinib are provided, which is a targeting ligand for the EGFR and ErbB2 / 4 receptors. R denotes an exemplary point connecting spacers.

[0226] Figure 5B Non-limiting examples of axitinib are provided, which are targeting ligands for VEGFR1 / 2 / 3, PDGFRβ, and Kit receptors. R denotes an exemplary point connecting spacers.

[0227] Figures 5C-5D Non-limiting examples of bosutinib are provided, which is a targeting ligand for the BCR-Abl, Src, Lyn, and Hck receptors. R denotes an exemplary point connecting spacers.

[0228] Figure 5E Non-limiting examples of cabozantinib are provided, which are targeting ligands for RET, c-Met, VEGFR1 / 2 / 3, Kit, TrkB, Flt3, Axl, and Tie2 receptors. R denotes an exemplary point connecting spacers.

[0229] Figure 5F Non-limiting examples of ceritinib are provided, which is a targeting ligand for the ALK, IGF-1R, InsR, and ROS1 receptors. R denotes an exemplary point connecting spacers.

[0230] Figure 5G Non-limiting examples of crizotinib are provided, which are targeting ligands for the ALK, c-Met, HGFR, ROS1, and MST1R receptors. R denotes an exemplary point connecting a spacer.

[0231] Figure 5H Non-limiting examples of dabrafenib are provided, which is a targeting ligand of the B-Raf receptor. R denotes an exemplary point connecting spacers.

[0232] Figure 5INon-limiting examples of dasatinib are provided, which are targeting ligands for the BCR-Abl, Src, Lck, Lyn, Yes, Fyn, Kit, EphA2, and PDGFRβ receptors. R denotes an exemplary point connecting a spacer.

[0233] Figure 5J A non-limiting example of erlotinib is provided, which is a targeting ligand of the EGFR receptor. R denotes an exemplary point connecting spacers.

[0234] Figure 5K-5M Non-limiting examples of everolimus are provided, which are targeted ligands for the HER2 breast cancer receptor, PNET receptor, RCC receptor, RAML receptor, and SEGA receptor. R denotes an exemplary point connecting spacers.

[0235] Figure 5N Non-limiting examples of gefitinib are provided, which is a targeting ligand for the EGFR and PDGFR receptors. R denotes an exemplary point connecting spacers.

[0236] Figure 5O Non-limiting examples of ibrutinib are provided, ibrutinib being a targeting ligand of the BTK receptor. R denotes an exemplary point connecting spacers.

[0237] Figure 5P-5Q Non-limiting examples of imatinib are provided, which are targeting ligands for the BCR-Abl, Kit, and PDGFR receptors. R denotes exemplary points connecting spacers.

[0238] Figure 5R-5S Non-limiting examples of lapatinib are provided, which is a targeting ligand for the EGFR and ErbB2 receptors. R denotes an exemplary point connecting spacers.

[0239] Figure 5T Non-limiting examples of lenvatinib are provided, which are targeting ligands for VEGFR1 / 2 / 3, FGFR1 / 2 / 3 / 4, PDGFRα, Kit, and RET receptors. R denotes an exemplary point connecting spacers.

[0240] Figure 5U-5V Non-limiting examples of nilotinib are provided, which is a targeting ligand for the BCR-Abl, PDGRF, and DDR1 receptors. R denotes an exemplary point connecting spacers.

[0241] Figure 5W-5X Non-limiting examples of nintedanib are provided, which are targeting ligands for the receptors FGFR1 / 2 / 3, Flt3, Lck, PDGFRαDG, and VEGFR1 / 2 / 3. R denotes an exemplary point connecting a spacer.

[0242] Figure 5Y-5Z Non-limiting examples of palbociclib are provided, which is a targeting ligand of the CDK4 / 6 receptor. R denotes an exemplary point connecting spacers.

[0243] Figure 5AA Non-limiting examples of pazopanib are provided, which are targeting ligands for VEGFR1 / 2 / 3, PDGFRαDG, FGFR1 / 3, Kit, Lck, Fms, and Itk receptors. R denotes an exemplary point connecting a spacer.

[0244] Figure 5BB-5CC Non-limiting examples of panatinib are provided, which are targeting ligands for BCR-Abl, T315IVEGFR, PDGFR, FGFR, EphR, Src family kinases, Kit, RET, Tie2, and Flt3 receptors. R denotes an exemplary point connecting a spacer.

[0245] Figure 5DD Non-limiting examples of regorafenib are provided, which are targeting ligands for VEGFR1 / 2 / 3, BCR-Abl, B-Raf, B-Raf (V600E), Kit, PDGFRαDG, RET, FGFR1 / 2, Tie2, and Eph2A. R denotes an exemplary point connecting a spacer.

[0246] Figure 5EE Non-limiting examples of ruxolitinib are provided, which is a targeting ligand of the JAK1 / 2 receptor. R denotes an exemplary point connecting spacers.

[0247] Figure 5FF-5GG Non-limiting examples of sirolimus are provided, which is a targeting ligand of the FKBP12 / mTOR receptor. R denotes an exemplary point connecting spacers.

[0248] Figure 5HH Non-limiting examples of sorafenib are provided, which are targeting ligands for B-Raf, CDK8, Kit, Flt3, RET, VEGFR1 / 2 / 3, and PDGFR receptors. R denotes an exemplary point connecting spacers.

[0249] Figure 5II-5JJ Non-limiting examples of sunitinib are provided, which are targeting ligands for PDGFRαDG, VEGFR1 / 2 / 3, Kit, Flt3, CSF-1R, and RET. R denotes an exemplary point connecting a spacer.

[0250] Figure 5KK-5LL A non-limiting example of tansirolimus is provided, which is the targeting ligand FKBP12 / mTOR. R denotes an exemplary point connecting spacers.

[0251] Figure 5MM Non-limiting examples of tofacitinib are provided, which is a targeting ligand for the JAK3 receptor. R denotes an exemplary point connecting spacers.

[0252] Figure 5NN Non-limiting examples of trametinib are provided, which is a targeting ligand of the MEK1 / 2 receptor. R denotes an exemplary point connecting spacers.

[0253] Figure 500-5PP Non-limiting examples of vandetanib are provided, which are targeting ligands for EGFR, VEGFR, RET, Tie2, Brk, and EphR. R denotes an exemplary point connecting spacers.

[0254] Figure 5 QQ Non-limiting examples of vemurafenib are provided, which are targeting ligands for A / B / C-Raf, KSR1, and B-Raf (V600E) receptors. R denotes an exemplary point connecting spacers.

[0255] Figure 5RR Non-limiting examples of edralini are provided, which is a targeting ligand of the PI3Ka receptor. R denotes an exemplary point connecting spacers.

[0256] Figure 5SS A non-limiting example of buppanicyl is provided, which is a targeting ligand for the PI3Ka receptor. R denotes an exemplary point connecting spacers.

[0257] Figure 5TT Non-limiting examples of taselisib are provided, which is a targeting ligand for the PI3Ka receptor. R denotes an exemplary point connecting spacers.

[0258] Figure 5UU Non-limiting examples of cupannisi are provided, which are targeting ligands of PI3Ka. R denotes an exemplary point connecting spacers.

[0259] Figure 5VV Non-limiting examples of apelis are provided, which are targeting PI3Ka ligands. R denotes an exemplary point connecting spacers.

[0260] Figure 5WW Non-limiting examples of niclosamide are provided, which is a targeting ligand of CNNTB1. R denotes an exemplary point connecting spacers.

[0261] Figures 6A-6BNon-limiting examples of BRD4 bromodomains for PCAF and GCN5 receptor 1 targeting ligands are provided, where R denotes an exemplary site connecting spacers. 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).

[0262] Figures 6C-6D Non-limiting examples of G9a (EHMT2) targeting ligands are provided, where R denotes an exemplary site connecting the spacer. 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 lysine methyltransferase G9a”); Liu, F. et al. J. Med. Chem. 52: 7950 (2009); PDB crystal structure 3rjw (“A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells”); Vedadi, M. et al. Nat. Chem. Biol. 7: 566 (2011); PDB crystal structure 4nvq (“Discovery and development of potent and selective inhibitors of histone methyltransferase g9a”); and Sweis, RF et al. ACS Med Chem Lett 5: 205 (2014).

[0263] Figure 6E-6G Non-limiting examples of EZH2-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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 Commun 7: 11384 (2016); PDB Crystal Structure 5ls6 (“Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of HistoneMethyltransferase EZH2, Suitable for Phase I Clinical Trials for B-CellLymphomas”); Vaswani, RG et al. J. Med. Chem. 59: 9928 (2016); and PDB crystal structures 5ij8 and 5ls6.

[0264] Figure 6H-6I Non-limiting examples of EED-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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.

[0265] Figure 6J Non-limiting examples of KMT5A (SETD8) targeting ligands are provided, where R denotes an exemplary point connecting spacers. See, for example, the PDB crystal structure 5t5g.

[0266] Figure 6K-6L Non-limiting examples of DOT1L targeting ligands are provided, where R denotes an exemplary point connecting the spacer. 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 Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach”) Chen, C. et al. ACS Med. Chem. Lett. 7:735 (2016); PDB crystal structure 5dt2 (“Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach”); and Chen, C. et al. ACS Med. Chem. Lett. 7: 735 (2016).

[0267] Figure 6M-6N Non-limiting examples of PRMT3 targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see PDB crystal structure 3smq (“An allosteric inhibitor of protein arginine methyltransferase 3”); Siarheyeva, A. et al. Structure20: 1425 (2012); PDB crystal structure 4ryl (“A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)”); and Kaniskan, HU et al. Angew. Chem. Int. Ed. Engl. 54: 5166 (2015).

[0268] Figure 6O Non-limiting examples of CARM1 (PRMT4) targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the PDB crystal structures 2y1x and 2y1w and the related ligand described in “Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors.” Sack, JS, et al. Biochem. J 436: 331 (2011).

[0269] Figure 6P Non-limiting examples of PRMT5 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see PDB crystal structure 4x61 and the related ligand described below, “A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCLmodels”. Chan-Penebre, E. Nat. Chem. Biol 11: 432 (2015).

[0270] Figure 6Q Non-limiting examples of PRMT6 targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the PDB crystal structure 4y30 and the related ligand described below, “ArylPyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound”. (Mitchell, LH et al.) ACS Med. Chem. Lett 6:655 (2015).

[0271] Figure 6RNon-limiting examples of LSD1 (KDM1A) targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the PDB crystal structure 5lgu and the related ligand described below, “Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of HistoneLysine Demethylase KDM1A / LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship”. Vianello, P. et al. J. Med. Chem. 60: 1693 (2017).

[0272] Figure 6S-6T Non-limiting examples of KDM4-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see PDB crystal structure 3rvh; PDB crystal structure 5a7p and the related ligand described in “Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors.” Korczynska, M., et al. J. Med. Chem. 59: 1580 (2016); and the PDB crystal structure 3f3c and the related ligands described below: “8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.” Bavetsias, V. et al. J. Med. Chem. 59: 1388 (2016).

[0273] Figure 6UNon-limiting examples of KDM5-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see the PDB crystal structure 3fun and the related ligands described below in "Structural Analysis of Human Kdm5B Guides Histone Demethylase Inhibitor Development" by Johansson, C. et al. Nat. Chem. Biol. 12: 539 (2016) and the PDB crystal structure 5ceh and the related ligand described in the following article, “An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells”. Vinogradova, M. et al. Nat. Chem. Biol. 12:531 (2016).

[0274] Figure 6V-6W Non-limiting examples of KDM6-targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see PDB crystal structure 4ask and the related ligand described below, “A Selective Jumonji H3K27 Demethylase Inhibitor Modulates the Proinflammatory Macrophage Response”. Kruidenier, L. et al. Nature 488: 404 (2012).

[0275] Figure 6X Non-limiting examples of L3MBTL3 targeting ligands are provided, where R denotes an exemplary point connecting spacers. See, for example, the PDB crystal structure 4fl6.

[0276] Figure 6Y Non-limiting examples of Menin-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see the PDB crystal structure 4x5y and the related ligand described below in "Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo" by Borkin, D. et al. Cancer Cell27: 589 (2015) and the PDB crystal structure 4og8 and the related ligand described in the following "High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction" He, S. et al. J. Med. Chem. 57: 1543 (2014).

[0277] Figure 6Z-6AA Non-limiting examples of HDAC6 targeting ligands are provided, where R denotes an exemplary point connecting spacers. See, for example, the PDB crystal structures 5kh3 and 5eei.

[0278] Figure 6BB Non-limiting examples of HDAC7 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the PDB crystal structure 3c10 and the related ligand described in “Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.” Schuetz, A. et al. J. Biol. Chem. 283: 11355 (2008) and the PDB crystal structure PDB 3zns and the related ligands described in the following “Selective Class Iia HistoneDeacetylase Inhibition Via a Non-Chelating Zinc Binding Group”. Lobera, M. et al. Nat. Chem. Biol 9:319 (2013). Figures 7A-7C Non-limiting examples of protein tyrosine phosphatase type 1 non-receptor, PTP1B-targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see PDB crystal structure 1bzj, described in “Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics” Groves, MR et al. Biochemistry37:17773-17783 (1998); The crystal structure of PDB is described in "Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor". Han Y, Bioorg Med Chem Lett. 18:3200-5 (2008); PDB crystal structures 2azr and 2b07 are described in "Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors." Moretto, AF et al. Bioorg. Med. Chem 14: 2162-2177 (2006); PDB crystal structures PDB 2bgd, 2bge, 2cm7, 2cm8, 2cma, 2cmb, 2cmc are described in "Structure-Based Design of Protein Tyrosine Phosphatase-1B Inhibitors". Black, E. et al. Bioorg. Med. Chem. Lett. 15: 2503 (2005) and “Structural Basis for Inhibition ofProtein-Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic PhosphonateMimetics.” Ala, PJ et al. J. Biol. Chem. 281: 32784 (2006); PDB crystal structures 2f6t and 2f6w are described in "1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors". Klopfenstein, SR et al. Bioorg. Med. Chem. Lett. 16: 1574-1578 (2006); PDB crystal structures 2h4g, 2h4k, 2hb1 are described in "Monocyclic thiophenes as proteintyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48." Wan, ZK et al. Bioorg. Med. Chem. Lett.16: 4941-4945 (2006); PDB crystal structure 2zn7 is described in "Structure-based optimization of protein tyrosine phosphatase-1B inhibitors: capturing interactions with arginine 24". Wan, ZK et al. Chem Med Chem. 3:1525-9 (2008); PDB crystal structures 2nt7, 2nta are described in “Probing acid replacements of thiophenePTP1B inhibitors.” Wan, ZK et al. Bioorg. Med. Chem. Lett. 17: 2913-2920 (2007); and WO 2008148744 A1, transferred to Novartis AG, is titled “Thiadiazole derivatives as antidiabetic agents.” See also PDB crystal structures 1c84, 1c84, 1c85, 1c86, 1c88, 1l8g and described in “2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases”. Andersen, HS et al. J. Biol. Chem. 275: 7101-7108(2000); "Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase1B." Iversen, LF et al. J. Biol. Chem . 275: 10300-10307 (2000); "Sterichindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases". Iversen, LF et al. Biochemistry 40: 14812-14820 (2001).

[0279] Figure 7D Non-limiting examples of ligands targeting tyrosine protein phosphatase type 11 SHP2 are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see crystal structures PDB 4pvg and 305x and described in “Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)”, Zhang, X. et al. J. Med. Chem . 53: 2482-2493 (2010); and the crystal structure PDB 5ehr and the related ligand described in the following "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor." Garcia Fortanet, J. et al. J. Med. Chem. 59: 7773-7782 (2016). See also the crystal structure described in PDB 5ehr in “Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.” Garcia Fortanet, J. et al. J. Med. Chem. 59:7773-7782 (2016) and "Allosteric inhibition of SHP2 phosphatase inhibits cancersdriven by receptor tyrosine kinases." Chen, YP et al. Nature 535: 148-152 (2016).

[0280] Figure 7ENon-limiting examples of non-receptor type 22 target ligands for tyrosine protein phosphatase are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see Crystal Structure PDB 4j51 described in “APotent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases” by He, Y. et al. J. Med. Chem. 56: 4990-5008 (2013).

[0281] Figure 7F Non-limiting examples of DcpS target ligands for the scavenger mRNA uncapping enzyme are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see crystal structures PDB 3bl7, 3bl9, 3bla, 4qde, 4qdv, 4qeb and the related ligand described below, “DcpS as a therapeutic target for spinalmuscular atrophy.” Singh, J. et al. ACS Chem.Biol. 3: 711-722 (2008).

[0282] Figure 8A-8S Non-limiting examples of BRD4 Bromo domain 1-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures PDB 3u5k and 3u51 and the related ligand Filippakopoulos, P. below. et al. “Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family”, Bioorg. Med. Chem. 20: 1878-1886 (2012); crystal structure PDB 3u5l; crystal structure PDB 3zyu and related ligands described below, Dawson, MA et al., “Inhibition of Bet Recruitment to Chromatinas an Effective Treatment for Mll-Fusion Leukaemia.” Nature478: 529 (2011); crystal structure PDB 4bw1 and related ligands described below, Mirguet, O. et al. “Naphthyridines as NovelBet Family Bromodomain Inhibitors.” Chemmedchem 9: 589 (2014); crystal structure PDB 4cfl and related ligands described below, Dittmann, A. et al. “The Commonly Used Pi3-Kinase ProbeLy294002 is an Inhibitor of Bet Bromodomains” ACS Chem. Biol. 9:495 (2014); crystal structure PDB 4e96 and related ligands described below Fish, PV et al. “Identification of achemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.” J. Med. Chem. 55: 9831-9837 ( 2012); Crystal structure PDB 4clb and related ligands described below Atkinson, SJ et al. “The Structure BasedDesign of Dual Hdac / Bet Inhibitors as Novel Epigenetic Probes.” Medchemcomm 5:342 (2014); Crystal structure PDB 4f3i and related ligands described in the following article: Zhang, G. et al., “Down-regulation of NF-{kappa}B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.” J. Biol. Chem.287: 28840-28851 (2012); Crystal structure PDB4hxl and related ligands described in Zhao, L., “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.” J. Med. Chem. 56: 3833-3851 (2013); crystal structure PDB 4hxs and related ligands described below Zhao, L. et al. “Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of theHistone Reader BRD4 Bromodomain.” J. Med. Chem 56: 3833-3851 (2013); crystal structure PDB 4lrg and related ligands described below, Gehling, VS et al. “Discovery, Design, andOptimization of Isoxazole Azepine BET Inhibitors.” ACS Med Chem Lett 4: 835-840 (2013); crystal structure PDB 4mep and related ligands described in Vidler, LR, “Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.” et al. J. Med. Chem. 56: 8073-8088 (2013); crystal structures PDB 4nr8 and PDB 4c77 and related ligands described in Ember, SW et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem.Biol. 9:1160-1171 (2014); crystal structure PDB 4o7a and related ligands described below, Ember, SW et al.“Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4)Interacts with Diverse Kinase Inhibitors.” ACS Chem. Biol. 9: 1160-1171 (2014); crystal structure PDB 407b and related ligands described in “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.” Ember, SW et al. (2014) ACS Chem. Biol. 9: 1160-1171; Crystal structure PDB 4o7c and related ligands described in Ember, SW et al., “Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors”. ACS Chem. Biol. 9: 1160-1171 (2014); crystal structure PDB 4gpj; crystal structure PDB4uix and related ligands described below: Theodoulou, NH et al. “The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”. J. Med. Chem. 59: 1425 (2016); Crystal structure PDB 4uiz and related ligands described in Theodoulou, NH, et al. "The Discovery of I-Brd9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition". J. Med. Chem.59: 1425 (2016); Crystal structure PDB 4wiv and related ligands described below in McKeown, MR et al., “Biased multicomponent reactions to develop novel bromodomain inhibitors.” J. Med. Chem 57: 9019-9027 (2014); crystal structure PDB 4x2i and related ligands described below Taylor, AM et al. “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally ActiveInhibitors of BET Bromodomains.” ACS Med. Chem. Lett. 7: 145-150 (2016); crystal structure PDB 4yh3; and related ligands described below, Duffy, BC, “Discovery of a new chemicalseries of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.” Bioorg. Med. Chem. Lett. 25: 2818-2823 (2015); Crystal structure PDB 4yh4 and related ligands described below, Duffy, BC, “Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.” Bioorg. Med. Chem. Lett 25: 2818-2823 (2015); Crystal structure PDB 4z1q and related ligands described below. Taylor, AM “Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.” ACS Med. Chem. Lett.7: 145-150 (2016); crystal structure PDB 4zw1; crystal structure PDB 5a5s and related ligands described below, Demont, EH "Fragment-Based Discovery of Low-Micromolar Atad2 Bromodomain Inhibitors". J. Med. Chem. 58: 5649 (2015); Crystal structure PDB 5a85 and related ligands described in Bamborough, P. “Structure-Based Optimization of Naphthyridones Into Potent Atad2Bromodomain Inhibitors” J. Med. Chem. 58: 6151 (2015); Crystal structure PDB 5acy and related ligands described in the following article, Sullivan, JM, “Autism-Like Syndrome is Induced by Pharmacological Suppression of Bet Proteins in Young Mice.” J. Exp. Med. 212:1771 (2015); Crystal structure PDB 5ad2 and related ligands described below, Waring, MJ et al. “Potent andSelective Bivalent Inhibitors of Bet Bromodomains”. Nat. Chem. Biol. 12: 1097 (2016); Crystal structure PDB 5cfw and related ligands described below Chekler, EL et al. “Transcriptional Profiling of a Selective CREB Binding Protein BromodomainInhibitor Highlights Therapeutic Opportunities.” Chem. Biol.22: 1588-1596 (2015); crystal structure PDB 5cqt and related ligands described in the following article: Xue, X. et al., “Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation”. J. Med. Chem. 59: 1565-1579 (2016); crystal structure PDB 5d3r and related ligands described below, Hugle, M. et al. “4-Acyl Pyrrole Derivatives Yield Novel Vectors for DesigningInhibitors of the Acetyl-Lysine Recognition Site of BRD4(1)”. J. Med. Chem. 59:1518-1530 (2016); Crystal structure PDB 5dlx and related ligands described in Milhas, S. et al., “Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.” (2016) ACS Chem.Biol. 11: 2140-2148; Crystal structure PDB5dlz and related ligands described in Milhas, S. et al., “Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.” ACS Chem. Biol. 11: 2140-2148 (2016); Crystal structure PDB 5dw2 and related ligands described below, Kharenko, OA et al. “RVX-297- a novel BD2 selective inhibitor of BETbromodomains.” Biochem. Biophys. Res. Commun. 477: 62-67 (2016); crystal structure PDB5dlx; crystal structure PDB5his and related ligands described below Albrecht, BK et al. “Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials.” J. Med. Chem. 59: 1330-1339 (2016); crystal structure PDB 5ku3 and related ligands described in the following article: Crawford, TD et al., “Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP / EP300”. J. Med. Chem. 59: 10549-10563 (2016); crystal structure PDB5lj2 and related ligands described below, Bamborough, P. et al. "A Chemical Probe for the ATAD2Bromodomain." Angew. Chem. Int. Ed. Engl. 55: 11382-11386 (2016); crystal structure PDB5dlx and related ligands described below. Wang, L. “Fragment-based, structure-enabled discovery of novel pyridones and pyridone macrocycles as potent bromodomain and extra-terminal domain (BET) family bromodomain inhibitors”. J. Med. Chem.10.1021 / acs.jmedchem.7b00017 (2017); WO 2015169962 A1 entitled "Benzimidazole derivatives as BRD4 inhibitors and their preparation and use for the treatment of cancer" was 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" was assigned to Dana-Farber Cancer Institute, Inc, USA.

[0283] Figure 8T-8V Non-limiting examples of ALK-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 2xb7 and 2xba and related ligands described in Bossi, RT et al., “Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors”. Biochemistry 49: 6813-6825 (2010); Crystal structures PDB2yfx, 4ccb, 4ccu and 4cd0 and related ligands described in Huang, Q. et al., “Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.” J. Med. Chem.57: 1170 (2014); Crystal structures PDB, 4cli, 4cmo, and 4cnh and related ligands described below: 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 BrainExposure and Broad Spectrum Potency Against Alk-Resistant Mutations.” J. Med. Chem. 57: 4720 (2014); Crystal structure PDB 4fny and related ligands described in Epstein, LF et al., “The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase.” J. Biol. Chem. 287: 37447-37457 (2012). Crystal structure of PDB 4dce and related ligands described in Bryan, MC et al., “Rapid development of piperidine carboxamides aspotent and selective anaplastic lymphoma kinase inhibitors”. J. Med. Chem.55:1698-1705 (2012); Crystal structure PDB 4joa and related ligands described below, Gummadi, VR et al., “Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: wild type and mutant (L1196M) active compounds with unique binding mode.” (2013) Bioorg. Med. Chem. Lett. 23: 4911-4918; and the crystal structure PDB 5iui and the related ligands described in the following: Tu, CH et al., “Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).” J. Med. Chem. 59: 3906-3919 (2016).

[0284] Figure 8W-8X Non-limiting examples of BTK-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see crystal structures PDB 3gen, 3piz and the related ligand described below by 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 multipleligand complex structures" Protein Sci.20: 428-436" (2011); Crystal structure PDB 3ocs, 4ot6 and related ligands described below. Lou, Y. et al., "Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis" J. Med. Chem. 58: 512-516 (2015); Crystal structures PDB 5fbn and 5fbo and related ligands described below: Liu, J. et al., “Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.” ACS Med. Chem. Lett. 7: 198-203 (2016); Crystal structure PDB 3pix and related ligands described below, Kuglstatter, A. et al., “Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures.” Protein Sci. 20: 428-436 (2011); and the crystal structure PDB 3pij and the related ligands described in the following article, Bujacz, A. et al., “Crystal structures of the apo form of beta-fructofuranosidase from Bifidobacterium longum and its complex with fructose.” Febs J. 278: 1728-1744 (2011).

[0285] Figure 8YNon-limiting examples of FLT3-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see crystal structures PDB 4xuf and 4rt7 and the related ligand described below in Zorn, JA et al., “Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)”. Plos One 10: e0121177-e0121177 (2015).

[0286] Figure 8Z-8AA Non-limiting examples of TNIK-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 2x7f; crystal structures PDB 5ax9 and 5d7a; and the related ligand described in Masuda, M. et al., “TNIK inhibition abrogates colorectal cancer stemness”. Nat Commun 7: 12586-12586 (2016).

[0287] Figure 8BB-8CC Non-limiting examples of NTRK1, NTRK2, and NTRK3 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 4aoj and the related ligands described below in Wang, T. et al., “Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors.” ACS Med. Chem. Lett. 3: 705 (2012); Crystal structures PDB 4pmm, 4pmp, 4pms and 4pmt and related ligands described in the following article: Stachel, SJ et al., “Maximizing diversity from a kinase screen: identification of novel and selective pan-Trkinhibitors for chronic pain.” J. Med. Chem57: 5800-5816 (2014); Crystal structures PDB4yps and 4yne and related ligands described in Choi, HS et al., “(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.” ACS Med. Chem. Lett. 6: 562-567 (2015); Crystal structures PDB 4at5 and 4at3 and related ligands described in the following: Bertrand, T. et al., “The Crystal Structures of Trka and Trkb: Suggest Key Regions for Achieving Selective Inhibition.” J. Mol. Biol. 423:439 (2012); and the crystal structures PDB 3v5q and 4ymj and the related ligands described in the following article, “Discovery of GNF-5837, a selective TRK Inhibitor with efficacy in rodent cancer tumor models.” ACS Med. Chem. Lett. 3: 140–145 (2012) and Choi, HS et al. “(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potentand Selective Pan-TRK Inhibitors.” ACS Med Chem Lett 6: 562-567 (2015).

[0288] Figure 8DD-8EE Non-limiting examples of FGFR1-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see crystal structures PDB 3tto and 2fgi and the related ligand described below by Brison, Y. et al., “Functional and structural characterization of alpha-(1-2)branching sucrase derived from DSR-E glucansucrase.” J. Biol. Chem.287: 7915-7924 ​​(2012) and Mohammadi, M. et al. “Crystal structure of an angiogenesisinhibitor bound to the FGF receptor tyrosine kinase domain.” EMBO J. 17: 5896-5904 (1998); crystal structure PDB 4fb3; crystal structure PDB 4rwk and the related ligand described in Harrison, C. et al., “Polyomavirus large T antigen binds symmetrical repeats at the viral origin in an asymmetrical manner.” J. Virol. 87: 13751-13759 (2013); Crystal structure PDB 4rwl and related ligands described in the following article: Sohl, CD et al., “Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles' Heel of Targeted Therapy.” ACS Chem. Biol 10: 1319-1329 (2015); crystal structure PDB 4uwc; crystal structure PDB 4v01 and related ligands described below: Tucker, JA et al., “Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4.” Structure 22: 1764 (2014).; Crystal structure PDB 5a46 and related ligands described in the following article: Klein, T. et al., “Structural and Dynamic Insights Into the Energetics of Activation Loop Rearrangement in Fgfr1 Kinase.” Nat. Commun6: 7877 (2015); and the crystal structure PDB 5ew8 and the related ligands described in Patani, H. et al., “Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.” Oncotarget 7: 24252-24268 (2016).

[0289] Figure 8FF Non-limiting examples of FGFR2 and FGFR3 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal structure PDB 2pvf and the related ligand described below by Chen, H. et al., “A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.” Mol. Cell 27: 717-730 (2007); and "Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives asnovel FGFR3 inhibitors with high selectivity over VEGFR2" Bioorg Med Chem2020, 28, 115453.

[0290] Figure 8GG Non-limiting examples of FGFR4-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see the crystal structure PDB 4tyi and the related ligand described below in Lesca, E. et al., “Structural analysis of the human fibroblast growth factor receptor 4 kinase”. J. Mol. Biol. 426: 3744-3756 (2014).

[0291] Figure 8HH-8IINon-limiting examples of MET-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 3qti and 3zcl; crystal structures PDB 4xmo, 4xyf, and 3zcl; and the related ligand described in Peterson, EA, et al., "Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors." J. Med. Chem. 58: 2417-2430 (2015) and Cui, JJ et al. “Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2, 4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), anInhibitor of Receptor Tyrosine Kinase C-met with High Protein KinaseSelectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats.” J. Med. Chem. 56: 6651 (2013); Crystal structure PDB5eyd and related ligands described in Boezio, AA et al., “Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In VivoAntitumor Activity.” J. Med. Chem.59: 2328-2342 (2016); Crystal structure PDB 3ce3 and related ligands described in the following article: Kim, KS et al., “Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.” J. Med. Chem. 51: 5330-5341 (2008); crystal structure PDB 2rfn and related ligands described in Bellon, SF et al., “c-Met inhibitors with novel binding modeshow activity against several hereditary papillary renal cell carcinoma-related mutations”. J. Biol. Chem. 283: 2675-2683 (2008); and the crystal structure PDB 5dg5 and the related ligands described in Smith, BD et al., “Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.”. Mol. Cancer Ther. 14: 2023-2034 (2015).

[0292] Figure 8JJ Non-limiting examples of JAK1-targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see crystal structure PDB 4ivd and the related ligand described below in Zak, M. et al., “Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2”. J. Med. Chem.56: 4764-4785 (2013); crystal structure PDB 5e1e and related ligands described below: Vasbinder, MM et al., “Identification of azabenzimidazoles as potent JAK1 selective inhibitors.” Bioorg. Med. Chem. Lett. 26: 60-67 (2016); Crystal structure PDB 5hx8 and related ligands described in the following: Simov, V., et al., “Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.” Bioorg. Med. Chem. Lett. 26: 1803-1808 (2016); crystal structure PDB 5hx8 and related ligands described below Caspers, NL et al., “Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelatorsoaking system”. Acta Crystallogr. Sect. F 72: 840-845 (2016); and Kettle, JG, “Discovery of the JAK1 selective kinase inhibitor AZD4205,” AACR NationalMeeting, April 2017.

[0293] Figure 8KK-8LL Non-limiting examples of JAK2-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 3ugc and the related ligand described below by Andraos, R. et al., “Modulation of activation-loop phosphorylation by JAKinhibitors is binding mode dependent.” Cancer Discov2: 512-523 (2012); Crystal structures PDB 5cf4, 5cf5, 5cf6 and 5cf8 and related ligands described in Hart, AC et al., “Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridineInhibitors.” ACS Med. Chem. Lett. 6: 845-849 (2015); Crystal structure PDB 5aep and related ligands described in Brasca, MG et al., “Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders”. Bioorg. Med. Chem. 23:2387 (2015); Crystal structures PDB 4ytf, 4yth, and 4yti, and related ligands described in Farmer, LJ et al., “Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.” J. Med. Chem. 58: 7195-7216 (2015); Crystal structures PDB 4ytf, 4yth, 4yti and related ligands described in Menet, CJ et al., “Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634.” J. Med. Chem. 57: 9323-9342 (2014); crystal structure PDB 4ji9 and related ligands described in the following: Siu, M. et al., “2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors.” Bioorg. Med. Chem. Lett.23: 5014-5021 (2013); and crystal structures PDB 3io7 and 3iok and related ligands described in the following Schenkel, LB et al. “Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors.” J. Med. Chem. 54: 8440-8450 (2011).

[0294] Figure 8MM Non-limiting examples of JAK3-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 3zc6 and the related ligand described in Lynch, SM et al., “Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the JakFamily and the Kinome”. Bioorg. Med. Chem. Lett 23: 2793 (2013); and the crystal structures PDB4hvd, 4i6q, and 3zep, as well as the related ligands described in the following article by Soth, M. et al., “3-Amido Pyrrolopyrazine JAK Kinase Inhibitors: Development of a JAK3 vs JAK1 Selective Inhibitor and Evaluation in Cellular and in Vivo Models.” J. Med. Chem. 56: 345-356 (2013) and Jaime-Figueroa, S. et al. “Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.” Bioorg. Med. Chem. Lett. 23: 2522-2526 (2013).

[0295] Figure 8NN-8OONon-limiting examples of KIT-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 1t46 and the related ligand described below in Mol, CD et al., “Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase”. J. Biol. Chem. 279: 31655-31663 (2004); and the crystal structure PDB 4u0i and the related ligands described in the following article, Garner, AP et al., “Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients.” Clin. Cancer Res. 20: 5745-5755 (2014).

[0296] Figure 88PP-8VV provides a non-limiting example of an EGFR-targeting ligand, where R denotes an exemplary point connecting a spacer. 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 of Selective and Noncovalent Diaminopyrimidine-BasedInhibitors of Epidermal Growth Factor Receptor Containing the T790MResistance Mutation.” J. Med. Chem., 57, 10176–10191 (2014); Chan, BK et al. “Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor” J. Med. Chem. 59, 9080 (2016); Crystal structure PDB 5d41 and related ligands described in Jia, Y. et al., “Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors” Nature 534, 129 (2016); Ward, RA “Structure- and reactivity-based development of covalent inhibitors of theactivating and gatekeeper mutant forms of the epidermal growth factorreceptor (EGFR)” J. Med. Chem. 56, 7025-7048 (2013); Crystal structure PDB 4zau and related ligands described in the following article, “Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor” J. Med.Chem. , 57 (20), 8249–8267 (2014); crystal structure PDB5em7 and related ligands described in Bryan, MC et al., “Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR”. ACS Med. Chem. Lett. ,7 (1), 100–104 (2016); crystal structure PDB 3IKA and related ligands described in the following: Zhou, W. et al., “Novel mutant-selective EGFR kinase inhibitors against EGFR T790M”Nature 462(7276), 1070–1074 (2009); crystal structure see PDB 5feq and related ligands described below. Lelais, G., J. “Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R,ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers” Med.Chem., 59 (14), 6671–6689 (2016); Lee, H.-J. “Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M” Cancer Discov. 3(2):168–181 (2013); crystal structure PDB 5j7h and related ligands described below: Huang, WS. et al., “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.” J. Med. Chem 59:4948-4964 (2016); Crystal structure PDB 4v0g and related ligands described in Hennessy, EJ et al., “Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation”. ACS. Med. Chem. Lett.7: 514-519 (2016); Crystal structure PDB 5hg7 and related ligands described below: 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-ContainingEGFR Mutants.” J. Med. Chem. 59: 2005-2024 (2016); Hao, Y. “Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitorsagainst L858R / T790M Resistance Mutation . " J. Med. Chem. 59: 7111-7124 (2016); Crystal structures PDB 5ug8, 5ug9, and 5ugc and the related ligands described below. Planken, S. “Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.” J. Med. Chem.60: 3002-3019 (2017); Crystal structure PDB 5gnk and related ligands described below: Wang, A. “Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode.” J. Med. Chem. 60: 2944-2962 (2017); and Juchum, M. “Trisubstituted imidazoles with arigidized hinge binding motif act as single digit nM inhibitors of clinically relevant EGFR L858R / T790M and L858R / T790M / C797S mutants: An example of targethopping.” J. Med. Chem. DOI: 10.1021 / acs.jmedchem.7b00178 (2017).

[0297] Figure 8WW-8XX Non-limiting examples of PAK1-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see Rudolph, J. et al., “Chemically Diverse Group Ip21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window.” J. Med. Chem. 59, 5520-5541 (2016) and KarpovAS, et al. ACS Med Chem Lett. 22;6(7):776-81 (2015).

[0298] Figure 8YYNon-limiting examples of PAK4-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see Staben ST, et al. J Med Chem. 13;57(3):1033-45 (2014) and Guo, C. et al., “Discovery of pyrroloaminopyrazoles as novel PAK inhibitors” J. Med. Chem. 55, 4728–4739 (2012).

[0299] Figure 8ZZ-8AAA Non-limiting examples of IDO-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see Yue, EW, et al., “Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivopharmacodynamic activity and efficacy in a mouse melanoma model”. J. Med. Chem. 52, 7364-7367 (2009); Tojo, S.; et al. "Crystal structures and structure ,and activity relationships of imidazothiazole derivatives as IDO1inhibitors." ACS Med. Chem. Lett. 5, 1119-1123 (2014); Mautino, MR et al. "NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy" Abstract 491, AACR 104th Annual Meeting 2013; Apr 6-10,2013; Washington, DC; and WO2012142237 titled "Fused imidazole derivatives usefulas IDO inhibitors".

[0300] Figure 8BBB-8EEENon-limiting examples of ERK1 and ERK2 targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see crystal structures PDB 5K4I and 5K4J and the related ligand described below by Blake, JF et al., “Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1 / 2 (ERK1 / 2) Inhibitor in Early Clinical Development”. J. Med. Chem. 59: 5650-5660 (2016); Crystal structure PDB 5BVF and related ligands described in Bagdanoff, JT et al., “Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase”. Bioorg. Med. Chem. Lett. 25, 3788-3792 (2015); Crystal structure PDB 4QYY and related ligands described below: Deng, Y. et al., “Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase” J. Med. Chem. 57: 8817-8826 (2014); Crystal structures PDB 5HD4 and 5HD7 and related ligands described in Jha, S. et al., “Dissecting Therapeutic Resistance to ERK Inhibition”. Mol.Cancer Ther. 15: 548-559 (2016); Crystal structure PDB 4XJ0 and related ligands described below: Ren, L. et al., “Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1 / 2.” J. Med. Chem.58: 1976–1991 (2015); Crystal structures PDB 4ZZM, 4ZZN, 4ZZO and related ligands described below, 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.” AACR National Meeting 2017; Crystal structures PDB 3FHR and 3FXH and related ligands described below; Cheng, R. et al., “High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand”. Protein Sci. 19: 168-173 (2010); Crystal structures PDB 5NGU, 5NHF, 5NHH, 5NHJ, 5NHL, 5NHO, 5NHP, and 5NHV and related ligands described below in Ward, RA et al., “Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1 / 2 from a Modestly Active and Promiscuous Chemical Start Point.” J. Med. Chem.60, 3438–3450 (2017); Crystal structures of PDB 3SHE and 3R1N and related ligands are described in Oubrie, A. et al. Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control" J Med Chem2009, 52(20), 6362; WO2015051341; "Discovery of a Potent andSelective Oral Inhibitor of ERK1 / 2 (AZD0364) That Is Efficacious in BothMonotherapy and Combination Therapy in Models of Non-small Cell Lung Cancer(NSCLC)” J Med Chem2019, 62(24), 11004; and “ERK Inhibitor LY3214996 Targets ERKPathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine” MolCancer Ther2020, 19, 325.

[0301] Figure 8FFF-8III Non-limiting examples of ABL1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 1fpu and 2e2b and the related ligands described below: Schindler, T., et al., “Structural mechanism for STI-571 inhibition of abelsontyrosine kinase”. Science289: 1938–1942 (2000); and Horio, T. et al. “Structuralfactors contributing to the Abl / Lyn dual inhibitory activity of 3-substitutedbenzamide derivatives”, Bioorg. Med. Chem. Lett. 17: 2712-2717 (2007); Crystal structures PDB 2hzn and 2hiw and related ligands described in the following article, Cowan-Jacob, SW et al., “Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukemia”. Acta Crystallog. Sect. D 63: 80-93 (2007) and Okram, B. et al. “A general strategy for creating”, Chem. Biol. 13: 779-786 (2006); crystal structure PDB 3cs9 and related ligands described in the following: Weisberg, E. et al., “Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl”. Cancer Cell 7: 129-14 (2005); crystal structure PDB 3ik3 and related ligands described below: O'Hare, T. et al., "AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315Imutant and overcomes mutation-based resistance". Cancer Cell 16: 401-412 (2009); Crystal structure PDB 3mss and related ligands described below: Jahnke, W. et al., “Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay”. J. Am. Chem. Soc132: 7043-7048 (2010); crystal structure PDB 3oy3 and related ligands described in the following article: Zhou, T. et al., “Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance”. Chem. Biol. Drug Des. 77: 1-11 (2011); Crystal structures PDB 3qri and 3qrk and related ligands described below: Chan, WW et al., “Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036”. Cancer Cell 19: 556-568 (2011); crystal structures PDB5hu9 and 2f4j and related ligands described in the following article: Liu, F. et al., “Discovery and characterization of a novel potent type II native and mutant BCR-ABL inhibitor (CHMFL-074) for Chronic Myeloid Leukemia (CML)”. Oncotarget 7: 45562-45574 (2016) and Young, MA et al. "Structure of the kinase domain of an imatinib-resistant Abl mutant incomplex with the Aurora kinase inhibitor VX-680", Cancer Res. 66: 1007-1014 (2006); Crystal structures PDB 2gqg and 2qoh and related ligands described below, 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 T315IMutant of Abl Kinase”, Chem. Biol. Drug Des. 70: 171-181 (2007); Crystal structures PDB2gqg and 2qoh and related ligands described in Tokarski, JS et al., “The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants”. Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al., “Crystal Structure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des. 70: 171-181 (2007); Crystal structures PDB 2gqg and 2qoh and related ligands described in Tokarski, JS et al., “The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants”. Cancer Res. 66: 5790-5797 (2006) and Zhou, T. et al., “Crystal Structure of the T315I Mutant of Abl Kinase”, Chem. Biol. Drug Des .70: 171-181 (2007); Crystal structures PDB 3dk3 and 3dk8 and related ligands described in Berkholz, DS et al., “Catalytic cycle of human glutathione reductase near 1 A resolution”. J. Mol. Biol.382: 371-384 (2008); crystal structure PDB 3ue4 and related ligands described in the following article, “Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain”, Plos One 7: e29828-e29828 (2012); crystal structure PDB 4cy8 and related ligands described below. Jensen, CN et al., “Structures of the Apo and Fad-Bound Forms of 2-Hydroxybiphenyl 3-Monooxygenase (Hbpa) Locate Activity Hotspots Identified by Using Directed Evolution”. Chembiochem 16: 968 (2015); crystal structure PDB 2hz0 and related ligands described in the following article, Cowan-Jacob, SW et al., “Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia”. Acta Crystallogr D Biol Crystallogr. 63(Pt 1):80-93 (2007); Crystal structure PDB 3pyy and related ligands described in the following article: Yang, J. et al., “Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site”. Chem. Biol. 18: 177-186 (2011); and the crystal structure PDB 5k5v and the related ligands described below, 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.113: 12438-12443 (2016).

[0302] Figure 8JJJ Non-limiting examples of ABL2-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see the crystal structure PDB 2xyn and the related ligand described in Salah, E. et al., “Crystal Structures of Abl-Related Gene (Abl2) in Complex with Imatinib, Tozasertib (Vx-680), and a Type I Inhibitor of the Triazole Carbothioamide Class”. J. Med. Chem. 54: 2359 (2011); Crystal structure PDB 4xli and related ligands described in the following article, Ha, BH et al., “Structure of the ABL2 / ARG kinase in complex with dasatinib” Acta Crystallogr. Sect.F 71: 443-448 (2015); and the crystal structure of PDB 3gvu and the related ligands described in Salah, E. et al., “The crystal structure of human ABL2 in complex with Gleevec”, are forthcoming.

[0303] Figure 8KKK-8MMM Non-limiting examples of AKT1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. 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 pyrrolopyrimidine inhibitors of Akt", Bioorg. Med. Chem. Lett. 20: 5607-5612(2010); Kallan, N.C. et al. "Discovery and SAR of spirochromane Akt inhibitors", Bioorg. Med. Chem. Lett. 21: 2410-2414 (2011); Lin, K "An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt", Sci.Signal. 5: ra37-ra37 (2012); Addie, M. et al. "Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases", J. Med. Chem. 56: 2059-2073 (2013); Wu, W.I., et al. "Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. Plos One 5: 12913-12913 (2010); Ashwell, M.A. et al. "Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors", J. Med. Chem. 55: 5291-5310 (2012); and Lapierre, 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): An Orally Bioavailable, Selective, and Potent Allosteric AKTInhibitor”, J. Med. Chem. 59: 6455-6469 (2016).

[0304] Figure 8NNN-8OOO Non-limiting examples of AKT2-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal-structured PDB 2jdo and 2jdr and the related ligands described in Davies, TG et al., “A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera”. J. Mol. Biol 367:882 (2007); crystal structure PDB 2uw9 and related ligands described in the following article, Saxty, G. et al., “Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery”. J. Med. Chem. 50: 2293-2296 (2007); crystal structures PDB 2x39 and 2xh5 and related ligands described below: Mchardy, T. et al., “Discovery of 4-Amino-1-(7H-Pyrrolo[2,3-D]Pyrimidin-4-Yl)Piperidine-4-Carboxamides as Selective, Orally Active Inhibitors of Protein Kinase B (Akt)”. J. Med. Chem.53: 2239d (2010); crystal structure PDB 3d03 and related ligands described below by 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 . 130: 14129-14138 (2008); and crystal structures PDB 3e87, 3e8d and 3e88 and related ligands described in Rouse, MB et al., “Aminofurazans as potent inhibitors of AKT kinase”. Bioorg. Med. Chem. Lett. 19: 1508-1511 (2009).

[0305] Figure 8PPP Non-limiting examples of BMX-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see the crystal structures PDB 3sxr and 3sxr and the related ligands described below, Muckelbauer, J. et al., “X-ray crystal structure of bone marrow kinase in the xchromosome: a Tec family kinase”. Chem. Biol. Drug Des. 78: 739-748 (2011).

[0306] Figure 8QQQ-8SSS Non-limiting examples of CSF1R-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see crystal structures PDB 2i0v and 2i1m and the related ligand described below by Schubert, C. et al., “Crystal structure of the tyrosine kinase domain of colour-stimulating factor-1 receptor (cFMS) in complex with two inhibitors”. J. Biol. Chem.282: 4094-4101 (2007); crystal structure PDB 3bea and related ligands described in Huang, H. et al., “Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors”. Bioorg. Med. Chem. Lett. 18: 2355-2361 (2008); Crystal structure PDB 3dpk and related ligands described below: MT, McKay, DBOvergaard, “Structure of the Elastase of Pseudomonas aeruginosa Complexed with Phosphoramidon”, to be published; Crystal structures PDB 3krj and 3krl and related ligands described below: Illig, CR et al., “Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141”, J. Med. Chem. 54: 7860-7883 (2011); crystal structure PDB 4r7h and related ligands described in the following reference, Tap, WD et al., “Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor:, N Engl J Med 373:428-437 (2015); Crystal structures PDB 3lcd and 3lccoa and related ligands described below: Meyers, MJ et al., “Structure-based drug design enables conversion of a DFG-in binding CSF-1Rkinase inhibitor to a DFG-out binding mod”. Bioorg. Med. Chem. Lett.20: 1543-1547 (2010); crystal structure PDB 4hw7 and related ligands described below. Zhang, C. et al., “Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor”. Proc. Natl. Acad. Sci. USA 110: 5689-5694 (2013); and the crystal structure PDB 4r7i and the related ligands described in the following reference, Tap, WD et al., “Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor”. N Engl J Med 373: 428-437 (2015).

[0307] Figure 8 TTT Non-limiting examples of CSK-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see Levinson, NM et al., “Structural basis for the cognition of c-Src by its inactivator Csk”. Cell 134: 124-134 (2008).

[0308] Figure 8 UUU-8YYY Non-limiting examples of DDR1-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, see the crystal structures PDB 3zos and 4bkj and the related ligands described below by Canning, P. et al., “Structural Mechanisms Determining Inhibition of the Collagen Receptor Ddr1 by Selective and Multi-Targeted Type II Kinase Inhibitors”. J. Mol. Biol. 426: 2457 (2014); crystal structure PDB 4ckr and related ligands described in the following article, Kim, H. et al., “Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor”. ACS Chem. Biol8: 2145 (2013); Crystal structures PDB 5bvk, 5bvn and 5bvw and related ligands described in Murray, CW et al., “Fragment-Based Discovery of Potent and Selective DDR1 / 2 Inhibitors”, ACS Med.Chem.Lett. 6: 798-803 (2015); Crystal structure PDB5fdp and related ligands described in the following: Wang, Z. et al., “Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors”. J. Med. Chem. 59: 5911-5916 (2016); and the crystal structure PDB 5fdx and the related ligand described below, Bartual, SG et al., “Structure of DDR1 receptor tyrosinekinase in complex with D2164 inhibitor at 2.65 Angstroms resolution”, to be published.

[0309] Figure 8 ZZZ-8CCCC Non-limiting examples of EPHA2-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 5i9x, 5i9y, 5ia0, and 5ia1 and related ligands described below by Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”. ACS Chem. Biol 11: 3400-3411 (2016); Crystal structure PDB 5i9z and related ligands described below: Heinzlmeir, S. et al., “Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with danusertib (PHA739358)”. ACS Chem Biol11 3400-3411 (2016); and crystal structures PDB 5ia2, 5ia3, 5ia4 and 5ia5 and related ligands described below Heinzlmeir, S. et al., “Chemical Proteomics and Structural Biology Define EPHA2 Inhibition by Clinical Kinase Drug”, ACS Chem. Biol. 11: 3400-3411 (2016).

[0310] Figure 8 DDDD-8FFFF Non-limiting examples of EPHA3-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal structure PDB 4g2f and the related ligand described below by Zhao, H. et al., “Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics”. ACS Med. Chem. Lett. 3: 834-838 (2012); Crystal structures PDB 4gk2 and 4gk3 and related ligands described below, Lafleur, K. et al., “Optimization of Inhibitors of the Tyrosine Kinase EphB4.2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography”. J. Med. Chem. 56: 84-96 (2013); Crystal structure PDB 4gk3 and related ligands described below, Lafleur, K. et al., “Optimization of Inhibitors of the Tyrosine Kinase EphB4.2. Cellular Potency Improvement and Binding Mode Validation by X-ray Crystallography”. J. Med. Chem.56: 84-96 (2013); Crystal structures PDB 4p4c and 4p5q and related ligands described below: 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 VivoValidation”. J. Med. Chem. 57: 6834-6844 (2014); crystal structure PDB 4p5z and related ligands described below: 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 inVivo Validation”. J. Med. Chem. 57: 6834-6844 (2014); Crystal structure PDB 4twn and related ligands described in the following article, Dong, J. et al., “Structural Analysis of the Binding of Type I, I1 / 2, and II Inhibitors to Eph Tyrosine Kinases”. ACS Med.Chem.Lett 6: 79-83 (2015); crystal structure PDB 3dzq and related ligand described below Walker, JR “Kinase Domain of Human Ephrin Type-A Receptor 3 (Epha3) in Complex with ALW-II-38-3”, to be published.

[0311] Figure 8 GGGGNon-limiting examples of EPHA4-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal structure PDB 2y60 and the related ligand described below by Clifton, IJ et al., “The Crystal Structure of Isopenicillin N Synthase with Delta((L)-Alpha-Aminoadipoyl)-(L)-Cysteinyl-(D)-Methionine Reveals ThioetherCoordination to Iron”. Arch. Biochem. Biophys. 516:103 (2011) and the crystal structure PDB2xyu and the related ligands described in the following article, Van Linden, OP et al., “Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase”, Eur. J. Med. Chem. 47: 493 (2012).

[0312] Figure 8 HHHH Non-limiting examples of EPHA7-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal structure PDB 3dko and the related ligand described below, Walker, JR et al., “Kinase domain of human ephrin type-a receptor 7 (epha7) in complex with ALW-II-49-7”, forthcoming.

[0313] Figure 8 IIII-8LLLL Non-limiting examples of EPHB4-targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples and related ligands, see the crystal structure PDB 2vx1 and the related ligands described below, Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-Based Discovery and Optimization of 3,5-Bis Substituted Anilinopyrimidines”. Bioorg. Med. Chem. Lett.18: 5717 (2008); crystal structure PDB 2x9f and related ligands described in the following article, Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 3: Identification of Non-Benzodioxole-Based Kinase Inhibitors”. Bioorg. Med. Chem. Lett. 20: 6242-6245 (2010); crystal structure PDB 2xvd and related ligands described in the following article, Barlaam, B. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 4: Discovery and Optimization of a Benzylic Alcohol Series”. Bioorg. Med. Chem. Lett. 21:2207 (2011); Crystal structure PDB 3zew and related ligands described in the following article: Overman, RC et al., “Completing the Structural Family Portrait of the Human Ephb Tyrosine Kinase Domains”. Protein Sci. 23: 627 (2014); Crystal structure PDB 4aw5 and related ligands described in the following article, Kim, MH et al., “The Design, Synthesis, and Biological Evaluation of Potent Receptor Tyrosine Kinase Inhibitors”. Bioorg. Med. Chem. Lett. 22: 4979 (2012); Crystal structure PDB 4bb4 and related ligands described in Vasbinder, MM et al., “Discovery and Optimization of a Novel Series of Potent Mutant B-Raf V600E Selective Kinase Inhibitors”. J. Med. Chem.56: 1996. , (2013); Crystal structures PDB 2vwu, 2vwv and 2vww and related ligands described in the following: Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 1: Structure-Based Design and Optimization of a Series of 2,4-Bis-Anilinopyrimidines”, Bioorg. Med. Chem. Lett. 18: 2776-2780 (2008); Crystal structures PDB2vwx, 2vwy, and 2vwz and related ligands described in the following article, Bardelle, C. et al., “Inhibitors of the Tyrosine Kinase Ephb4. Part 2: Structure-Based Discovery and Optimization of 3,5-Bis Substituted Anilinopyrimidines”. Bioorg. Med. Chem. Lett. 18: 5717 (2008); and the crystal structure PDB 2vxo and the related ligands described in the following article, Welin, M. et al., “SubstrateSpecificity and Oligomerization of Human Gmp Synthetas”. J. Mol. Biol. 425:4323 (2013).

[0314] Figure 8 MMMM Non-limiting examples of ERBB2 targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples and related ligands, see the crystal structure and related ligands described below by Aertgeerts, K. et al., “Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein”. J. Biol. Chem286: 18756-18765 (2011) and the crystal structure and description of the related ligands are given below by Ishikawa, T. et al., “Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2) / Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold”. J. Med. Chem. 54: 8030-8050 (2011).

[0315] Figure 8 NNNN Non-limiting examples of ERBB3-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. 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).

[0316] Figure 8 OOOO Non-limiting examples of ERBB4-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. 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-anilinesas tunable covalent modifiers of ErbB kinases", Proc. Natl. Acad. Sci. Usa 105:2773-2778 (2008).

[0317] Figure 8 PPPP-8QQQQNon-limiting examples of FES-targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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).

[0318] Figure 8 RRRR Non-limiting examples of FYN-targeting ligands are provided, where R denotes an exemplary point connecting spacers. 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).

[0319] Figure 8 SSSS-8VVVV Non-limiting examples of GSG2 (Haspin) targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structures PDB 3e7v, PDB 3f2n, 3fmd and the related ligand described below: Filippakopoulos, P. et al., “Crystal Structure of Human Haspin with a pyrazolo-pyrimidine ligand” (to be published); crystal structure PDB 3iq7 and the related ligand described below: Eswaran, J. et al., “Structure and functional characterization of the atypical human kinase haspin”. Proc. Natl. Acad. Sci. USA106: 20198-20203 (2009); and the crystal structure PDB 4qtc and the related ligands described in the following article, Chaikudad, A. et al., “A unique inhibitor-binding site in ERK1 / 2 is associated with slow-binding kinetics”. Nat. Chem. Biol. 10: 853-860 (2014).

[0320] Figure 8 WWWW-8AAAAA Non-limiting examples of HCK-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 1qcf and the related ligand described below by Schindler, T. et al., “Crystal structure of Hck in complex with a Src family-selective tyrosine kinase inhibitor”. Mol. Cell 3: 639-648 (1999); crystal structures PDB2c0i and 2c0t and related ligands described in the following: Burchat, A. et al., “Discovery of A-770041, a Src-Family Selective Orally Active Lck Inhibitor that Prevents Organ Allograft Rejection”. Bioorg. Med. Chem. Lett. 16: 118 (2006); Crystal structure PDB 2hk5 and related ligands described below: Sabat, M. et al., “The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck)”. Bioorg. Med. Chem. Lett. 16: 5973-5977 (2006); crystal structures PDB 3vry, 3vs3, 3vs6 and 3vs7 and related ligands described in the following article: Saito, Y. et al., “A Pyrrolo-Pyrimidine Derivative Targets Human PrimaryAML Stem Cells in Vivo”. Sci Transl Med5: 181ra52-181ra52 (2013); and the crystal structure PDB4lud and the related ligand described in the following Parker, LJ et al., “Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002”. Acta Crystallogr.,Sect.D 70: 392-404 (2014).

[0321] Figure 8 BBBBB-8FFFFF Non-limiting examples of IGF1R targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples and related ligands, see crystal structure PDB 2oj9 and the related ligand described below by Velaparthi, U. et al., “Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R)”. Bioorg. Med. Chem. Lett. 17: 2317-2321 (2007); crystal structure PDB 3i81 and related ligands described below: Wittman, MD et al., “Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development.” J. Med. Chem. 52: 7360-7363 (2009); crystal structure PDB 3nw5 and related ligands described below, Sampognaro, AJ et al., “Prolineisosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase”. Bioorg. Med. Chem. Lett.20: 5027-5030 (2010); crystal structure PDB 3qqu and related ligands described below by Buchanan, JL et al., “Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors”. Bioorg. Med. Chem. Lett. 21: 2394-2399 (2011); Crystal structure PDB 4d2r and related ligands described below: Kettle, JG et al., “Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a MekResistance Hypothesis”. J. Med. Chem. 58: 2834 (2015); Crystal structure PDB 3fxq and related ligands described below. Monferrer, D. et al., “Structural studies on the full-length LysR-type regulator TsaR from Comamonas testosteroni T-2 reveal a novel openconformation of the tetrameric LTTR fold”, Mol. Microbiol. 75: 1199-1214 (2010); Crystal structure PDB 5fxs and related ligands described below: Degorce, S. et al., “Discovery of Azd9362, a Potent Selective Orally Bioavailable and Efficacious Novel Inhibitor of Igf-R1”, forthcoming; Crystal structure PDB 2zm3 and related ligands described below: Mayer, SC et al., “Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment”. Bioorg. Med. Chem. Lett.18: 3641-3645 (2008); Crystal structure PDB 3f5p and related ligands described in the following document, “Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment” Bioorg. Med. Chem. Lett. 19: 62-66 (2009); Crystal structure PDB 3lvp and related ligands described in Nemecek, C. et al., “Design of Potent IGF1-R Inhibitors Related to Bis-azaindoles” Chem. Biol. Drug Des. 76: 100-106 (2010); crystal structure PDB 3o23 and related ligands described below: Lesuisse, D. et al., “Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: Advantages in comparison with competitive inhibitors”. Bioorg. Med. Chem. Lett. 21: 2224-2228 (2011); crystal structure PDB 3d94 and related ligands described below. (Wu, J. et al., “Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor”) Embo J. 27: 1985–1994 (2008); and the crystal structure of PDB 5hzn and the related ligands described in the following: Stauffer, F. et al., “Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors”. Bioorg. Med. Chem. Lett. 26: 2065-2067 (2016).

[0322] Figure 8 GGGGG-8JJJJJNon-limiting examples of INSR-targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples and related ligands, see the crystal structure PDB 2z8c and the related ligand described below in Katayama, N. et al., “Identification of a key element for hydrogen-bonding patterns between protein kinases and their inhibitors”. Proteins 73: 795-801 (2008); Crystal structure PDB 3ekk and related ligands described below: Chamberlain, SD et al., “Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: Potent inhibitors of the IGF-1R receptor tyrosine kinase”, (2009). Bioorg. Med. Chem. Lett. 19: 469-473; Crystal structure PDB 3ekn and related ligands described in Chamberlain, SD et al., “Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R tyrosine kinase inhibitors towards JNK selectivity”. Bioorg. Med. Chem. Lett. 19: 360-364 (2009); Crystal structure PDB 5e1s and related ligands described in the following article: Sanderson, MP et al., “BI 885578, a Novel IGF1R / INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis”. Mol. Cancer Ther.14: 2762-2772”, (2015); Crystal structure PDB 3eta and related ligands described below: 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. 19: 3136-3140 (2009); crystal structure PDB5hhw and related ligands described in the following: Stauffer, F. et al., “Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors”. Bioorg. Med. Chem. Lett. 26: 2065-2067 (2016); and the crystal structure PDB4ibm and the related ligand described in 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. 288: 28068-28077 (2013).

[0323] Figure 8 KKKKK-8PPPPP Non-limiting examples of HBV-targeting ligands are provided, where R represents an exemplary site for spacer linkage, Y is methyl or isopropyl, and X is N or C. For further examples and related ligands, see Weber, O., et al., “Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model.” Antiviral Res.54, 69-78 (2002); Deres, K.; et al. "Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids." Science , 299, 893-896 (2003); Stray, S. J.; Zlotnick, A. "BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly." J. Mol. Recognit. 19, 542-548 (2006); Stray, S. J.; et al. "heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly." Proc. Natl. Acad. Sci. U. S. A. , 102, 8138-8143 (2005); Guan, H.; et al. "The novel compound Z060228 inhibits assembly of the HBV capsid." Life Sci. 133, 1-7 (2015); Wang, X. Y.; et al. "In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations." Antiviral Ther.17, 793-803 (2012); Klumpp, K.; et al. "High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein." 112, 15196-15201 (2015); Qiu, Z.; et al. "Design and synthesis of orally bioavailable 4-methylheteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors." J. Med. Chem. 59, 7651-7666 (2016); Zhu, X.; et al. "2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly." Bioorg. Med. Chem. Lett. 20, 299-301 (2010); Campagna, M. R.; et al. "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids." J. Virol. 87, 6931-6942 (2013); Campagna, M. R.; et al. "Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids." J. Virol.87, 6931-6942 (2013); WO 2013096744 A1 is titled "Hepatitis B antiviral agents"; WO 2015138895 is titled "Hepatitis B core protein allosteric modulators"; Wang, YJ, et al., "A novel pyridazinone derivative inhibits hepatitis B virus replication by inducing genome-free capsid formation." Antimicrob. Agents Chemother. 59, 7061-7072 (2015); WO 2014033167 is entitled "Fusedbicyclic sulfamoyl derivatives for the treatment of hepatitis"; US20150132258 is entitled "Azepane derivatives and methods of treating hepatitis Binfections"; and WO 2015057945 is entitled "Hepatitis B viral assembly effector".

[0324] Figure 9 It is a phylogenetic diagram of the human Bromo domain family organized into eight subfamilies, which involves epigenetic signaling and chromatin biology. According to the present invention, one can select... Figure 9 Any Bromo domain family protein can be used as a target protein.

[0325] Figure 10A and Figure 10B Non-limiting examples of CBP and / or P300 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For example, other examples of targeting ligands can be found in “GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)” J Med Chem 2017, 60(22), 9162; CCS-1477, WO2018073586; FT-7051 and WO2019055869.

[0326] Figure 11A and 11B Non-limiting examples of BRD9 targeting ligands are provided, where R is the point of ligand attachment. For other examples, please see: Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor " J Med Chem 2016, 59(10) , 4462;WO2016139361。

[0327] Figure 12A-12C Non-limiting examples of CBL-B targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see WO 201914800.

[0328] Figure 13 Non-limiting examples of ERK-targeting ligands are provided, where R is the point of ligand attachment. For other examples, see: Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control " J Med Chem 2009, 52(20) , 6362;WO2015051341;“ Discovery of a Potent and Selective Oral Inhibitor of ERK1 / 2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC) " J Med Chem 2019, 62(24) , 11004; ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine " Mol Cancer Ther 2020, 19 , 325.

[0329] Figure 14A-14CNon-limiting examples of WDR5 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see “Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)” J Med Chem 2016, 59(6), 2478; WO2017147700; “Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity” Cell Rep 2019, 26(11), 2916; “Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WDRepeat-Containing Protein 5–MYC Protein–Protein Interaction” J Med Chem 2019, 62(24), 11232).

[0330] Figure 15 Non-limiting examples of NSP3-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see: “Severe Acute Respiratory Syndrome Coronavirus Papain-like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation”, J Med Chem 2010, 53, 4968; “X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases”, J Med Chem 2014, 57, 2393).

[0331] Figure 16 Non-limiting examples of RET-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see: Pralsetinib “Precision Targeted Therapy with BLU-667 for RET-Driven Cancers” Cancer Discovery, 2018, 8(7), 836; Selpercatinib, WO2018071447; “A Pyrazolo[3,4‐d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants” J Med Chem, 2016, 59, 358).

[0332] Figures 17A-17C Non-limiting examples of CTNNB1-targeting ligands are provided, where R is the point of ligand attachment. For other examples, see: "Direct Targeting of b-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt / b-Catenin Signaling" Cell Rep 2016, 16(1) , 28 “Rational Design of Small-Molecule Inhibitors for β-Catenin / T-Cell Factor Protein-Protein Interactions by BioisostereReplacement” ACS Chem Biol 2013, 8 , 524 and “Allosteric inhibitor of β-catenin selectively targets oncogenic Wnt signaling in colon cancer” Sci Rep 2020, 10 ,8096.

[0333] Figures 18A-18CNon-limiting examples of IRAK4 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples and related ligands, please refer to the crystal structures of PDB 6UYA, 4YP8, 5UIU and 6F3I in the relevant literature (Rajapaksa NS et al. "Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity." ACS Med. Chem. Lett. 11: 327-333 (2020); McElroy W.T. et al. "Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation." ACS Med. Chem. Lett. 6: 677-682 (2015); Nunes J. et al. "Targeting IRAK4 for Degradation with PROTACs" ACSMed. Chem. Lett. 10: 1081-1085 (2019); 4); Degorce SL et al. "Optimization ofpermeability in a series of pyrrolotriazine inhibitors of IRAK4". Bioorg. Med. Chem. 26: 913-924 (2018); WO2019099926 and WO2019133531.

[0334] Figures 19A-19D Non-limiting examples of FGFR2 and FGFR3 targeting ligands are provided, where R is the junction point of the linker. For other examples, see: "Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2". Bioorg Med Chem 2020, 28 , 115453.

[0335] Figure 20A-20DNon-limiting examples of SMARCA2 targeting ligands are provided, where R is the point of adapter attachment. For other examples, see: WO2020023657, US20200038378, WO2020010227, WO2020078933, WO2019207538, and WO2016138114, “Discovery of Orally Active Inhibitors of BrahmaHomolog (BRM) / SMARCA2 ATPase Activity for the Treatment of Brahma RelatedGene 1 (BRG1) / SMARCA4-Mutant Cancers”. J Med Chem 2018, 61 , 10155; 2)WO2020035779.

[0336] Figure 21A-21JNon-limiting examples of NRAS-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see “Small-molecule Ligands Bing to a Distinct Pocket in Ras and Inhibit SOS-Mediated Nucleotide Exchange Activity” PNAS 2012 109 (14) 5299-5304; crystal structure PDB 4EPY. (“Discovery of Small Molecules that Bind to K-Ras and Inhibit SOS-Mediated Activation” Angew. Chem. Int. Ed 2012, 51, 6140–6143); crystal structure PDB 6GQY, 6GQT, (“Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds” 2019 PNAS 116 (7), 2545-2550); crystal structure PDB 6FA4, 1HE8, (“Small-molecule inhibitors of RAS-effector protein”). interactions derived using anintracellular antibody fragment” 2018 Nature Communications 9(1), 3169); and “Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors ThatDisrupt Effector Binding” ACS Omega 2019, 4, 2921-2930.

[0337] Figure 22Non-limiting examples of ADAR targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples, see crystal structure PDB 6VFF, (Thuy-Boun, AS, et al., Nucleic Acids Res, 2020, 48, 7958-7972); and crystal structures PDB 5HP2, 5HP3, 5ED1, 5ED2 (Mathews, MM, et al., NatStruct Mol Biol., 2016, 23, 426-433).

[0338] Figure 23 Non-limiting examples of NSD2 or WHSC1 targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples, see crystal structures PDB 6XCG (Zhou, MQ, et al., “Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934”, forthcoming); crystal structure PDB 6UE6 (Liu, Y, et al., “PWWP1 domain of NSD2 in complex with MR837”, forthcoming); crystal structures PDB5LSS, 5LSU, 5LSX, 5LSY, 5LSZ, 5LT6, 5LT7, 5LT8 (Tisi, D., et al., “Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.”, ACS Chem Biol., 2016, 11: 3093-3105).

[0339] Figure 24 Non-limiting examples of PI3KCA targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 3HHM, 3HIZ (Mandelker, D., et al., “A frequentkinase domain mutation that changes the interaction between PI3K{alpha} and the membrane.”, Proc Natl Acad Sci US A., 2009, 106: 16996-17001).

[0340] Figure 25Non-limiting examples of RIT1-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 4KLZ (Shah, DM, et al., “Inhibition of SmallGTPases by Stabilization of the GDP Complex, a Novel Approach applied to Rit1, a Target for Rheumatoid Arthritis”, forthcoming).

[0341] Figure 26 Non-limiting examples of WRN-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 2FC0 (Perry, JJ, et al., “WRN exonuclease structure and molecular mechanism imply an editing role in DNA endprocessing.”, Nat Struct Mol Biol., 2006, 13: 414-422); and crystal structure PDB 6YHR (Newman, JA, et al., “Crystal structure of Werner syndrome helicase”, forthcoming).

[0342] Figure 27Non-limiting examples of ALK fusion-targeting ligands, such as EML4-ALK or NMP-ALK, are provided, where R denotes an exemplary point connecting spacers.For other examples, see crystal structures PDB 4CGB, 4CGC (Richards, MW, et al., “Microtubule Association of Eml Proteins and the Eml4-Alk Variant3 Oncoprotein Require an N-Terminal Trimerization Domain”, Biochem J., 2015, 467: 529); crystal structure PDB 3AOX (Sakamoto, H., et al., “CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant”, Cancer Cell, 2011, 19: 679-690); crystal structure PDB 6MX8 (Huang, WS, et al., “Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase”, J Med Chem., 2016, 59: 4948-4964); 4Z55 (Michellys, PY, et al., “Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.”, Bioorg Med Chem Lett., 2016, 26:1090-1096); and crystal structures PDB 4FOB, 4FOC, 4FOD (Lewis, RT, et al., “The Discovery and Optimization of a Novel Class of Potent, Selective, and OrallyBioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with PotentialUtility for the Treatment of Cancer.", J Med Chem., 2012, 55: 6523-6540).

[0343] Figure 28Non-limiting examples of BAP1 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 2W12, 2W13, 2W14, 2W15 (Lingott, TJ et al., “High-Resolution Crystal Structure of the Snake Venom Metalloproteinase Bap1 Complexed with a Peptidomimetic: Insight into Inhibitor Binding”, Biochemistry, 2009, 48: 6166).

[0344] Figure 29 Non-limiting examples of EPAS1 or HIF2α targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structure PDB 5UFP (Cho, H., et al., “On-target efficacy of a HIF-2 alpha antagonist in preclinical kidney cancer models.”, Nature, 2016, 539: 107-111); crystal structure PDB 6D09 Du, X, (“Crystal structure of PT1940 bound to HIF2a-B…”). :ARNT-B (complex, to be published); crystal structure PDB 5TBM (Wallace, EM, et al., "A Small-Molecule Antagonist of HIF2 alpha Is Efficacious in Preclinical Models of Renal Cell Carcinoma.", Cancer Res., 2016, 76: 5491-5500); and crystal structures PDB 6E3S, 6E3T, 6E3U (Wu, D., et al., "Bidirectional modulation of HIF-2 activity through chemical ligands.", Nat Chem Biol., 2019, 15: 367-376).

[0345] Figure 30A and Figure 30BNon-limiting examples of GRB2 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 1CJ1 (Furet, P., et al., “Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic”, J Med Chem., 1999, 42:2358-2363); crystal structures PDB 2AOA, 2AOB (Phan, J., et al., “Crystal Structures of a High-affinity Macrocyclic Peptide Mimetic in Complex with the Grb2 SH2 Domain”, J Mol Biol., 2005, 353: 104-115); crystal structures PDB 3KFJ, 3IN7, 3IMJ, 3IMD, 3IN8 (Delorbe, JE, et al., “Thermodynamic and Structural Effects of Conformational Constraints in Protein-Ligand) Interactions. Entropic Paradoxy Associated with Ligand Preorganization. J Am Chem Soc., 2009, 131: 16758-16770); crystal structures PDB 2HUW, 3C71 (Benfield, AP, et al., “Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein-Ligand Interactions.”, Angew Chem Int Ed Engl., 2006, 45: 6830-6835); and crystal structure PDB 1X0N (Ogura, K, et al., “NMR structure of growth factor receptor binding protein SH2 domain complexed with the inhibitor”, forthcoming).

[0346] Figure 31 Non-limiting examples of KMT2D or MLL2 / MLL4 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 7BRE (Li, Y., et al., “Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases.”, Structure, 2020); PDB 4ZAP (Zhang, Y., et al., “Evolving Catalytic Properties of the MLL Family SET Domain.”, Structure, 2015, 23: 1921-1933); PDB 6KIZ (Xue, H., et al., “Structural basis of nucleosome recognition and modification by MLL methyltransferases.”, Nature, 2019, 573: 445-449); and PDB 3UVK (Zhang, P., et al., “The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone”). methyltransferases.", Nucleic Acids Res., 2012,40: 4237-4246).

[0347] Figure 32Non-limiting examples of MLLT1 or ENL targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 6HT0, 6HT1 (Moustakin, M. et al., “Discovery of an MLLT1 / 3 YEATS Domain Chemical Probe”, Angew Chem Int Ed Engl., 2018, 57: 16302-16307); crystal structures PDB 6T1I, 6T1J, 6TIL, 6T1M, 6T1N, 6T1O (Ni, X. et al., “Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1”, ACS Med Chem Lett., 2019, 10: 1661-1666); and crystal structures PDB 6HPW, 6HPY, 6HPX, 6HPZ (Heidenreich, D. et al., “Structure-Based Approach toward Identification of Inhibitory”). Fragments for Eleven-Nineteen-Leukemia Protein (ENL)", J Med Chem., 2018, 61: 10929-10934).

[0348] Figure 33Non-limiting examples of NSD3-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 6G24, 6G25, 6G29, 6G2B, 6G2C, 6G2E, 6G2F, 6G2O, 6G3T (Bottcher, J., et al., “Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3”, Nat Chem Biol., 2019, 15: 822-829); crystal structure PDB 5UPD (Tempel, W., et al., “Methyltransferase domain of human Wolf-Hirschhorn Syndrome Candidate 1-Like protein 1 (WHSC1L1)”, forthcoming); and crystal structure PDB 6CEN (Morrison, MJ, et al., “Identification of a peptide inhibitor for the histonemethyltransferase WHSC1”, PLoS One, 2018, 13: e0197082-e0197082).

[0349] Figure 34 Non-limiting examples of PPM1D or WIP1 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 3UYH, ADA3, 4DAQ (Micco, M., et al., “Structure-based design and evaluation of naphthalene diimide g-quadruplex ligands as telomere targeting agents in pancreatic cancer cells”, J MedChem., 2013, 56: 2959-2974).

[0350] Figures 35A-35BNon-limiting examples of SOS1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples, see crystal structures PDB 5OVE, 5OVF, 5OVG, 5OVH, 5OVI (Hillig, RC, et al., “Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction”, Proc Natl Acad Sci US A., 2019, 116: 2551-2560); crystal structure PDB 6F08 (Ballone, A., et al., “Structural characterization of 14-3-3 zeta in complex with the human Son of sevenlesshomolog 1 (SOS1)”, J Struct Biol., 2018, 202: 210-215); crystal structure PDB 6D5E, 6D5G, 6D5H, 6D5J, 6D5L, 6D5M, 6D5V, 6D5W, 6D55, 6D59 (Hodges, TR et al., “Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS”, J Med Chem., 2018, 61: 8875-8894); crystal structures PDB 6SCM, 6SFR (Kessler, D. et al., “SOS1 in Complex with Inhibitor BI-3406”, pending publication); crystal structures PDB 6V94, 6V9J, 6V9L, 6V9M, 6V9N (Sarkar, D. et al., “Discovery of Sulfonamide-Derived Agonists ...V94, 6V9J, 6V9L, 6V9M, 6V9N (Sarkar, D. et al., “Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide RASUsing Fragment-Based Methods.", J Med Chem., 2020, 63: 8325-8337).

[0351] Figure 36 provides non-limiting examples of TBXT or Brachyury targeting ligands, where R denotes exemplary points connecting spacers. For other examples, see crystal structures PDB 5QS6, 5QSC, 5QSE, 5QSF, 5QRW (Newman, JA, et al., “PanDDA analysis group deposition”, forthcoming); and crystal structure PBD 6ZU8 (Newman, JA, et al., “Crystal structure of human Brachyury G177D variant incomplex with Afatinib”, forthcoming).

[0352] Figures 37A-37C Non-limiting examples of USP7 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 5UQV, 5UQX (Kategaya, L., et al., “USP7 small-molecule inhibitors interfere with ubiquitin binding”, Nature, 2017, 550:534-538); crystal structures PDB 6VN2, 6VN3, 6VN4, 6VN5, 6VN6 (Leger, PR, et al., “Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Antititumor Activity.”, J Med Chem., 2020, 63: 5398-5420); and crystal structures PDB 5N9R, 5N9T (Gavory, G., et al., “Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.”, Nat Chem Biol., 2018, 14: 118-125); and crystal structures PDB 5NGE, 5NGF (Turnbull, AP, et al., “Molecular basis of USP7 inhibition by selective small-molecule inhibitors”, Nature, 2017, 550: 481-486).

[0353] Figure 38 Non-limiting examples of BKV and JCV targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 5J4V, 5J4Y (Bonafoux, D., et al., “Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.”, J MedChem., 2016, 59: 7138-7151).

[0354] Figure 39 Non-limiting examples of CK1α (casein kinase 1α) targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples, see crystal structures PDB 5ML5, 5MQV (Halekotte, J., et al., “Optimized 4,5-Diarylimidazoles as Potent / Selective Inhibitors of ProteinKinase CK1 delta and Their Structural Relation to p38 alpha MAPK.”, Molecules, 2017, 22).

[0355] Figure 40 Non-limiting examples of GSPT1 / ERF3 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 5LZT, 5LZS, 5LZV, 5LZU, 5LZX, 5LZW, 5LZZ, 5LZY (Shao, S., et al., “Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes”, Cell, 2016, 167: 1229-1240.e15).

[0356] Figure 41Non-limiting examples of IFZV targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see the crystal structure PDB (Iyer, S., et al., “The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0 Aresolution.”, J Biol Chem., 2001, 276: 12153-12161); and the crystal structure PDB IRV6 (Christinger, HW, et al., “The crystal structure of placental growth factor incomplex with domain 2 of vascular endothelial growth factor receptor-1”, JBiol Chem., 2004, 279: 10382-10388).

[0357] Figure 42 Non-limiting examples of NSD2 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structure PDB 6XCG (Zhou, MQ, “Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934”, forthcoming); and crystal structure PDB6UE6 (Liu, Y., et al., “PWWP1 domain of NSD2 in complex with MR837”, forthcoming).

[0358] Figure 43 Non-limiting examples of TAU-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 6VA2, 6VA3 (Chen, JL et al., “Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing.”, J Am Chem Soc., 2020, 142: 8706-8727).

[0359] Figure 44Non-limiting examples of CYP17A1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structures PDB 3RUK, 3SWZ (Devore, NM et al., “Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001”, Nature, 2012, 482: 116-119); and crystal structures PDB 6CHI, 6CIZ (Fehl, C. et al., “Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2”, J Med Chem., 2018, 61: 4946-4960).

[0360] Figure 45 Non-limiting examples of SALL4 targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 7BQU, 7BQV (Furihata, H., et al., “Structuralbases of IMiD selectivity that emerges by 5-hydroxythalidomide”, Nat Commun., 2020, 11: 4578-4578); and crystal structure PDB 6UML (Matyskiela, ME, et al., “Crystalstructure of the SALL4-pomalidomide-cereblon-DDB1 complex”, Nat Struct MolBiol., 2020, 27: 319-322).

[0361] Figure 46 Non-limiting examples of FAM38 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 6KG7 (Wang, L., et al., “Structure and mechanogating of the mammalian tactile channel PIEZO2.”, Nature, 2019, 573:225-229).

[0362] Figure 47 Non-limiting examples of CYP20A1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see Durairaj et al. Biological Chemistry , 2020, 401(3), 361-365.

[0363] Figure 48 Non-limiting examples of HTT-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 5XI1 (Khan, E., et al., “Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington's Disease (HD) and Spino Cerebellar Ataxia (SCAs)”, ACS Chem Biol., 2018, 13: 180-188).

[0364] Figure 49 Non-limiting examples of KRAS-targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 6CU6 (Hobbs, GA, et al., “Atypical KRASG12RMutantIs Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer.”, Cancer Discov., 2020, 10: 104-123); crystal structures PDB 6GJ5, 6GJ6, 6GJ8, 6JG7 (“Drugging an Undruggable Pocket on KRAS” PNAS 2019 116 (32) 15823-15829); and crystal structure PDB 6BP1 (Lu, J., et al., “KRAS Switch Mutants D33E and A59G Crystallizein the State 1 Conformation.”, Biochemistry, 2018, 57: 324-333).

[0365] Figure 50Non-limiting examples of NRF2 (NFE2L2) targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For other examples, see crystal structures PDB 5CGJ (Winkel, AF, et al., “Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling.”, J Biol Chem., 2015, 290: 28446-28455), and 6TYM, 6TYP (Ma, B., et al., “Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators”, Bioorg Med ChemLett., 2020, 30: 126852-126852).

[0366] Figure 51 Non-limiting examples of P300-targeting ligands are provided, where R denotes an exemplary site connecting the spacer. For other examples, see crystal structures PDB 4PZR, 4PZS, 4PZT (Maksimoska, J., et al., “Structure of the p300 Histone Acetyltransferase Bound to Acetyl-Coenzyme A and Its Analogues”, Biochemistry, 2014, 53: 3415-3422); and crystal structure PDB 6PGU (Gardberg, AS, et al., “Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT”, Struct Dyn., 2019, 6: 054702-054702).

[0367] Figure 52Non-limiting examples of PIK3CA targeting ligands are provided, where R denotes an exemplary site connecting spacers. For other examples, see crystal structure PDB 6OAC (Rageot, D., et al., “(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase”, J Med Chem., 2019, 62: 6241-6261); and crystal structures PDB 5SX8, 5SWP (Miller, MS, et al., “Identification of allosteric binding sites for PI3K alpha oncogenic mutant specific inhibitor design.”, Bioorg Med Chem., 2017, 25: 1481-1486).

[0368] Figure 53 Non-limiting examples of SARM1 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see crystal structure PDB 6QWV (Sporny, M., et al., “Structural Evidence for an Octameric Ring Arrangement of SARM1”, J Mol Biol., 2019, 431: 3591-3605); and crystal structures PDB 6O0Q, 6O0R, 6O0T, 6O0V, 6O0W (Horsefield, S., et al., “NAD+ cleavage activity by animal and plant TIR domains in cell death pathways”, Science, 2019, 365: 793-799).

[0369] Figure 54Non-limiting examples of SNCA-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. For other examples, see crystal structures PDB 4I5M, 4I5P, 4I6B, 4I6F, 4I6H (Aubele, DL, et al., “Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce alpha-synuclein phosphorylation in rat brain”, Chem Med Chem., 2013, 8: 1295-1313).

[0370] Figure 55 Non-limiting examples of MAPT-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. Examples include crystal structures PDB 6VI3, 6VHL (Arakhamia, T., et al., “Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains”, Cell, 2020, 180: 633-644.e12) and crystal structures PDB 6FAU, 6FAV, 6FAW, 6FBW, 6FBY, 6FI4, 6FI5 (Andrei, SA, et al., “Inhibition of 14-3-3 / Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes.”, ACS Chem Neurosci., 2018, 9: 2639-2654).

[0371] Figure 56 Non-limiting examples of PTPN2 or TCPTP targeting ligands are provided, where R denotes an exemplary point connecting the spacer. For example, crystal structures PDB 2FJN, 2FJM (Asante-Appiah, E., et al., “Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitorselectivity over T-cell protein-tyrosine phosphatase”, J Biol Chem., 2006, 281: 8010-8015).

[0372] Figure 57 Non-limiting examples of STAT3-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. Examples shown here are from compounds including Zheng, W. et al. MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain See Yang, L. et al., Theranostics 2017, 7(18):4632 and US2006 / 0247318. For other examples, see Yang, L. et al. Novel Activators and Small- Molecule Inhibitors of STAT3 in Cancer , Cytokine&Growth Factor Reviews2019,49, 10-22.

[0373] Figure 58 Non-limiting examples of MyD88 targeting ligands are provided, where R denotes an exemplary point connecting spacers. Examples shown here are from compounds including those from Sucking, C. et al. Small Molecule Analogues of the parasitic worm product ES-62 interact with the TIR domain of MyD88 to inhibit pro-inflammatory signaling (2018) 8:2123 and Loiarro, M. et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound. Journal of Leukocyte Biology , (2007)82:801-810.

[0374] Figure 59 Non-limiting examples of PTP4A3 targeting ligands are provided, where R denotes an exemplary point connecting a spacer. Examples shown herein are from compounds including those by Ahn, J. et al. Synthesis and Biological Evaluation of RhodanineD derivatives as PRL-3 Inhibitors Bioorganic&MedicinalChemistry Letters (2006) 16( 11 ):2996-2999 and Min, G. et al. Rhodanine-Based PRL-3 Inhibitors Blocked the Migration and Invasion of Metastatic Cancer Cells Bioorganic&Medicinal Chemistry Letters (2013) 23( 13 ):3769-3774. For other examples, see Tasker, N. et al. Tapping the Therapeutic Potential of Protein Tyrosine Phosphatase 4A with Small Molecule Inhibitors Bioorganic&MedicinalChemistry Letters (2019) 29( 16 ):2008-2015.

[0375] Figure 60 Non-limiting examples of SF3B1-targeting ligands are provided, where R denotes an exemplary point connecting a spacer. Examples shown here are from compounds including those from Kaida, D. et al. Spliceostatin A Targets SF3b and Inhibits Both Splicing and Nuclear Retention of pre-mRNA Nature Chemical Biology (2007) 3 :576-583 and Kotake, Y. et al. Splicing Factor SF3b as a Target of the Antitumor Natural Product Pladienolide Nature Chemical Biology (2007) 3 570-575. For other examples, see Effenberger, K. Modulating Splicing with Small Molecular Inhibitors of the Spliceosome WIREs RNA (2016) 8:e1381.

[0376] Figure 61 Non-limiting examples of ARID1B and ARID2 targeting ligands are provided, where R denotes an exemplary point connecting spacers. For other examples, see Chory et al. ACS Chemical Biology 2020, 15(6), 1685.

[0377] Figure 62 Non-limiting examples of target ligands for class II BRAF mutants are provided, where R denotes an exemplary point connecting spacers. For other examples, see Cho et al. Biochemical and Biophysical Research Communications 2020, 352(2), 315.

[0378] Figure 63 NRAS is provided Q61K Non-limiting examples of targeted ligands, where R denotes an exemplary point connecting spacers. For other examples, see Song et al. Am J Cancer Research 2017, 7(4), 831 and Johnson et al. Curr Treat OptionsOncol. 2015, 16(4), 15.

[0379] Figures 64A-64E Non-limiting examples of ataxia-telangiectasia mutant (ATM) kinase-targeting ligands are provided, where R denotes an exemplary site of linker connection. Other examples are provided in J Med Chem, 2019, 62: 2988-3008.

[0380] Figures 65A-65BNon-limiting examples of ATR-targeting ligands are provided, where R denotes an exemplary point of adapter attachment. Other examples are provided in the Journal of Molecular Biology, Volume 429, Issue 11, 2 June 2017, Pages 1684-1704.

[0381] Figures 66A-66C Non-limiting examples of BPTF-targeted ligands are provided, where R denotes an exemplary site of linker connection. Other examples are provided in Organic & Biomolecular Chemistry 2020, 18(27): 5174-5182.

[0382] Figures 67A-67B Non-limiting examples of DNA-PK targeting ligands are provided, where R denotes an exemplary site of adapter ligand connection. Other examples are provided in J. Med. Chem. 2020, 63, 7, 3461–3471.

[0383] Figures 68A-68B Non-limiting examples of elf4E targeting ligands are provided, where R denotes an exemplary point of ligand connection. Other examples are provided in J. Am. Chem. Soc. 2020, 142, 4960-4964.

[0384] Figure 69 Non-limiting examples of TEADs, such as TEAD1, TEAD2, TEAD3 and / or TEAD4 targeting ligands, are provided, where R denotes an exemplary point of ligand connection.

[0385] Figure 70 Non-limiting examples of YAP-targeting ligands are provided, where R represents an exemplary point of connector connection.

[0386] Figure 71 Non-limiting representative molecular formulas of the target protein degradation compounds of the present invention are provided. Detailed Implementation

[0387] Compounds, their uses, and preparation methods are provided, which mediate the degradation of disease target proteins via the ubiquitin-proteasome pathway (UPP), and are therefore used to treat conditions that respond to protein degradation. The present invention provides compounds of general formula I, II, or III, or pharmaceutically acceptable salts thereof, comprising a targeting ligand binding to a target protein, an E3 ligase-binding moiety (tricyclic hydroxycerebroside ligand), a linker covalently linking the targeting ligand to a spacer, and a spacer covalently linking the linker to the E3 ligase-binding moiety.

[0388] The compounds of the present invention provided herein, or pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable compositions thereof, may be used to treat conditions mediated by target proteins. Target proteins are typically mutated, altered, or overexpressed proteins, wherein the mutation, alteration, or overexpression transforms their normal function into a dysfunction that causes or contributes to disease. In some aspects, disease is abnormal cell proliferation, such as cancer or tumor. In some embodiments, a method of treating a patient suffering from a condition mediated by target proteins is provided, comprising administering an effective amount of one or more compounds as described herein, or pharmaceutically acceptable salts thereof, to the patient, typically a human, optionally in a pharmaceutically acceptable composition.

[0389] The tricyclic heterobifunctional compounds presented in this article are catalytic. Target protein degradation mediated by these compounds typically occurs rapidly, taking only milliseconds from the initial target ligase encounter to polyubiquitination and release for proteasome degradation. Once a molecule of the target protein undergoes targeted protein degradation, the degrading agent is released, and the process is repeated using the same degrading agent molecule. This recursive process of target protein binding, ternary complex formation with E3 ligase, ubiquitination, and degradation release can occur thousands of times in the case of a single degradation molecule.

[0390] I. Definition 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 also include plural forms unless the context clearly requires otherwise. While methods and materials similar to or equivalent to those described herein may be used in the practice and testing of this application, suitable methods and materials are described below. All disclosures, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not considered prior art to the claimed applications. In the event of conflict, this specification, including its definitions, shall prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be restrictive.

[0391] 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.

[0392] In certain embodiments of each compound described herein, the compound may be a racemic mixture, an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, or a tautomer. N -Oxides or isomers; for example, rotational isomers, as each is specifically described unless the context explicitly excludes them.

[0393] The terms "an" and "a" do not indicate a limitation on quantity, but rather the presence of at least one referenced item. The term "or" means "and / or". Unless otherwise stated herein, the enumeration of numerical ranges is intended only as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recorded herein. The endpoints of all ranges are included within the range and can be combined independently. All methods described herein can be performed in a suitable order unless otherwise stated herein or otherwise obviously contradicted by the context. The use of examples or exemplary language (e.g., "for example") is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention unless otherwise claimed.

[0394] This invention includes compounds described herein that have at least one desired atomic isotopic substitution in an amount higher than the natural abundance of the isotope, i.e., enriched. An isotope is an atom with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. If isotopic substitution is used, the usual substitution is replacing at least one hydrogen atom with a deuterium atom.

[0395] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 35 S and 36 Cl. In a non-limiting example, isotope-labeled compounds can be used for metabolic studies (e.g., using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in patient radiotherapy. Furthermore, any hydrogen atoms present in the compounds of this invention can be... 18 F-atom substitution, which may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents through the procedures disclosed in the following embodiments or examples, and the preparation methods described below.

[0396] As a general example and not a limitation, isotopes of hydrogen, such as deuterium (… 2H) and tritium (3H) can be used anywhere in the described structure to achieve the desired result. Alternatively or additionally, isotopes of carbon, such as 13 C and 14 C.

[0397] 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 at any site of interest by 90%, 95%, or 99% or more of the isotope. In a non-limiting embodiment, deuterium is enriched at the desired site by 90%, 95%, or 99%.

[0398] In a non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom may be provided in any of the compounds described herein. For example, when any group is or contains, for example, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting examples, CDH2, CD2H, CD...). 3、 CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc. In some other embodiments, the unsubstituted carbon can be deuterated when the two substituents combine to form a ring. In some embodiments, at least one deuterium is located on an atom with a bond that breaks during metabolism in the compound, or on one, two, or three atoms of a bond far removed from metabolism (e.g., this may be referred to as α, β, or γ, or a primary, secondary, or tertiary isotope effect).

[0399] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds described herein. 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 can be substituted with an isotope, such as D₂O, d₆-acetone, d₆-DMSO. Solvates may be in liquid or solid form.

[0400] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[0401] "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 an independent species. For example, the term C1-C6 alkyl as used herein refers to a straight-chain or branched alkyl group 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. For example, the term C1-C4 alkyl as used herein refers to a straight-chain or branched alkyl group 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, Uncle Butyl, n-pentyl, isopentyl, Uncle Pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. Unless otherwise specified, the term alkyl includes cycloalkyl or carbocyclic.

[0402] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may appear at stable points along the chain. The specified range used herein refers to an alkenyl group having each member of the range described as a separate class, as described above with respect to the alkyl portion. In one non-limiting embodiment, the alkenyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In some embodiments, the alkenyl group is C2, C2-C3, C2-C4, C2-C5, or C2-C6. 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 alternatively, "E" and "Z" alkenyl geometries. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one unsaturated point.

[0403] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can appear at any stable point on 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. In one non-limiting embodiment, the alkynyl group contains 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In some embodiments, the alkynyl group is C2, C2-C3, C2-C4, C2-C5, or C2-C6. 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. The term "alkynyl" also includes cycloalkyl or carbocyclic groups having at least one triple bond unsaturation point.

[0404] "Halogen" and "halogen" are, independently, fluorine, chlorine, bromine, or iodine.

[0405] "Haloalkyl" is a branched or straight-chain alkyl group that is substituted with one or more of the aforementioned halogen atoms (up to the maximum permissible number of halogen atoms). Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Hyperhaloalkyl" refers to an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0406] As used herein, "aryl" refers to a monocyclic or polycyclic compound having 6–14 ring carbon atoms and providing zero heteroatoms in the aromatic ring system. For example, Two- or three-ring aromatic ring systems (4n+2 aromatic ring systems) For example, Groups (“C”) with 6, 10, or 14 π electrons in the ring array 6–14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”). For example, Phenyl). In some embodiments, the aryl group has 10 cyclic carbon atoms (“C10”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C14”). 14 "Aryl"; for example, anthracene. "Aryl" also includes a ring system in which an aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the group or connecting point is on the aryl ring, and in this case, the number of carbon atoms continuously represents the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4 to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.

[0407] "Arylalkyl" means an alkyl group as defined herein that is substituted with an aryl group as defined herein, or an aryl group as defined herein that is substituted with an alkyl group as defined herein.

[0408] The term "heterocyclic" refers to a saturated or partially saturated heteroatom-containing cyclic group having one, two, three, or four heteroatoms independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic groups can comprise monocyclic 3- to 10-membered rings and 5- to 16-membered bicyclic systems (which may include bridged fused and spirofused bicyclic systems). It does not include rings containing -OO-, -OS-, or -SS- motifs. Examples of saturated heterocyclic groups include: saturated 3- to 6-membered heterocyclic monocyclic groups containing one to four nitrogen atoms [e.g., pyrrolyl, imidazolyl, piperidinyl, pyrrololinyl, piperazinel]; saturated 3- to 6-membered heterocyclic monocyclic groups containing one to two oxygen atoms and one to three nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heterocyclic monocyclic groups containing one to two sulfur atoms and one to three nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyranoyl, dihydrofuranoyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazolyl, piperidinyl, pyrrololino, pyrazolyl, piperazinyl, morpholino, tetrahydropyranoyl, thiazolyl, dihydrothiophene, 2,3-dihydro-benzo[1,4]dioxyl, indololino, isoyindololino, dihydrobenzothiophene, dihydrobenzofuranoyl, isochromyl, chromanyl, 1,2-dihydroquinolino, 1,2,3,4-tetrahydro-isoquinolino. 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.

[0409] "Heterocycle" also includes groups in which a heterocyclic group is fused / condensed with an aryl or carbocyclic group, wherein the linking point is a heterocycle. "Heterocycle" also includes groups in which a heterocyclic group is oxidized by an oxo group (i.e., Substituent groups. For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as dihydroindole or isodihydroindole; partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 to 2 oxygen atoms or sulfur atoms.

[0410] The term "heterocycle" also includes "bicyclic heterocycle." The term "bicyclic heterocycle" refers to a heterocycle as defined herein, wherein a bridging, fused, or spirocyclic portion of the heterocycle is present. The bridging, fused, or spirocyclic portion of the heterocycle can be a carbocyclic, heterocyclic, or aryl group, as long as it produces a stable molecule. Unless the context excludes, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups in which the fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include: , , , , , , , , , and .

[0411] "Heterocyclic alkyl" means an alkyl group as defined herein that is substituted with a heterocyclic group as defined herein, or a heterocyclic group as defined herein that is substituted with an alkyl group as defined herein.

[0412] The term "heteroaryl" refers to a stable aromatic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from O, N, and S, wherein the ring 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, such as... Examples include 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; and unsaturated 5- to 6-membered heterocyclic monocyclic 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]. In some embodiments, the "heteroaryl" group is an 8, 9, or 10-membered bicyclic system. Examples of 8, 9, or 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxalinyl, naphthidyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazole, and benzotriazolyl.

[0413] "Heteroarylene alkyl" means an alkyl group as defined herein that is substituted with a heteroarylene group as defined herein, or a heteroarylene group as defined herein that is substituted with an alkyl group as defined herein.

[0414] As used herein, “carbocyclic,” “carbocyclic,” or “cycloalkyl” includes saturated or partially unsaturated (i.e., non-aromatic) groups containing all carbocyclic atoms and 3 to 14 cyclic carbon atoms (“C…”). 3-14 cycloalkyl groups ("cycloalkyl") and non-aromatic ring systems with zero heteroatoms. In some embodiments, cycloalkyl groups have 3 to 10 ring carbon atoms ("C10") 3–10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 9 cyclic carbon atoms (“C”). 3–9 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3–7 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4–6 cycloalkyl group (“cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5–10 (Cycloalkyl). Example C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Example C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10As illustrated in the preceding examples, in some embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double bonds. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above is fused with a heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in this case, the number of carbons continuously represents the number of carbons in the carbocyclic system. The term "cycloalkyl" also includes ring systems in which the cycloalkyl ring as defined above has a spirocyclic heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in this case, the number of carbons continuously represents the number of carbons in the carbocyclic system. The term "cycloalkyl" also includes bicyclic or polycyclic fused, bridged, or spirocyclic systems containing 5 to 14 carbon atoms and zero heteroatoms in a non-aromatic ring system. Representative examples of "cycloalkyl" include, but are not limited to, those including, those... , , , , and .

[0415] The term "bicyclic" refers to a ring system in which two rings are fused together, and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl rings. Non-limiting examples of bicyclic groups include: , , , , , , and .

[0416] When the term "bicyclic" is used for divalent residues such as R 20 R 21 R 22 R 23 Or R 24 In this context, the connection points can be on different rings or on the same ring. In some embodiments, the two connection points are on the same ring. In some embodiments, the two connection points are on different rings. Non-limiting examples of bicyclic groups include: , , , , and .

[0417] “Aliphatic” refers to a saturated or unsaturated straight-chain, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and is therefore incorporated into each of these definitions. In some embodiments, “aliphatic” is used to refer to 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 in cis or trans configurations. In some embodiments, 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 some embodiments, 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 a separate class. For example, as used herein, the term C1-C6 aliphatic 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 distinct class. For example, as used herein, the term C1-C4 aliphatic 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 distinct class. In some embodiments, the aliphatic group is replaced by one or more functional groups that result in the formation of a stable moiety.

[0418] The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in the chain, such as amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms replacing carbon atoms. In some embodiments, the only heteroatom is nitrogen. In some embodiments, the only heteroatom is oxygen. In some embodiments, the only heteroatom is sulfur. "Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloynyl moieties. In some embodiments, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In some embodiments, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic portions include polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolic acid, thioether, ether, alkyl-heterocyclic-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0419] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, balls, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, sublingual tablets, topical preparations, gels, and mucosal preparations. "Dosage form" can also include implants, such as optical implants.

[0420] As used in this article, “endogenous” means any material that originates from or is produced within an organism, cell, tissue, or system.

[0421] As used herein, the term “exogenous” means any material introduced from or generated outside of an organism, cell, tissue, or system.

[0422] As used herein, the term "modulation" refers to mediating a detectable increase or decrease in a subject's response level compared to the subject's response level in the absence of treatment or the compound and / or the response level of other subjects who are otherwise identical but not treated. This term includes disrupting and / or influencing natural signals or responses, thereby mediating a beneficial therapeutic response in the subject, preferably in a human.

[0423] "Parenteral" administration of compounds includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion.

[0424] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent, as described herein, of a selected active compound, and at least one other substance, such as a carrier. A “pharmaceutical combination” is a combination of at least two active agents that may be supplied together in a single dosage form or in separate dosage forms, and includes instructions for using the active agents together to treat any of the conditions described herein.

[0425] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compounds, wherein the parent compound is modified by preparing an inorganic or organic acid or base addition salt having biologically acceptable non-toxicity. 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 can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., sodium hydroxide, calcium hydroxide, magnesium hydroxide, or potassium hydroxide, carbonate, bicarbonate, etc.), 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 or an organic solvent or a mixture of both. Typically, where feasible, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Salts of the compounds of the present invention further comprise the compound and a solvate of the compound salt.

[0426] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and basic or organic acid salts of acidic residues such as carboxylic acids. 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 salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocyanate, and HOOC-(CH2). 1-4 -COOH (where n is 0-4), etc., or different acids that produce the same counterion. A list of other suitable salts can be found, for example... Remington's Pharmaceutical Sciences Found in 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985).

[0427] The term "carrier" means a diluent, excipient, or medium for using or delivering an active agent.

[0428] "Pharmaceutically acceptable excipients" means excipients that can be used to prepare pharmaceutical compositions / combinations that are generally safe and, biologically or otherwise, not unsuitable for administration to a host, typically human. In some embodiments, veterinary-acceptable excipients are used.

[0429] "Patient," "host," or "subject" is a human or non-human animal that requires treatment for any condition specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0430] 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 alleviation of the disease itself, when administered to a host.

[0431] In some embodiments, a "prodrug" is a form of the parent molecule that is metabolized or chemically converted into the parent molecule in vivo, such as in mammals or humans. Non-limiting examples of prodrugs include esters, amides such as primary or secondary amines, carbonates, carbamates, phosphate esters, ketals, imines, oxazolidinyl and thiazolidinyl. Prodrugs can be programmed to release the parent molecule upon action of a pH change (e.g., in the stomach or intestine) or by an enzyme (e.g., an esterase or amidase).

[0432] In some embodiments, "stable" means that less than 10%, 5%, 3%, or 1% of the compound degrades under ambient conditions, with a shelf life of at least 3, 4, 5, or 6 months. In some embodiments, compounds stored under ambient conditions are stored at approximately room temperature and exposed to air and relative humidity less than approximately 40%, 50%, 60%, or 70%. In some embodiments, compounds stored under ambient conditions are stored at approximately room temperature under an inert gas (e.g., argon or nitrogen). Generally, the portion described herein does not have more than one or two heteroatoms directly bonded to each other, unless the portion is heteroaromatic.

[0433] Throughout this disclosure, various aspects of the invention can be presented in a scope manner. It should be understood that this scope description is merely for convenience and should not be construed as limiting the scope of the invention. It should be considered that the description of the scope specifically discloses all possible sub-scopes and the various numerical values ​​within those scopes. For example, it should be considered that the description of a scope such as 1 to 6 specifically discloses sub-scopes, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the various numbers within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the scope.

[0434] II. Compounds of the present invention Implementation scheme of "alkyl" In some implementations, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0435] In some implementations, "alkyl" has one carbon atom.

[0436] In some implementations, "alkyl" has two carbon atoms.

[0437] In some implementations, "alkyl" has three carbon atoms.

[0438] In some implementations, "alkyl" has four carbon atoms.

[0439] In some implementations, "alkyl" has five carbon atoms.

[0440] In some implementations, "alkyl" has six carbon atoms.

[0441] In some implementations, "alkyl" has seven carbons.

[0442] In some implementations, "alkyl" has eight carbon atoms.

[0443] In some implementations, the "alkyl" has nine carbon atoms.

[0444] In some implementations, "alkyl" has ten carbon atoms.

[0445] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0446] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0447] Other non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0448] Other non-limiting examples of "alkyl" include: Uncle Butyl, Uncle pentyl and Uncle Jiji.

[0449] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0450] Implementation scheme of "halogenated alkyl" In some implementations, "haloalkyl" is C1-C 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0451] In some implementations, the "halogenated alkyl" has one carbon atom.

[0452] In some implementations, the "halogenated alkyl" has one carbon atom and one halogen.

[0453] In some implementations, the "halogenated alkyl" has one carbon atom and two halogens.

[0454] In some implementations, the "halogenated alkyl" has one carbon atom and three halogens.

[0455] In some implementations, the "halogenated alkyl" has two carbon atoms.

[0456] In some implementations, the "halogenated alkyl" has two carbon atoms and one halogen.

[0457] In some implementations, the "halogenated alkyl" has two carbon atoms and two halogens.

[0458] In some implementations, the "halogenated alkyl" has two carbon atoms and three halogens.

[0459] In some implementations, the "halogenated alkyl" has two carbon atoms and four halogens.

[0460] In some implementations, the "halogenated alkyl" has two carbon atoms and five halogens.

[0461] In some implementations, the "halogenated alkyl" has three carbons.

[0462] In some implementations, the "halogenated alkyl" has three carbon atoms and one halogen.

[0463] In some implementations, the "halogenated alkyl" has three carbons and two halogens.

[0464] In some implementations, the "halogenated alkyl" has three carbons and three halogens.

[0465] In some implementations, the "halogenated alkyl" has three carbons and four halogens.

[0466] In some implementations, the "halogenated alkyl" has three carbons and five halogens.

[0467] In some implementations, the "halogenated alkyl" has three carbons and six halogens.

[0468] In some implementations, the "halogenated alkyl" has three carbons and seven halogens.

[0469] In some implementations, the "halogenated alkyl" has four carbons.

[0470] In some implementations, the "halogenated alkyl" has five carbons.

[0471] In some implementations, the "halogenated alkyl" has six carbons.

[0472] Non-limiting examples of “halogenated alkyl” include: , and .

[0473] Other non-limiting examples of “haloalkyl” include: , , , , , , , , , and .

[0474] Other non-limiting examples of “haloalkyl” include: , , , , , , , and .

[0475] Other non-limiting examples of “haloalkyl” include: , and .

[0476] Other non-limiting examples of “haloalkyl” include: , and .

[0477] Implementation plan for "Aryl" In some implementations, "aryl" is a six-carbon aromatic group (phenyl). In some implementations, "aryl" is an aromatic group with 10 carbon atoms (naphthyl). In some embodiments, "aryl" is a 6-carbon aromatic group fused with a heterocycle, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on an aromatic ring.

[0478] For example, It is an "aryl" group.

[0479] However, It is a "heterocyclic" group.

[0480] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a cycloalkyl group, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[0481] For example, It is an "aryl" group.

[0482] However, It is a "cycloalkyl" group.

[0483] Implementation plan of "hybrid aromatics" In some implementations, "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0484] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0485] Other non-limiting examples of 5-membered "heteroaryl" groups include: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0486] In some embodiments, "heteroaryl" is a six-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing one, two, or three nitrogen atoms.

[0487] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include: , , , , , , , , ,and .

[0488] In some embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen and sulfur.

[0489] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole, and benzothiazol.

[0490] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , , and .

[0491] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0492] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0493] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0494] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0495] In some embodiments, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two nitrogen atoms.

[0496] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[0497] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0498] Other non-limiting examples of bicyclic "heteroaryl" groups include: , , , , and .

[0499] "Cycloalkyl" implementation scheme In some embodiments, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0500] In some implementations, "cycloalkyl" has three carbons.

[0501] In some implementations, "cycloalkyl" has four carbons.

[0502] In some implementations, "cycloalkyl" has five carbons.

[0503] In some implementations, "cycloalkyl" has six carbons.

[0504] In some implementations, "cycloalkyl" has seven carbons.

[0505] In some implementations, "cycloalkyl" has eight carbons.

[0506] In some implementations, "cycloalkyl" has nine carbons.

[0507] In some implementations, "cycloalkyl" has ten carbons.

[0508] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0509] Other non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the connection point of each group is on the cycloalkyl ring.

[0510] For example: It is a "cycloalkyl" group.

[0511] However, It is an "aryl" group.

[0512] Implementation plan of "heterocyclic" In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0513] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0514] In some implementations, a "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0515] In some implementations, a "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0516] In some implementations, a "heterocycle" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0517] Non-limiting examples of "heterocyclic" include aziridine, ethylene oxide, thioheterocyclic propane, azirocyclic butane, 1,3-diazaheterocyclic butane, oxoheterocyclic butane, and thioheterocyclic butane.

[0518] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[0519] Other non-limiting examples of "heterocyclic rings" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxothiocyclopentane, and 1,3-oxothiocyclopentane.

[0520] Other non-limiting examples of "heterocyclic" compounds include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[0521] Other non-limiting examples of "heterocycles" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on the heterocycle.

[0522] For example, It is a "heterocyclic" group.

[0523] However, It is an "aryl" group.

[0524] Non-limiting examples of "heterocycles" also include: , , , , , , , , and .

[0525] Other non-limiting examples of "heterocycles" include: , , , , , , and .

[0526] Other non-limiting examples of "heterocycles" include: , , , , , , and .

[0527] Non-limiting examples of "heterocycles" also include: , and .

[0528] Non-limiting examples of "heterocycles" also include: , , , , , , and .

[0529] Other non-limiting examples of "heterocycles" include: , , , , and .

[0530] Other non-limiting examples of "heterocycles" include: , , , , and .

[0531] Optional substituents In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by a single substituent.

[0532] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by two substituents.

[0533] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by three substituents.

[0534] In some embodiments, the portion described herein that can be replaced by 1, 2, 3 or 4 substituents is replaced by four substituents.

[0535] R 1 and / or R 2 Non-restrictive implementation scheme In some implementations, each R 1 and / or R 2 Independently selected from alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 , cyano and nitro.

[0536] In some implementations, each R 1 and / or R 2 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; In some implementations, each R 1 and / or R 2 Independently selected from halogens, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 , cyano and nitro.

[0537] In some implementations, each R 1 and / or R 2 Independently selected from halogens, -S(O)R 12 -SO2R 12 , cyano and nitro.

[0538] In some implementations, each R 1 and / or R 2 Independently selected from alkyl, haloalkyl, -OR 10 and -SR 10 .

[0539] In some implementations, each R 1 and / or R2 It is independently selected from alkyl, haloalkyl and cyano groups.

[0540] In some implementations, each R 1 and / or R 2 It is hydrogen.

[0541] In some implementations, each R 1 and / or R 2 It is an alkyl group.

[0542] In some implementations, each R 1 and / or R 2 It is halogen.

[0543] In some implementations, each R 1 and / or R 2 It is a haloalkyl group.

[0544] In some implementations, each R 1 and / or R 2 Yes - OR 10 .

[0545] In some implementations, each R 1 and / or R 2 It is -SR 10 .

[0546] In some implementations, each R 1 and / or R 2 It is -S(O)R 12 .

[0547] In some implementations, each R 1 and / or R 2 Yes - SO2R 12 .

[0548] In some implementations, each R 1 and / or R 2 Yes -NR 10 R 11 .

[0549] In some implementations, each R 1 and / or R 2 It is a cyano group.

[0550] In some implementations, each R 1 and / or R 2 It is a nitro group.

[0551] In some implementations, each R 1 and / or R 2 It is a heteroaryl group.

[0552] In some implementations, each R 1 and / or R 2 It is an aryl group.

[0553] In some implementations, each R 1 and / or R 2 It is a heterocyclic ring.

[0554] In some implementations, only one R exists on ring-A or ring-C. 1 Substituents.

[0555] In some implementations, only two Rs exist on ring-A or ring-C. 1 Substituents.

[0556] In some implementations, three Rs exist on ring-A or ring-C. 1 Substituents.

[0557] In some implementations, only one R exists on ring-B. 1 Substituents.

[0558] In some implementations, only two Rs exist on ring-B. 1 Substituents.

[0559] In some implementations, there are three Rs on ring-B. 1 Substituents.

[0560] In some implementations, only one R exists on ring-D. 2 Substituents.

[0561] In some implementations, only two Rs exist on ring-D. 2 Substituents.

[0562] In some implementations, there are three Rs on ring-D. 2 Substituents.

[0563] In some implementations, an R 1 The substituent is halogen.

[0564] In some implementations, two R 1 The substituent is halogen.

[0565] In some implementations, the three Rs 1 The substituent is halogen.

[0566] In some implementations, an R 2 The substituent is halogen.

[0567] In some implementations, two R 2 The substituent is halogen.

[0568] In some implementations, the three Rs 2 The substituent is halogen.

[0569] In some implementations, an R 1 The substituent is a haloalkyl group.

[0570] In some implementations, two R 1 The substituent is a haloalkyl group.

[0571] In some implementations, the three Rs 1 The substituent is a haloalkyl group.

[0572] In some implementations, an R 2 The substituent is a haloalkyl group.

[0573] In some implementations, two R 2 The substituent is a haloalkyl group.

[0574] In some implementations, the three Rs 2 The substituent is a haloalkyl group.

[0575] In some implementations, an R 1 The substituent is an alkyl group.

[0576] In some implementations, two R 1 The substituent is an alkyl group.

[0577] In some implementations, the three Rs 1 The substituent is an alkyl group.

[0578] In some implementations, an R 2 The substituent is an alkyl group.

[0579] In some implementations, two R 2 The substituent is an alkyl group.

[0580] In some implementations, the three Rs 2 The substituent is an alkyl group.

[0581] In some implementations, two R 1 The groups combine to form a fused benzene ring.

[0582] In some implementations, two R 1 The groups combine to form a fused 5-membered heteroaryl ring.

[0583] In some implementations, two R 1 The groups combine to form a fused 6-membered heteroaryl ring.

[0584] In some implementations, R1 Group and R 2 The groups combine to form a fused 6-membered heterocycle.

[0585] In some implementations, R 1 Group and R 2 The groups combine to form a fused 5-membered heterocycle.

[0586] In some implementations, two R 2 The groups combine to form a fused benzene ring.

[0587] In some implementations, two R 1 The groups combine to form a fused benzene ring.

[0588] In some implementations, two R 2 The groups combine to form a fused 5-membered heteroaryl ring.

[0589] In some implementations, two R 2 The groups combine to form a fused 6-membered heteroaryl ring.

[0590] R 3 Non-restrictive implementation scheme In some implementations, R 3 Selected from hydrogen and halogens.

[0591] In some implementations, R 3 Selected from alkyl and haloalkyl groups.

[0592] In some implementations, R 3 It is hydrogen.

[0593] In some implementations, R 3 It is halogen.

[0594] In some implementations, R 3 It is an alkyl group.

[0595] In some implementations, R 3 It is a haloalkyl group.

[0596] In some implementations, R 3 It's fluorine.

[0597] In some implementations, R 3 It is chlorine.

[0598] In some implementations, R 3 It is bromine.

[0599] In some implementations, R 3 It's iodine.

[0600] In some implementations, R 3It is a methyl group.

[0601] In some implementations, R 3 It is an ethyl group.

[0602] In some implementations, R 3 It is trifluoromethyl.

[0603] In some implementations, R 3 It is pentafluoroethyl.

[0604] In some implementations, R 3 It is difluoromethyl.

[0605] In some implementations, R 3 It is a fluoromethyl group.

[0606] In some implementations, R 3 With R 4 Groups combine to form a 1-carbon link.

[0607] In some implementations, R 3 With R 4 Groups combine to form 2-carbon linkages.

[0608] In some implementations, R 3 With R 4 Groups combine to form 3-carbon linkages.

[0609] In some implementations, R 3 With R 4 Groups combine to form 4-carbon linkages.

[0610] In some implementations, R 3 With R 4 Groups combine to form double bonds.

[0611] In some implementations, R 3 With R 6 Groups combine to form a 1-carbon link.

[0612] In some implementations, R 3 With R 6 Groups combine to form 2-carbon linkages.

[0613] In some implementations, R 3 With R 6 Groups combine to form 3-carbon linkages.

[0614] In some implementations, R 3 With R 6 Groups combine to form 4-carbon linkages.

[0615] R 6 and R7 Non-restrictive implementation scheme In some implementations, R 6 and R 7 It is independently selected from hydrogen, alkyl, halogen and haloalkyl.

[0616] In some implementations, R 6 and R 7 Independently selected from -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 .

[0617] In some implementations, R 6 and R 7 Independently selected from alkyl, -OR 10 -SR 10 and -NR 10 R 11 .

[0618] In some implementations, R 6 With R 3 Groups combine to form a 1-carbon link.

[0619] In some implementations, R 6 With R 3 Groups combine to form 2-carbon linkages.

[0620] In some implementations, R 6 With R 3 Groups combine to form 3-carbon linkages.

[0621] In some implementations, R 6 With R 3 Groups combine to form 4-carbon linkages.

[0622] R 10 and R 11 Non-restrictive implementation scheme In some implementations, R 10 It is hydrogen.

[0623] In some implementations, R 10 It is an alkyl group.

[0624] In some implementations, R 10 It is a haloalkyl group.

[0625] In some implementations, R 10 It is a heterocyclic ring.

[0626] In some implementations, R 10 It is an aryl group.

[0627] In some implementations, R 10 It is a heteroaryl group.

[0628] In some implementations, R 10 It is -C(O)R 12 .

[0629] In some implementations, R 10 It is -S(O)R 12 .

[0630] In some implementations, R 10 Yes - SO2R 12 .

[0631] In some implementations, R 11 It is hydrogen.

[0632] In some implementations, R 11 It is an alkyl group.

[0633] In some implementations, R 11 It is a haloalkyl group.

[0634] In some implementations, R 11 It is a heterocyclic ring.

[0635] In some implementations, R 11 It is an aryl group.

[0636] In some implementations, R 11 It is a heteroaryl group.

[0637] In some implementations, R 11 It is -C(O)R 12 .

[0638] In some implementations, R 11 It is -S(O)R 12 .

[0639] In some implementations, R 11 Yes - SO2R 12 .

[0640] R 12 Non-restrictive implementation scheme: In some implementations, R 12 It is hydrogen.

[0641] In some implementations, R 12 It is an alkyl group.

[0642] In some implementations, R12 It is a haloalkyl group.

[0643] In some implementations, R 12 It is a heterocyclic ring.

[0644] In some implementations, R 12 It is an aryl group.

[0645] In some implementations, R 12 It is a heteroaryl group.

[0646] In some implementations, R 12 Yes -NR 13 R 14 .

[0647] In some implementations, R 12 Is it OR 13 .

[0648] R 13 Non-restrictive implementation scheme: In some implementations, R 13 It is hydrogen.

[0649] In some implementations, R 13 It is an alkyl group.

[0650] In some implementations, R 13 It is a haloalkyl group.

[0651] In some implementations, R 14 It is hydrogen.

[0652] In some implementations, R 14 It is an alkyl group.

[0653] In some implementations, R 14 It is a haloalkyl group.

[0654] In some implementations, R 13 It is hydrogen and R 14 It is hydrogen.

[0655] In some implementations, R 13 It is hydrogen and R 14 It is an alkyl group.

[0656] In some implementations, R 13 It is hydrogen and R 14 It is a haloalkyl group.

[0657] In some implementations, R 13 It is an alkyl group and R 14 It is hydrogen In some implementations, R 13It is an alkyl group and R 14 It is an alkyl group.

[0658] In some implementations, R 13 It is an alkyl group and R 14 It is a haloalkyl group.

[0659] In some implementations, R 13 It is a haloalkyl and R 14 It is hydrogen.

[0660] In some implementations, R 13 It is a haloalkyl and R 14 It is an alkyl group.

[0661] In some implementations, R 13 It is a haloalkyl and R 14 It is a haloalkyl group.

[0662] X 1 and X 2 Non-restrictive implementation scheme: In some implementations, X 1 It is a key.

[0663] In some implementations, X 1 It is a heterocyclic ring.

[0664] In some implementations, X 1 It is a heteroaryl group.

[0665] In some implementations, X 1 It is an aryl group.

[0666] In some implementations, X 1 It is a double ring.

[0667] In some implementations, X 1 It is an alkyl group.

[0668] In some implementations, X 1 They are adipose-dependent individuals.

[0669] In some implementations, X 1 It is a mixed fatty acid.

[0670] In some implementations, X 1 It is -C(NR) 27 )-.

[0671] In some implementations, X 1 It is CR 40 R 41 -

[0672] In some implementations, X 1It is -C(O)-.

[0673] In some implementations, X 1 It is -C(NR) 27 )-.

[0674] In some implementations, X 1 It is -C(S)-.

[0675] In some implementations, X 1 It is -S(O)-.

[0676] In some implementations, X 1 It is -S(O)2-.

[0677] In some implementations, X 1 Yes -S-.

[0678] In some implementations, X 1 It is a 5-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0679] In some implementations, X 1 It is a 5-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0680] In some implementations, X 1 It is a 6-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0681] In some implementations, X 1 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0682] In some implementations, X 1 It is a 6-membered aromatic heterocycle with the connection point in the 1,4 direction.

[0683] In some implementations, X 1 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0684] In some implementations, X 1 It is a 5-membered heterocyclic ring with the connection point in directions 1 and 2. In some implementations, X 1 It is a 5-membered heterocyclic ring with the connection point in the 1,3 direction.

[0685] In some implementations, X 1 It is a 6-membered heterocyclic ring with the connection point in the 1 and 2 directions.

[0686] In some implementations, X 1 It is a 6-membered heterocyclic ring with the connection point in the 1,3 direction.

[0687] In some implementations, X1 It is a 6-membered heterocyclic ring with the connection point in the 1, 4 direction.

[0688] In some implementations, X 1 It is a bicyclic heterocycle with one heteroatom. In some implementations, X 1 It is a bicyclic heterocycle with two heteroatoms.

[0689] In some implementations, X 1 It is a bicyclic heterocycle with one heteroatom, and one bonded to nitrogen and the other bonded to carbon. In some implementations, X 1 It is a bicyclic heterocycle with one heteroatom, and the two bonding sites are bonded to carbon. In some implementations, X 1 It is a bicyclic heterocycle with two heteroatoms and both bonding sites are attached to nitrogen.

[0690] In some implementations, X 1 It is a bicyclic heterocycle with two heteroatoms.

[0691] In some implementations, X 1 It is a fused bicyclic alkane.

[0692] In some implementations, X 1 It is a spirobicycloalkane.

[0693] In some implementations, X 1 Selected from: In some implementations, X 2 It is a key.

[0694] In some implementations, X 2 It is a heterocyclic ring.

[0695] In some implementations, X 2 It is a heteroaryl group.

[0696] In some implementations, X 2 It is an aryl group.

[0697] In some implementations, X 2 It is a double ring.

[0698] In some implementations, X 2 It is an alkyl group.

[0699] In some implementations, X 2 They are adipose-dependent individuals.

[0700] In some implementations, X 2 It is a mixed fatty acid.

[0701] In some implementations, X 2 It is -C(NR) 27 )-.

[0702] In some implementations, X 2 It is CR 40 R 41 -

[0703] In some implementations, X 2 It is -C(O)-.

[0704] In some implementations, X 2 It is -C(NR) 27 )-.

[0705] In some implementations, X 2 It is -C(S)-.

[0706] In some implementations, X 2 It is -S(O)-.

[0707] In some implementations, X 2 It is -S(O)2-.

[0708] In some implementations, X 2 Yes -S-.

[0709] In some implementations, X 2 It is a 5-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0710] In some implementations, X 2 It is a 5-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0711] In some implementations, X 2 It is a 6-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0712] In some implementations, X 2 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0713] In some implementations, X 2 It is a 6-membered aromatic heterocycle with the connection point in the 1,4 direction.

[0714] In some implementations, X 2 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0715] In some implementations, X 2 It is a 5-membered heterocyclic ring with the connection point in directions 1 and 2. In some implementations, X 2It is a 5-membered heterocyclic ring with the connection point in the 1,3 direction.

[0716] In some implementations, X 2 It is a 6-membered heterocyclic ring with the connection point in the 1 and 2 directions.

[0717] In some implementations, X 2 It is a 6-membered heterocyclic ring with the connection point in the 1,3 direction.

[0718] In some implementations, X 2 It is a 6-membered heterocyclic ring with the connection point in the 1, 4 direction.

[0719] In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom. In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms.

[0720] In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom, and one bonded to nitrogen and the other bonded to carbon. In some implementations, X 2 It is a bicyclic heterocycle with one heteroatom, and the two bonding sites are bonded to carbon. In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms and both bonding sites are attached to nitrogen.

[0721] In some implementations, X 2 It is a bicyclic heterocycle with two heteroatoms.

[0722] In some implementations, X 2 It is a fused bicyclic alkane.

[0723] In some implementations, X 2 It is a spirobicycloalkane.

[0724] X 3 Non-restrictive implementation scheme: In some implementations, X 3 It is a key.

[0725] In some implementations, X 3 It is a heterocyclic ring.

[0726] In some implementations, X 3 It is a heteroaryl group.

[0727] In some implementations, X 3 It is an aryl group.

[0728] In some implementations, X 3It is a double ring.

[0729] In some implementations, X 3 It is an alkyl group.

[0730] In some implementations, X 3 They are adipose-dependent individuals.

[0731] In some implementations, X 3 It is a mixed fatty acid.

[0732] In some implementations, X 3 It is -C(NR) 27 )-.

[0733] In some implementations, X 3 It is CR 40 R 41 -

[0734] In some implementations, X 3 It is -C(O)-.

[0735] In some implementations, X 3 It is -C(NR) 27 )-.

[0736] In some implementations, X 3 It is -C(S)-.

[0737] In some implementations, X 3 It is -S(O)-.

[0738] In some implementations, X 3 It is -S(O)2-.

[0739] In some implementations, X 3 Yes -S-.

[0740] In some implementations, X 3 It is a 5-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0741] In some implementations, X 3 It is a 5-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0742] In some implementations, X 3 It is a 6-membered aromatic heterocycle with the connection point in the 1,2 direction.

[0743] In some implementations, X 3 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0744] In some implementations, X 3It is a 6-membered aromatic heterocycle with the connection point in the 1,4 direction.

[0745] In some implementations, X 3 It is a 6-membered aromatic heterocycle with the connection point in the 1,3 direction.

[0746] In some implementations, X 3 It is a 5-membered heterocyclic ring with the connection point in directions 1 and 2. In some implementations, X 3 It is a 5-membered heterocyclic ring with the connection point in the 1,3 direction.

[0747] In some implementations, X 3 It is a 6-membered heterocyclic ring with the connection point in the 1 and 2 directions.

[0748] In some implementations, X 3 It is a 6-membered heterocyclic ring with the connection point in the 1,3 direction.

[0749] In some implementations, X 3 It is a 6-membered heterocyclic ring with the connection point in the 1, 4 direction.

[0750] In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom. In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms.

[0751] In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom, and one bonded to nitrogen and the other bonded to carbon. In some implementations, X 3 It is a bicyclic heterocycle with one heteroatom, and the two bonding sites are bonded to carbon. In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms and both bonding sites are attached to nitrogen.

[0752] In some implementations, X 3 It is a bicyclic heterocycle with two heteroatoms.

[0753] In some implementations, X 3 It is a fused bicyclic alkane.

[0754] In some implementations, X 3 It is a spirobicycloalkane.

[0755] R 15 R 16 and R 17 Non-restrictive implementation scheme: In some implementations, R15 It is a key.

[0756] In some implementations, R 15 It is an alkyl group.

[0757] In some implementations, R 15 It is -C(O)-.

[0758] In some implementations, R 15 It is -C(O)O-.

[0759] In some implementations, R 15 It is -OC(O)-.

[0760] In some implementations, R 15 It is -SO2-.

[0761] In some implementations, R 15 It is -S(O)-.

[0762] In some implementations, R 15 It is -C(S)-.

[0763] In some implementations, R 15 It is C(O)NR 27 -

[0764] In some implementations, R 15 Yes -NR 27 C(O)-.

[0765] In some implementations, R 15 Yes -O-.

[0766] In some implementations, R 15 Yes -S-.

[0767] In some implementations, R 15 Yes -NR 27 -

[0768] In some implementations, R 15 It is C(R) 40 R 41 )-.

[0769] In some implementations, R 15 It is P(O)(OR) 26 )O-.

[0770] In some implementations, R 15 It is -P(O)(OR) 26 )-.

[0771] In some implementations, R15 It is a double ring.

[0772] In some implementations, R 15 It is an olefin.

[0773] In some implementations, R 15 It is an alkyne.

[0774] In some implementations, R 15 It is a haloalkyl group.

[0775] In some implementations, R 15 It is an alkoxy group.

[0776] In some implementations, R 15 It is aryl In some implementations, R 15 It is a heterocyclic ring.

[0777] In some implementations, R 15 It is a mixed fatty acid.

[0778] In some implementations, R 15 It is a heteroaryl group.

[0779] In some implementations, R 15 It is lactic acid In some implementations, R 15 It is glycolic acid.

[0780] In some implementations, R 15 It is an arylalkyl group.

[0781] In some implementations, R 15 It is a heterocyclic alkyl group.

[0782] In some implementations, R 15 It is a heteroarylalkyl group.

[0783] In some implementations, R 16 It is a key.

[0784] In some implementations, R 16 It is an alkyl group.

[0785] In some implementations, R 16 It is -C(O)-.

[0786] In some implementations, R 16 It is -C(O)O-.

[0787] In some implementations, R 16 It is -OC(O)-.

[0788] In some implementations, R 16 It is -SO2-.

[0789] In some implementations, R 16 It is -S(O)-.

[0790] In some implementations, R 16 It is -C(S)-.

[0791] In some implementations, R 16 It is C(O)NR 27 -

[0792] In some implementations, R 16 Yes -NR 27 C(O)-.

[0793] In some implementations, R 16 Yes -O-.

[0794] In some implementations, R 16 Yes -S-.

[0795] In some implementations, R 16 Yes -NR 27 -

[0796] In some implementations, R 16 It is C(R) 40 R 41 )-.

[0797] In some implementations, R 16 It is P(O)(OR) 26 )O-.

[0798] In some implementations, R 16 It is -P(O)(OR) 26 )-.

[0799] In some implementations, R 16 It is a double ring.

[0800] In some implementations, R 16 It is an olefin.

[0801] In some implementations, R 16 It is an alkyne.

[0802] In some implementations, R 16 It is a haloalkyl group.

[0803] In some implementations, R 16 It is an alkoxy group.

[0804] In some implementations, R16 It is aryl In some implementations, R 16 It is a heterocyclic ring.

[0805] In some implementations, R 16 It is a mixed fatty acid.

[0806] In some implementations, R 16 It is a heteroaryl group.

[0807] In some implementations, R 16 It is lactic acid In some implementations, R 16 It is glycolic acid.

[0808] In some implementations, R 16 It is an arylalkyl group.

[0809] In some implementations, R 16 It is a heterocyclic alkyl group.

[0810] In some implementations, R 16 It is a heteroarylalkyl group.

[0811] In some implementations, R 17 It is a key.

[0812] In some implementations, R 17 It is an alkyl group.

[0813] In some implementations, R 17 It is -C(O)-.

[0814] In some implementations, R 17 It is -C(O)O-.

[0815] In some implementations, R 17 It is -OC(O)-.

[0816] In some implementations, R 17 It is -SO2-.

[0817] In some implementations, R 17 It is -S(O)-.

[0818] In some implementations, R 17 It is -C(S)-.

[0819] In some implementations, R 17 It is C(O)NR 27 -

[0820] In some implementations, R 17 Yes -NR27 C(O)-.

[0821] In some implementations, R 17 Yes -O-.

[0822] In some implementations, R 17 Yes -S-.

[0823] In some implementations, R 17 Yes -NR 27 -

[0824] In some implementations, R 17 It is C(R) 40 R 41 )-.

[0825] In some implementations, R 17 It is P(O)(OR) 26 )O-.

[0826] In some implementations, R 17 It is -P(O)(OR) 26 )-.

[0827] In some implementations, R 17 It is a double ring.

[0828] In some implementations, R 17 It is an olefin.

[0829] In some implementations, R 17 It is an alkyne.

[0830] In some implementations, R 17 It is a haloalkyl group.

[0831] In some implementations, R 17 It is an alkoxy group.

[0832] In some implementations, R 17 It is aryl In some implementations, R 17 It is a heterocyclic ring.

[0833] In some implementations, R 17 It is a mixed fatty acid.

[0834] In some implementations, R 17 It is a heteroaryl group.

[0835] In some implementations, R 17 It is lactic acid In some implementations, R 17 It is glycolic acid.

[0836] In some implementations, R 17 It is an arylalkyl group.

[0837] In some implementations, R 17 It is a heterocyclic alkyl group.

[0838] In some implementations, R 17 It is a heteroarylalkyl group.

[0839] R 20 R 21 and R 22 R 23 and R 24 Non-restrictive implementation scheme: In some implementations, R 20 It is a key.

[0840] In some implementations, R 20 It is an alkyl group.

[0841] In some implementations, R 20 It is -C(O)-.

[0842] In some implementations, R 20 It is -C(O)O-.

[0843] In some implementations, R 20 It is -OC(O)-.

[0844] In some implementations, R 20 It is -SO2-.

[0845] In some implementations, R 20 It is -S(O)-.

[0846] In some implementations, R 20 It is -C(S)-.

[0847] In some implementations, R 20 It is C(O)NR 27 -

[0848] In some implementations, R 20 Yes -NR 27 C(O)-.

[0849] In some implementations, R 20 Yes -O-.

[0850] In some implementations, R 20 Yes -S-.

[0851] In some implementations, R 20 Yes -NR27 -

[0852] In some implementations, R 20 It is C(R) 40 R 41 )-.

[0853] In some implementations, R 20 It is P(O)(OR) 26 )O-.

[0854] In some implementations, R 20 It is -P(O)(OR) 26 )-.

[0855] In some implementations, R 20 It is a double ring.

[0856] In some implementations, R 20 It is an olefin.

[0857] In some implementations, R 20 It is an alkyne.

[0858] In some implementations, R 20 It is a haloalkyl group.

[0859] In some implementations, R 20 It is an alkoxy group.

[0860] In some implementations, R 20 It is aryl In some implementations, R 20 It is a heterocyclic ring.

[0861] In some implementations, R 20 It is a mixed fatty acid.

[0862] In some implementations, R 20 It is a heteroaryl group.

[0863] In some implementations, R 20 It is lactic acid In some implementations, R 20 It is glycolic acid.

[0864] In some implementations, R 20 It is an arylalkyl group.

[0865] In some implementations, R 20 It is a heterocyclic alkyl group.

[0866] In some implementations, R 20 It is a heteroarylalkyl group.

[0867] In some implementations, R 21 It is a key.

[0868] In some implementations, R 21 It is an alkyl group.

[0869] In some implementations, R 21 It is -C(O)-.

[0870] In some implementations, R 21 It is -C(O)O-.

[0871] In some implementations, R 21 It is -OC(O)-.

[0872] In some implementations, R 21 It is -SO2-.

[0873] In some implementations, R 21 It is -S(O)-.

[0874] In some implementations, R 21 It is -C(S)-.

[0875] In some implementations, R 21 It is C(O)NR 27 -

[0876] In some implementations, R 21 Yes -NR 27 C(O)-.

[0877] In some implementations, R 21 Yes -O-.

[0878] In some implementations, R 21 Yes -S-.

[0879] In some implementations, R 21 Yes -NR 27 -

[0880] In some implementations, R 21 It is C(R) 40 R 41 )-.

[0881] In some implementations, R 21 It is P(O)(OR) 26 )O-.

[0882] In some implementations, R 21 It is -P(O)(OR) 26 )-.

[0883] In some implementations, R 21 It is a double ring.

[0884] In some implementations, R 21 It is an olefin.

[0885] In some implementations, R 21 It is an alkyne.

[0886] In some implementations, R 21 It is a haloalkyl group.

[0887] In some implementations, R 21 It is an alkoxy group.

[0888] In some implementations, R 21 It is aryl In some implementations, R 21 It is a heterocyclic ring.

[0889] In some implementations, R 21 It is a mixed fatty acid.

[0890] In some implementations, R 21 It is a heteroaryl group.

[0891] In some implementations, R 21 It is lactic acid In some implementations, R 21 It is glycolic acid.

[0892] In some implementations, R 21 It is an arylalkyl group.

[0893] In some implementations, R 21 It is a heterocyclic alkyl group.

[0894] In some implementations, R 21 It is a heteroarylalkyl group.

[0895] In some implementations, R 22 It is a key.

[0896] In some implementations, R 22 It is an alkyl group.

[0897] In some implementations, R 22 It is -C(O)-.

[0898] In some implementations, R 22 It is -C(O)O-.

[0899] In some implementations, R 22 It is -OC(O)-.

[0900] In some implementations, R 22 It is -SO2-.

[0901] In some implementations, R 22 It is -S(O)-.

[0902] In some implementations, R 22 It is -C(S)-.

[0903] In some implementations, R 22 It is C(O)NR 27 -

[0904] In some implementations, R 22 Yes -NR 27 C(O)-.

[0905] In some implementations, R 22 Yes -O-.

[0906] In some implementations, R 22 Yes -S-.

[0907] In some implementations, R 22 Yes -NR 27 -

[0908] In some implementations, R 22 It is C(R) 40 R 41 )-.

[0909] In some implementations, R 22 It is P(O)(OR) 26 )O-.

[0910] In some implementations, R 22 It is -P(O)(OR) 26 )-.

[0911] In some implementations, R 22 It is a double ring.

[0912] In some implementations, R 22 It is an olefin.

[0913] In some implementations, R 22 It is an alkyne.

[0914] In some implementations, R 22 It is a haloalkyl group.

[0915] In some implementations, R 22 It is an alkoxy group.

[0916] In some implementations, R 22 It is aryl In some implementations, R 22 It is a heterocyclic ring.

[0917] In some implementations, R 22 It is a mixed fatty acid.

[0918] In some implementations, R 22 It is a heteroaryl group.

[0919] In some implementations, R 22 It is lactic acid In some implementations, R 22 It is glycolic acid.

[0920] In some implementations, R 22 It is an arylalkyl group.

[0921] In some implementations, R 22 It is a heterocyclic alkyl group.

[0922] In some implementations, R 22 It is a heteroarylalkyl group.

[0923] In some implementations, R 23 It is a key.

[0924] In some implementations, R 23 It is an alkyl group.

[0925] In some implementations, R 23 It is -C(O)-.

[0926] In some implementations, R 23 It is -C(O)O-.

[0927] In some implementations, R 23 It is -OC(O)-.

[0928] In some implementations, R 23 It is -SO2-.

[0929] In some implementations, R 23 It is -S(O)-.

[0930] In some implementations, R 23 It is -C(S)-.

[0931] In some implementations, R 23 It is C(O)NR 27 -

[0932] In some implementations, R 23Yes -NR 27 C(O)-.

[0933] In some implementations, R 23 Yes -O-.

[0934] In some implementations, R 23 Yes -S-.

[0935] In some implementations, R 23 Yes -NR 27 -

[0936] In some implementations, R 23 It is C(R) 40 R 41 )-.

[0937] In some implementations, R 23 It is P(O)(OR) 26 )O-.

[0938] In some implementations, R 23 It is -P(O)(OR) 26 )-.

[0939] In some implementations, R 23 It is a double ring.

[0940] In some implementations, R 23 It is an olefin.

[0941] In some implementations, R 23 It is an alkyne.

[0942] In some implementations, R 23 It is a haloalkyl group.

[0943] In some implementations, R 23 It is an alkoxy group.

[0944] In some implementations, R 23 It is aryl In some implementations, R 23 It is a heterocyclic ring.

[0945] In some implementations, R 23 It is a mixed fatty acid.

[0946] In some implementations, R 23 It is a heteroaryl group.

[0947] In some implementations, R 23 It is lactic acid In some implementations, R 23 It is glycolic acid.

[0948] In some implementations, R 23 It is an arylalkyl group.

[0949] In some implementations, R 23 It is a heterocyclic alkyl group.

[0950] In some implementations, R 23 It is a heteroarylalkyl group.

[0951] In some implementations, R 24 It is a key.

[0952] In some implementations, R 24 It is an alkyl group.

[0953] In some implementations, R 24 It is -C(O)-.

[0954] In some implementations, R 24 It is -C(O)O-.

[0955] In some implementations, R 24 It is -OC(O)-.

[0956] In some implementations, R 24 It is -SO2-.

[0957] In some implementations, R 24 It is -S(O)-.

[0958] In some implementations, R 24 It is -C(S)-.

[0959] In some implementations, R 24 It is C(O)NR 27 -

[0960] In some implementations, R 24 Yes -NR 27 C(O)-.

[0961] In some implementations, R 24 Yes -O-.

[0962] In some implementations, R 24 Yes -S-.

[0963] In some implementations, R 24 Yes -NR 27 -

[0964] In some implementations, R 24 It is C(R) 40 R41 )-.

[0965] In some implementations, R 24 It is P(O)(OR) 26 )O-.

[0966] In some implementations, R 24 It is -P(O)(OR) 26 )-.

[0967] In some implementations, R 24 It is a double ring.

[0968] In some implementations, R 24 It is an olefin.

[0969] In some implementations, R 24 It is an alkyne.

[0970] In some implementations, R 24 It is a haloalkyl group.

[0971] In some implementations, R 24 It is an alkoxy group.

[0972] In some implementations, R 24 It is aryl In some implementations, R 24 It is a heterocyclic ring.

[0973] In some implementations, R 24 It is a mixed fatty acid.

[0974] In some implementations, R 24 It is a heteroaryl group.

[0975] In some implementations, R 24 It is lactic acid In some implementations, R 24 It is glycolic acid.

[0976] In some implementations, R 24 It is an arylalkyl group.

[0977] In some implementations, R 24 It is a heterocyclic alkyl group.

[0978] In some implementations, R 24 It is a heteroarylalkyl group.

[0979] R 26 Non-restrictive implementation scheme: In some implementations, R 26 It is hydrogen.

[0980] In some implementations, R 26 It is an alkyl group.

[0981] In some implementations, R 26 It is an arylalkyl group.

[0982] In some implementations, R 26 It is a heteroarylalkyl group.

[0983] In some implementations, R 26 It is an olefin.

[0984] In some implementations, R 26 It is an alkyne.

[0985] In some implementations, R 26 It is an aryl group.

[0986] In some implementations, R 26 It is a heteroaryl group.

[0987] In some implementations, R 26 It is a heterocyclic ring.

[0988] In some implementations, R 26 It belongs to the fatty group.

[0989] R 27 Non-restrictive implementation scheme: In some implementations, R 27 It is hydrogen.

[0990] In some implementations, R 27 It is an alkyl group.

[0991] In some implementations, R 27 It is an arylalkyl group.

[0992] In some implementations, R 27 It is a heteroarylalkyl group.

[0993] In some implementations, R 27 It is an olefin.

[0994] In some implementations, R 27 It is an alkyne.

[0995] In some implementations, R 27 It is an aryl group.

[0996] In some implementations, R 27 It is a heteroaryl group.

[0997] In some implementations, R 27 It is a heterocyclic ring.

[0998] In some implementations, R 27 They are adipose-dependent individuals.

[0999] In some implementations, R 27 It is a mixed fatty acid.

[1000] In some implementations, R 27 It is -C(O) (aliphatic).

[1001] In some implementations, R 27 It is -C(O)(aryl).

[1002] In some implementations, R 27 It is -C(O) (heteroaliphatic).

[1003] In some implementations, R 27 It is -C(O)(heteroaryl).

[1004] In some implementations, R 27 It is -C(O)O (aliphatic).

[1005] In some implementations, R 27 It is -C(O)O(aryl).

[1006] In some implementations, R 27 It is -C(O)O (heteroaliphatic).

[1007] In some implementations, R 27 It is -C(O)O (heteroaryl).

[1008] R 40 Non-restrictive implementation scheme: In some implementations, R 40 It is hydrogen.

[1009] In some implementations, R 40 It is R 27 .

[1010] In some implementations, R 40 It is an alkyl group.

[1011] In some implementations, R 40 It is an olefin.

[1012] In some implementations, R 40 It is an alkyne.

[1013] In some implementations, R 40 It's fluorine.

[1014] In some implementations, R 40It is bromine.

[1015] In some implementations, R 40 It is chlorine.

[1016] In some implementations, R 40 It is a hydroxyl group.

[1017] In some implementations, R 40 It is an alkoxy group.

[1018] In some implementations, R 40 It is an azide group.

[1019] In some implementations, R 40 It is an amino group.

[1020] In some implementations, R 40 It is a cyano group.

[1021] In some implementations, R 40 It is -N (aliphatic, including alkyl)2.

[1022] In some implementations, R 40 It is -NHSO2 (aliphatic, including alkyl).

[1023] In some implementations, R 40 It is -N (aliphatic, including alkyl)SO2 alkyl.

[1024] In some implementations, R 40 It is -NHSO2 (aryl, heteroaryl, or heterocyclic).

[1025] In some implementations, R 40 It is -N(alkyl)SO2 (aryl, heteroaryl or heterocyclic).

[1026] In some implementations, R 40 It is -NHSO2 alkenyl.

[1027] In some implementations, R 40 It is -N(alkyl)SO2 alkenyl.

[1028] In some implementations, R 40 It is an -NHSO2 acetylinyl group.

[1029] In some implementations, R 40 It is -N(alkyl)SO2 ynyl group.

[1030] In some implementations, R 40 It is a haloalkyl group.

[1031] In some implementations, R40 They are adipose-dependent individuals.

[1032] In some implementations, R 40 It is a mixed fatty acid.

[1033] In some implementations, R 40 It is an aryl group.

[1034] In some implementations, R 40 It is a heteroaryl group.

[1035] In some implementations, R 40 It is a heterocyclic ring.

[1036] In some implementations, R 40 It is oxygenation.

[1037] In some implementations, R 40 It is a cycloalkyl group.

[1038] Non-limiting examples of compounds of formula I, II or III In some embodiments, the compounds of the present invention are selected from: .

[1039] In some embodiments, the compounds of the present invention are selected from: and .

[1040] In the structure described herein, hydroxyl groups (e.g., R) 1 Or R 2 The group () is located on a heteroaryl ring carbon adjacent to nitrogen. Unless otherwise stated herein, only one tautomer is shown as a shorthand for individually referring to each individual tautomer or mixture thereof, and each individual tautomer or mixture thereof is incorporated in the specification as if it were individually referenced herein. This is demonstrated by the following non-limiting examples: It includes and .

[1041] In some embodiments, the compounds of the present invention are selected from: and .

[1042] In some embodiments, the compounds of the present invention are selected from: and .

[1043] In some embodiments, the compounds of the present invention are selected from: and .

[1044] In some embodiments, the compounds of the present invention are selected from: and .

[1045] In some embodiments, the compounds of the present invention are selected from: . and .

[1046] In some embodiments, the compounds of the present invention are selected from: and .

[1047] In some embodiments, the compounds of the present invention are selected from: and .

[1048] In some embodiments, the compounds of the present invention are selected from: and .

[1049] In some embodiments, the compounds of the present invention are selected from: and .

[1050] In some embodiments, the compounds of the present invention are selected from: and .

[1051] In some embodiments, the compounds of the present invention are selected from: and .

[1052] In some embodiments, the compounds of the present invention are selected from: and .

[1053] In some embodiments, the compounds of the present invention are selected from: and .

[1054] In some embodiments, the compounds of the present invention are selected from: and In some embodiments, the compounds of the present invention are selected from: and .

[1055] In some implementations, the tricyclic hydroxycerebroside ligand is: .

[1056] In some implementations, the spacer is the bond.

[1057] Implementation schemes for ring-A, ring-B, ring-C, and ring-D In some implementations, and Selected from Below, dashed lines indicate potential connection lines to spacers / connectors: and .

[1058] In some implementations, and Selected from: and .

[1059] In some implementations, and Selected from: and .

[1060] In some implementations, and Selected from: . , In some implementations, and Selected from: , , , , , , , and .

[1061] In some implementations, and Selected from: and .

[1062] In some implementations, and Selected from: and .

[1063] In some implementations, and Selected from: and .

[1064] In some implementations, and Selected from: and .

[1065] In some implementations, and Selected from: . and .

[1066] In some implementations, and Selected from: and .

[1067] In some implementations, and Selected from: and .

[1068] In some implementations, and Selected from: and .

[1069] In some implementations, and Selected from: and .

[1070] In some implementations, and Selected from: and .

[1071] In some implementations, and Selected from: and .

[1072] In some implementations, and Selected from: and .

[1073] In some implementations, and Selected from: and .

[1074] In some implementations, and Selected from: and .

[1075] In some implementations, and Selected from: and .

[1076] In some implementations, Selected from: and .

[1077] In some implementations, Selected from: and .

[1078] In some implementations, Selected from: and .

[1079] In some implementations, Selected from: and .

[1080] In some implementations, Selected from: and .

[1081] In some implementations, Selected from: and .

[1082] In some implementations, Se...

Claims

1. A compound having the following formula: Or its pharmaceutically acceptable salt; in: The tricyclic hydroxycerebroside ligand is selected from one of the following portions, wherein the bond in parentheses indicates that the tricyclic portion is covalently connected to the spacer / connector via a ring-A, ring-B, ring-C, or ring-D. ； n is 0, 1, or 2; X is NR 10 NR 6’ , O or S; X' is NR 10 O, CH2 or S; Q is CR 7 Or N; Q' and Q'' are independently selected from CR 1 and N; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring-A is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring -B is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 2 Substituents of the substituents; The ring -C is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein each ring -C is optionally composed of 1, 2, or 3 independently selected from R, as permitted by the valence. 1 Substituents of the substituents; Ring-D is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 6-membered heterocyclic, 5- to 6-membered cycloalkyl, or 5- to 6-membered cycloalkenyl, wherein each ring-D is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 2 Substituents of the substituents; R 1 and R 2 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or alternatively, if valence and stability permit, R 1 Or R 2 It can be a divalent part, such as =O, =S, or =NR. 41 ; and R 1 The group can optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings, which can bridge ring-A and ring-B or ring-C and ring-D, depending on the situation and need; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 They can combine to form 1 or 2 carbon bonds; Or R 3 and R 4 They can be combined to form 1, 2, 3, or 4 carbon connections; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; R 4 and R 5 Independently selected from hydrogen, alkyl, halogen, and haloalkyl; R 6 and R 7 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 and -NR 10 R 11 , R 6 It is hydrogen, alkyl, or haloalkyl; Or R 3 and R 6 'Combined to form 1 or 2 carbon bonds; R 10 and R 11 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each instance is independently selected from hydrogen, alkyl, and haloalkyl; Spacers are bivalent connections with the following structure: X 3 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 The divalent moiety of -, -C(S)-, -S(O)-, -S(O)2-, and -S-; or it can be an arylalkyl, heterocyclic alkyl, or heteroarylalkyl group, wherein each of the heterocycle, aryl, heteroaryl, and bicyclic groups can be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 15 R 16 R 17 and R 18 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、-NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; Where X 3 and R 15-18 Together, the tricyclic hydroxycerebroside ligand is covalently attached to the stable portion of the connector; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R 27 Each time it appears, it is independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic or heteroaryl), olefin and alkyne; R 40 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic)2, -NHSO2 (aliphatic), -N (aliphatic)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo and cycloalkyl; R 41 It is aliphatic, aryl, heteroaryl, or hydrogen; The targeting ligand is the part that binds to the target protein and is covalently linked to the tricyclic hydroxycerebroside ligand via the linker-spacer; Target proteins are selected proteins that cause or contribute to disease; and The connector is a divalent linker group.

2. A compound having the following formula: Or its pharmaceutically acceptable salt; in The key in parentheses indicates that the three-ring portion is connected to the spacer / connector via a covalent bond on ring A or ring B; n is 0, 1, or 2; Ring-A is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring-A is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 1 Substituents of the substituents; Ring -B is a fused ring selected from phenyl, 5- or 6-membered heteroaryl, 5- to 8-membered heterocyclic, 5- to 8-membered cycloalkyl, or 5- to 8-membered cycloalkenyl, wherein ring -B is optionally composed of 1, 2, or 3 independently selected from R, as permitted by valence. 2 Substituents of the substituents; R 1 and R 2 In each case, it is independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 -SR 10 -S(O)R 12 -SO2R 12 -NR 10 R 11 Cyano, nitro, heteroaryl, aryl, and heterocyclic; or alternatively, if valence and stability permit, R 1 Or R 2 It can be a divalent part, such as =O, =S, or =NR. 41 ; and R 1 The group can optionally be combined with another R 1 Group or R 2 Groups can be combined to form fused rings or bicyclic rings, which can bridge ring-A and ring-B or ring-C and ring-D, depending on the situation and need; R 3 It is hydrogen, alkyl, halogen, or haloalkyl; Or R 3 and R 6 They can combine to form 1 or 2 carbon bonds; Or R 3 and R 4 They can be combined to form 1, 2, 3, or 4 carbon connections; Or R 3 and R 3 Adjacent R 4 Groups combine to form double bonds; R 10 and R 11 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R 12 -S(O)R 12 and -SO2R 12 ; Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocyclic, aryl, heteroaryl, -NR 13 R 14 and OR 13 ; R 13 and R 14 Each instance is independently selected from hydrogen, alkyl, and haloalkyl; Spacers are bivalent connections with the following structure: X 3 It is selected from bonds, heterocycles, aryl groups, heteroaryl groups, bicyclic groups, and -NR groups. 27 -、-CR 40 R 41 -、-O-、-C(O-、-C(NR) 27 The divalent moiety of -, -C(S)-, -S(O)-, -S(O)2-, and -S-; or it can be an arylalkyl, heterocyclic alkyl, or heteroarylalkyl group, wherein each of the heterocycle, aryl, heteroaryl, and bicyclic groups can be 1, 2, 3, or 4 independently selected from R 40 Substituents of the substituents; R 15 R 16 R 17 and R 18 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 27 -、 -NR 27 C(O)-, -O-, -S-, -NR 27 -、-C(R 40 R 41 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, olefin, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, arylalkyl, heterocyclic alkyl, and heteroarylalkyl; wherein each is optionally selected independently by 1, 2, 3, or 4 from R 40 Substituents of the substituents; Where X 3 and R 15-18 Together, the tricyclic hydroxycerebroside ligand is covalently attached to the stable portion of the connector; R 26 Each time it appears, it is independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl, olefin, alkyne, aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic; R 27 Each time it appears, it is independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic or heteroaryl), olefin and alkyne; R 40 Each time it appears, it is independently selected from hydrogen, R 27 Alkyl, olefin, alkyne, fluorine, bromine, chlorine, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic), -N (aliphatic)2, -NHSO2 (aliphatic), -N (aliphatic)SO2alkyl, -NHSO2 (aryl, heteroaryl, or heterocyclic), -N (alkyl)SO2 (aryl, heteroaryl, or heterocyclic), -NHSO2alkenyl, -N (alkyl)SO2alkenyl, -NHSO2ynyl, -N (alkyl)SO2ynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, oxo and cycloalkyl; R 41 It can be aliphatic, aryl, heteroaryl, or hydrogen; The targeting ligand is the portion that binds to the target protein and is covalently linked to the tricyclic hydroxycerebroside ligand via the linker-spacer, wherein the targeting ligand does not include the following substructures. or Target proteins are selected proteins in the body that cause or contribute to the disease to be treated, wherein the target protein is not a PTP enzyme; and The connector is a divalent linker group.

3. The compound of claim 1 or 2, wherein the target protein is selected from: AATK, ABL, ABL2, ALK, AXL, BLK, BMX, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3 , EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, IGF1R, ILK, INSR, INSRR, ITK, JAK 1. JAK2, JAK3, KDR, KIT, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MET, MLTK, MST1R, MUSK, NPR1, NTRK1, NTRK2, NTRK3, PDGFRA, PDGFRB, PLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1 and ZAP70.

4. The compound of claim 1 or 2, wherein the target protein is a serine or threonine kinase.

5. The compound of claim 1 or 2, wherein the target protein is selected from: Casein kinase 2, protein kinase A, protein kinase B, protein kinase C, Raf kinase, CaM kinase, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, Aurora kinase A, Aurora kinase B, Aurora kinase C, CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1, ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB1, LOK, MAPKAPK2, MAPK APK, MNK1, MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PI M1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-β, TLK2, TSSK1, TSSK2, ULK1 and ULK2.

6. The compound of claim 1 or 2, wherein the target protein is a cyclin-dependent kinase.

7. The compound of claim 1 or 2, wherein the target protein is selected from: CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12 and CDK13.

8. The compound of claim 1 or 2, wherein the target protein is a protein containing the BET bromo domain.

9. The compound of claim 1 or 2, wherein the target protein is selected from: ASH1L, ATAD2, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8, BRD9, BRD10, BRDT, BRPF1, BRPF3, BRWD3, CECR2, CREBBP, EP300, FALZ, GCN 5L2, KIAA1240, LOC93349, MLL, PB1, PCAF, PHIP, PRKCBP1, SMARCA2, SMARCA4, SP100, SP110, SP140, TAF1, TAF1L, TIF1a, TRIM28, TRIM33, TRIM66, WDR9, ZMYND11, and MLL4.

10. The compound of claim 1 or 2, wherein the target protein is a nucleoprotein.

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