Benzofuran derivatives for targeting autophagy

Abstract

Provided herein are compounds of formula (I), (II), and (III), or pharmaceutically acceptable salts, stereoisomers, or deuterated forms thereof, wherein X1, X2, X3, R1, R2, a, b, L0, L1, L2, and A are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), or (III), or pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof, and methods of using a compound of formula (I), (II), or (III), or pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof, e.g., in the treatment of a disease or disorder by modulating autophagic degradation and / or p62 activity.

Description

BENZOFURAN DERIVATIVES FOR TARGETING AUTOPHAGYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 563,122, filed on March 8, 2024, the content of which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] Autophagy is a major degradation pathway for maintaining cellular homeostasis. Autophagy eliminates unnecessary, aged, dysfunctional, or damaged intracellular components through lysosome-mediated degradation. The autophagy process can degrade bulky cellular cargoes (e.g., proteins aggregates, intracellular pathogens) that cannot be degraded by other processes, such as the ubiquitin-proteasome system (UPS).

[0003] During autophagy, cytoplasmic contents are delivered into the lysosomal system by double-membraned organelles called autophagosomes. Specifically, cytoplasmic material is sequestered into autophagosomes, which subsequently fuse with lysosomes where degradation occurs via the action of acidic lysosomal hydrolases. Autophagy helps to keep cells healthy, and dysregulation of this process can contribute to a wide range of diseases, including cancer, inflammation, neurodegeneration, and infectious diseases.

[0004] Sequestosome-1, also known as ubiquitin-binding protein p62 (SQSTM1 or p62, hereinafter “p62”), is a key autophagy receptor for targeted degradation. p62 operates as an autophagy adaptor that brings ubiquitinated substrates (e.g., damaged proteins) into contact with autophagosomes in preparation for autophagy. In addition to autophagic degradation, p62 also plays an important role in the UPS, cellular signaling, metabolism, and apoptosis.

[0005] There is a need to develop therapeutics that target p62 and modulate autophagy.SUMMARY

[0006] In one aspect, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0007] In another aspect, the present disclosure provides a compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle;a is an integer of 0-3; and b is an integer of 0 or 1.

[0008] In a further aspect, the present disclosure provides a compound of formula (III)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1A illustrates general synthetic route A for preparing compounds of the present disclosure.

[0010] FIG. IB illustrates general synthetic route B for preparing compounds of the present disclosure.

[0011] FIG. 1C illustrates general synthetic route C for preparing compounds of the present disclosure.

[0012] FIG. ID illustrates general synthetic route D for preparing compounds of the present disclosure.

[0013] FIG. IE illustrates general synthetic route E for preparing compounds of the present disclosure.

[0014] FIG. IF illustrates general synthetic route F for preparing compounds of the present disclosure.

[0015] FIG. 1G illustrates general synthetic route G for preparing compounds of the present disclosure.

[0016] FIG. 1H illustrates general synthetic route H for preparing compounds of the present disclosure.

[0017] FIG. II illustrates general synthetic route I for preparing compounds of the present disclosure.

[0018] FIG. 1J illustrates general synthetic route J for preparing compounds of the present disclosure.

[0019] FIG. IK illustrates general synthetic route K for preparing compounds of the present disclosure.

[0020] FIG. IL illustrates general synthetic route L for preparing compounds of the present disclosure.

[0021] FIG. IM illustrates general synthetic route M for preparing compounds of the present disclosure.

[0022] FIGS. 2A-C shows representative western blots for p62 oligomerization of compounds 2 (FIG. 2A), 15 (FIG. 2B), and 49 (FIG. 2C).

[0023] FIGS. 3A-C shows representative Western blots for LC3 lipidation of compounds 2 (FIG. 3A), 37 (FIG. 3B), and 43 (FIG. 3C).

[0024] FIGS. 4A-B shows representative Western blots for protein degradation by compound 101 (FIG. 4 A) and compound 100 (FIG. 4B).

[0025] FIG. 5 shows representative Western blots for protein degradation by compound 104.DETAILED DESCRIPTION

[0026] Targeted Protein degradation (TPD) has emerged as a promising modality in drug discovery, typically involving heterobifunctional molecules that combine a target binder with a degradation-inducing moiety (Bekes, Miklos, David R. Langley, and Craig M. Crews. 2022. “PROTAC Targeted Protein Degraders: The Past Is Prologue.” Nature Reviews. Drug Discovery 21 (3): 181-200, incorporated herein by reference in its entirety). This approach is particularly attractive for targeting proteins previously considered undruggable. However, current TPD technologies, such as PROteolysis-TArgeting Chimeras (PROTACs), are primarily limited to inducing ubiquitination of target substrates for degradation. Despite its potential, PROTAC technology faces limitations due to challenges in forming substrate- PROTAC-E3 ligase complexes, restricting its application to a limited set of targets and E3 ligases.

[0027] Autophagy is a vital cellular process that manages the degradation and recycling of cellular components (Lamark, Trond, and Terje Johansen. 2021. “Mechanisms of Selective Autophagy.” Annual Review of Cell and Developmental Biology 37 (October): 143-69; Aman, Yahyah, Tomas Schmauck-Medina, Malene Hansen, Richard I. Morimoto, Anna Katharina Simon, Ivana Bjedov, Konstantinos Palikaras, et al. 2021. “Autophagy in Healthy Aging and Disease.” Nature Aging 1 (8): 634-50; each incorporated herein by reference in their entirety). It plays a crucial role in maintaining cellular homeostasis by removing damaged or dysfunctional organelles and proteins. The process of autophagy involves the formation of autophagosomes, which engulf cellular debris and fuse with lysosomes for degradation. This mechanism is essential for cellular health, and its dysfunction is associated with various diseases, including neurodegenerative disorders, cancers, and metabolic diseases. Autophagy can be broadly classified into macroautophagy, microautophagy, and chaperone-mediated autophagy, with each type serving specific functions in the cell.

[0028] Autophagy plays a dual role in disease pathology. While it can prevent the accumulation of toxic protein aggregates and damaged organelles, its dysregulation can also contribute to disease progression. In neurodegenerative diseases such as Alzheimer's,Parkinson's, and Huntington's disease, impaired autophagy leads to the accumulation of misfolded proteins, exacerbating neurodegeneration. In cancer, autophagy can have both tumor-suppressive and tumor-promoting roles, depending on the context. Enhancing or inhibiting autophagy has been explored as a therapeutic strategy in various diseases. For instance, autophagy inducers are being investigated for their potential to clear protein aggregates in neurodegenerative diseases, while autophagy inhibitors are being explored in certain cancers (Maiuri, Maria Chiara, and Guido Kroemer. 2019. “Therapeutic Modulation of Autophagy: Which Disease Comes First?” Cell Death and Differentiation 26 (4): 680-89, incorporated herein by reference in its entirety).

[0029] p62 is a multifunctional protein that plays a significant role in autophagy, particularly in selective autophagy (Kumar, Anita V., Joslyn Mills, and Louis R. Lapierre. 2022. “Selective Autophagy Receptor P62 / SQSTM1, a Pivotal Player in Stress and Aging.” Frontiers in Cell and Developmental Biology 10 (February): 793328, incorporated herein by reference in its entirety). It acts as a link between LC3 (a protein associated with autophagosomes) and ubiquitinated substrates. p62 binds to ubiquitin-tagged proteins and aggregates, delivering them to autophagosomes for degradation. It is also involved in the formation of protein aggregates known as aggresomes, which are targeted for autophagic degradation. The regulation of p62 and its interaction with other autophagy-related proteins are critical for the efficient execution of selective autophagy.

[0030] p62 is a key autophagy adaptor involved in the autophagic degradation of ubiquitinated substrates. p62 also interacts with ATG8 proteins that are found on the surface of developing autophagosomes. As such, p62 enables selective degradation by directing ubiquitinated substrates to the growing autophagosomes. Oligomerization of individual p62 units (i.e., p62 oligomer) has been shown to provide a stronger interaction with autophagosome. In addition to autophagic degradation, p62 influences other cellular pathways and is associated with pathological conditions including neurodegenerative diseases and cancer.

[0031] The N-degron pathway recognizes specific N-terminal amino acids (N-degrons) of proteins for degradation (Varshavsky, Alexander. 2019. “N-Degron and C-Degron Pathways of Protein Degradation.” Proceedings of the National Academy of Sciences of the United States of America 116 (2): 358-66, incorporated herein by reference in its entirety). The Arginylation branch of this pathway utilizes Arg, Lys, His (type 1), and Phe, Tyr, Trp, Leu, He (type 2) as N-degrons. Recent discoveries have shown that the Arg / N-degron pathway mediates not only ubiquitylation-dependent proteasomal clearance but also macroautophagic protein degradation. In this process, p62 / SQSTMl acts as an N-recognin, binding type-1 and type-2 N-degrons viaits ZZ domain, activating p62 into an autophagy-compatible form for efficient autophagosome biogenesis (Kwon, Do Hoon, Ok Hyun Park, Leehyeon Kim, Yang Ouk Jung, Yeonkyoung Park, Hyeongseop Jeong, Jaekyung Hyun, Yoon Ki Kim, and Hyun Kyu Song. 2018. “Insights into Degradation Mechanism of N-End Rule Substrates by P62 / SQSTM1 Autophagy Adapter.” Nature Communications 9 (1): 3291; Cha-Molstad, Hyunjoo, Ji Eun Yu, Zhiwei Feng, Su Hyun Lee, Jung Gi Kim, Peng Yang, Bitnara Han, et al. 2017. “P62 / SQSTM1 / Sequestosome-1 Is an N-Recognin of the N-End Rule Pathway Which Modulates Autophagosome Biogenesis.” Nature Communications 8 (1): 1-17; each incorporated herein by reference in their entirety).

[0032] p62 (SQSTM1) and NBR1 are key autophagy receptors that mediate the selective degradation of ubiquitinated proteins by bridging cargo to the autophagic machinery. Both proteins share several conserved domains critical to their function, including the ZZ-type zinc finger domain (ZZ domain), a PB 1 domain for oligomerization, a UBA domain for binding polyubiquitinated substrates, and an LC3 -interacting region (LIR) essential for autophagosome recruitment.

[0033] A defining feature of p62 and NBR1 is their ability to bind LC3, a core autophagy component embedded in the autophagosome membrane. This interaction, driven by their LIR motifs, is crucial for targeting cargo to autophagosomes for subsequent lysosomal degradation. Oligomerization through the PB1 domain promotes the clustering of cargo, enhancing both LC3 binding and autophagosome formation. The ZZ domain further stabilizes this process by indirectly facilitating interactions with ubiquitinated substrates and upstream signalling proteins involved in autophagy initiation.

[0034] Given the high degree of conservation between p62 and NBR1, the designed warheads could potentially interact with both receptors, offering a broad mechanism for modulating selective autophagy.

[0035] This disclosure presents compositions and methods for the manipulation of the intrinsic autophagic pathway for the selective degradation of pathogenic proteins. The disclosure comprises novel heterobifunctional compounds designed to engage the autophagy adaptor protein p62 / SQSTMl, thereby triggering its activation and subsequent assembly of autophagosomes. These chimeric molecules are composed of a targeting ligand (also referred to as a “protein binding component” or “PBC”), which exhibits high-affinity binding to designated pathogenic proteins, conjoined via a designed, flexible linker to a p62 activating moiety (also referred to as a “warhead”). This bifunctional architecture enables the precise orchestration of p62 oligomerization and spatial localization, thereby enhancing the sequestration of the targeted proteins within nascent autophagosomes. The utility of thisinventive approach lies in its capacity to harness the cell's autophagic machinery, thereby offering a therapeutic modality with broad-spectrum applicability in the attenuation of diseases characterized by aberrant protein accumulation or defective protein clearance.

[0036] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.Definitions

[0037] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0038] Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0039] The term “about” when immediately preceding a numerical value means a range encompassing said numerical value plus or minus an acceptable amount of variation in the art (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, . . .”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0040] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs-6 alkyl.

[0041] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0042] “Cyano” refers to the -CN radical.

[0043] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0044] “ Oxo” refers to the =0 substituent.

[0045] “Halo,” “halogen” or “halide” refers to fluoro (-F), chloro (-C1), bromo (-Br), and iodo (-1).

[0046] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 50 are included. An alkyl comprising up to 50 carbon atoms is a C1-C50 alkyl, an alkyl comprising up to 24 carbon atoms is a C1-C24 alkyl, an alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, zz-propyl, z-propyl, ec-propyl, zz-butyl, z-butyl, sec-butyl, / -butyl, zz-pentyl, t- amyl, zz-hexyl, zz-heptyl, zz-octyl, zz-nonyl, zz-decyl, zz-undecyl, and zz-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0047] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from 1 to 50 carbon atoms. Non-limiting examples of C2-C50 alkylene include ethylene, propylene, n-butylene, ethenylene, propenylene, zz-butenylene, propynylene, zz-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted. Non-limiting examples of substituted alkylene include -CH(CH3)-, -CH2-CH(CH3)-, and the like.

[0048] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 25 are included. An alkenyl group comprising up to 25 carbon atoms is a C2-C25 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl, and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includesCs alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2 -m ethyl- 1 -propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 1 -pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 4- hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0049] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from 2 to 25 carbon atoms, and having one or more carboncarbon double bonds. Non-limiting examples of C2-C25 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0050] “ Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from 2 to 25 carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 25 are included. An alkynyl group comprising up to 25 carbon atoms is a C2-C25 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes Cs alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs,C9 and Cio alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C25 alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0051] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from 2 to 25 carbon atoms, and having one or more carboncarbon triple bonds. Non-limiting examples of C2-C25 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0052] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0053] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy groups. As used herein, the term “hydroxyalkyl” encompasses alkyls having a primary (terminal) hydroxy group, such as -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH(CH3)CH2OH, and -CH2CH2CH2CH2OH, those having branched (non-terminal) hydroxy groups, such as -CH(OH)CH3, -CH2CH(CH3)OH, and those having both primary and branched hydroxy groups, such as -CH2CH(OH)CH2CH2OH.

[0054] “Alkylamino” refers to a radical of the formula -NHRaor -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0055] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0056] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rcis one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an arylalkyl group can be optionally substituted.

[0057] “Carbocycle,” “carbocyclyl,” or “carbocyclic ring” or refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0058] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0059] “Cycloalkylene” refers to a divalent, non-aromatic, and fully saturated monocyclic or polycyclic hydrocarbon ring having 3 to 20 carbon atoms, or 3 to 8 carbon atoms. Non-limiting examples of C3-8 cycloalkylene include

[0060] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0061] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiro ring systems, having from three totwenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0062] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[0063] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. The haloalkyl group of the present disclosure can be e.g., a Ci-io haloalkyl group, a Ci-6 haloalkyl group, or a C1-3 haloalkyl group. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0064] “Heterocyclyl” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, saturated or partially unsaturated ring radical which consists of two to twelve carbon ring atoms and from one to six heteroatoms as ring atoms selected from nitrogen, oxygen or sulfur, at least one non-aromatic, saturated or partially unsaturated ring containing at least one heteroatom as a ring atom. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In embodiments where “L” is heterocyclyl, the heterocyclyl radical is a diradical. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0065] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising one to thirteen carbon ring atoms, one to six heteroatoms as ring atoms selected from nitrogen, oxygenand sulfur, and at least one aromatic ring containing at least one heteroatom as a ring atom. For purposes of this disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0066] “Leaving group” refers to a functional group that can be substituted by another functional group during a chemical reaction. Exemplary leaving groups can be found in e.g., Organic Chemistry, Francis Carey, 2ndedition, pages 328-331, McGraw-Hill Book Company, 1992, incorporated by reference herein. Non-limiting examples of leaving group include halogens (e.g., Cl, Br, I), methanesulfonyl (mesyl, Ms), p-toluenesulfonyl (tosyl, Ts), fluoromethanesulfonyl, difluoromethanesulfonyl, trifluoromethylsulfonyl (tritiate, Tf), ethanesulfonyl, diazonium group,

[0067] “Protecting group” refers to a moiety that, when attached to a chemically reactive group in a molecule, masks or reduces chemical reactivity of the group. Protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene, et al., 3rdedition, John Wiley & Sons, 1999, incorporated by reference herein. Non-limiting examples of an amino protecting group (also referred to as a nitrogen protecting group) include those forming carbamates, such as tert-Butyloxycarbonyl (BOC) group, Carbobenzyl oxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, suchas acetyl, trifluoroacetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, etc., and others such as p-methoxyphenyl. Non-limiting examples of a hydroxy protecting group (also referred to as an oxygen protecting group) include those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-m ethoxy ethoxymethyl (MEM), etc., those forming silyl ethers, such as trymethyl silyl (TMS), triethylsilyl (TES), triisopropyl silyl (TIPS), t-butyldimethylsilyl (TBDMS), etc., those forming acetals or ketals, such as tetrahydropyranyl (THP), and those forming esters such as formate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc..

[0068] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups.

[0069] “ Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SChRg, -OSO2Rg, -SChORg, =NSO2Rg, and -SO2NRgRh. “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further includes any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0070] As used herein, the symbol “ - !- ” or “ —I ’ ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example,XY— I —XY“ I ” or“ «” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference.

[0071] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0072] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0073] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all suchpossible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparati on / isolati on of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0074] The present disclosure is intended to encompass deuterated forms of the compounds described herein, which include isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon include13C and14C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes and methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0075] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0076] A “derivative” refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and derivable from that parent compound. Derivatization (i.e., modification) may involve substitution of one or more moieties within the parent compound (e.g., a change in functional group). For example, when ligand A of the present disclosure is a derivative of a compound, ligand A can have a structure in which part of the structure of the compound is modified by binding to linker L2. Exemplary modifications include replacement of a substituent (e.g., H, halogen, etc.) for subsequent formation of a bond via chemical process such as amidation, amination, acylation, alkylation, esterification, or dehydration.

[0077] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, such as a mammal. The mammal may be, for example, a mouse, a rat, arabbit, a cat, a dog, a pig, a sheep, a horse, a non-human primate (e.g., cynomolgus monkey, chimpanzee), or a human.

[0078] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0079] An “effective amount” means the amount compound or pharmaceutical formulation, that when administered to a patient for treating a state, disorder or condition is sufficient to affect such treatment.

[0080] The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof. A “therapeutically effective amount”, in some embodiments, is a dose or amount of a compound or pharmaceutical formulation that is sufficient to result in prophylaxis after administration to a patient in need thereof.

[0081] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.Compounds

[0082] This disclosure presents compositions and methods for the manipulation of the intrinsic autophagic pathway for the selective degradation of pathogenic proteins. The disclosure comprises novel heterobifunctional compounds designed to engage the autophagy adaptor protein p62 / SQSTMl, thereby triggering its activation and subsequent assembly of autophagosomes. These chimeric molecules are composed of a targeting ligand (also referred to as a “protein binding component” or “PBC”), which exhibits high-affinity binding to designated pathogenic proteins, conjoined via a designed, flexible linker to a p62 activating moiety (also referred to as a “warhead”). This bifunctional architecture enables the precise orchestration of p62 oligomerization and spatial localization, thereby enhancing the sequestration of the targeted proteins within nascent autophagosomes. The utility of this inventive approach lies in its capacity to harness the cell's autophagic machinery, thereby offering a therapeutic modality with broad-spectrum applicability in the attenuation of diseases characterized by aberrant protein accumulation or defective protein clearance.

[0083] In embodiments, the compounds of the present disclosure can be useful for targeted protein degradation, including for inducing targeted autophagy. In embodiments, the compounds of the present disclosure can be also useful for modulating activity of p62.

[0084] In one aspect, the disclosure provides compounds that target p62 and thereby modulating autophagy (e.g., compounds of formula (X-I), (I), (I- A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (X-II), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (D-D-1), (II- D-2), (ILD-3), (ILD-4)). These compounds can be used on their own as therapeutics for modulating autophagy and treating diseases such as neurodegeneration and cancer. Alternatively or additionally, these compounds can be utilized in targeted protein degradation by functioning as adapter protein warheads (hereinafter “warheads”) that engage p62, and thereby bring p62 into proximity with a protein targeted for degradation. To leverage p62 for targeted protein degradation, in aspects, the disclosure provides for bifunctional compounds.WarheadPBC

[0085] As illustrated above, these bifunctional compounds contain: (1) a first component (“warhead”) that targets and recruits an autophagy adaptor such as p62, and (2) a second component (“protein binding component” or “PBC”) that binds to a protein target to be degraded. In some embodiments, ligand A in the formulas described herein is a PBC. In embodiments, bifunctional compounds contain (3) a linker that covalently couples the warhead to the protein binding component. As such, the compounds disclosed herein can be applied for therapeutically degrading any specific targets, including, but not limited to, proteins, protein aggregates, protein complexes, lipids, lipid droplets, or pathogens (e.g., viruses) within the cell. Additional autophagy adaptor proteins include, but are not limited to, LC3, Optineurin, TAX1BP1, NBR1, NDP52, NUFIP1, WDFY3, RETREG1, Nix, and TOLLIP.

[0086] In some embodiments, ligand A and L2, which will be detailed further below, function as the protein binding component (PBC) and linker, respectively, of the bifunctional compounds of formula (X-III), (III), (III- A), (III-B), (III-C), (III-D), (III-A-1), (III-A-2), (III- A-3), (III-A-4), (ni-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (IILC-2), (III-C-3), (IILC- 4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4) described herein.

[0087] In embodiments, the present disclosure provides a compound of formula (X-I):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: ring W is 6,5-fused heteroaryl or 6,5-fused heterocycle ring, wherein each ring W contains 1, 2, or 3 heteroatoms selected from N, O, or S, and at least 1 of the heteroatoms is N or O;L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen, or two R2form an oxo;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxy cycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0-2.

[0088] In embodiments, the present disclosure provides a compound of formula (X-I):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein: ring W is 6,5-fused heteroaryl or 6,5-fused heterocycle ring, wherein each ring W contains 1, 2, or 3 heteroatoms selected from N, O, or S, and at least 1 of the heteroatoms is N or O;L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen, or two R2form an oxo;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0-2.

[0089] In embodiments, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0090] In embodiments, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0091] In embodiments, the present disclosure provides a compound of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0092] In embodiments, the present disclosure provides a compound of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0093] In embodiments, the present disclosure provides a compound of of formula (I-A-l), (I- A-2), (LA-3), or (LA-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0094] In embodiments, the present disclosure provides a compound of of formula (I-A-l), (I- A-2), (LA-3), or (LA-4):(LA-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0095] In embodiments, the present disclosure provides a compound of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(O)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0096] In embodiments, the present disclosure provides a compound of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0097] In embodiments, the present disclosure provides a compound of formula (I-B-l), (I-B- 2), (I-B-3), or (I-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0098] In embodiments, the present disclosure provides a compound of formula (I-B-l), (I-B- 2), (I-B-3), or (I-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0099] In embodiments, the present disclosure provides a compound of formula (I-C) or (I-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(O)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0100] In embodiments, the present disclosure provides a compound of formula (I-C) or (I-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0101] In embodiments, the present disclosure provides a compound of formula (I-C-l), (I-C- 2), (I-C-3), (I-C-4), (I-D-l), (I-D-2), (I-D-3), or (I-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRA- C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -C1-6 alkylene- O-C1-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0102] In embodiments, the present disclosure provides a compound of formula (I-C-l), (I-C- 2), (I-C-3), (I-C-4), (I-D-l), (I-D-2), (I-D-3), or (I-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof,wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(O)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.L°

[0103] In embodiments of the compound of formula (X-I), (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-NRARB, -C1-6 alkylene-NRA-Ci-6 alkylene-RB, - C1-6 alkylene-NRA-C3-8 cycloalkylene-RB, -C1-6 alkylene-NRAC(O)NRARB, -C1-6 alkylene- NRAC(O)-RB, -C1-6 alkylene-O-Ci-6 alkylene-NRARB, -C1-6 alkylene-O-Ci-6 alkylene- C(O)NRARB, -C1-6 alkylene-O-Ci-6 alkylene-NRAC(O)-RB, -C1-6 alkylene-heterocyclylene-O- C1-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(O)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted. In embodiments of the compound of formula (X-I), (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene-NRAC(O)NRARB, -Ci-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, - C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene-NRARB, -NRAC(O)RB, - NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted. In embodiments, the alkylene is optionally substituted with -OH, halogen, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C1-6 alkoxy, -NH2, NH(Ci-Ce alkyl), N(Ci-Ce alkyl)2, S(Ci-C6alkyl), -SO(Ci-6 alkyl), -SO2(Ci-6 alkyl), -SO2N(CI-6alkyl), -SO2NH2, - SO2NH(Ci-Ce alkyl), -SO2N(Ci-Ce alkyl)2, carbocycle, heterocycle, aryl, or heteroaryl. In embodiments, the alkylene is optionally substituted with -OH or halogen. In embodiments, each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In embodiments, each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In embodiments, each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene- SH.

[0104] In embodiments of the compound of formula (X-I), (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -(C1-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -(C1-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -(C1-6 alkylene)-N(H)(Ci-6 alkoxy), -(C1-6 alkylene)-N(H)(Ci-6 alkylene)(Ci-6 alkoxy), -C(O)N(H)(CI-6 hydroxyalkyl), -(C1-6 alkylene)-N(H)(C3-8 cycloalkylene)(Ci-6 alkoxy), -(C1-6 alkylene)-N(Ci-6 alkyl)(Ci-6 alkoxy), -(C1-6 alkylene)- N(H)C(O)(CI-6 alkoxy), -(C1-6 alkylene)-N(Ci-6 alkyl)C(O)(Ci-6 alkoxy), -(C1-6 alkylene)- N(H)C(O)N(H)(CI-6alkoxy), -(C1-6 alkylene)-N(Ci-6alkyl)C(O)N(Ci-6 alkyl)(Ci-6 alkoxy), - (C3-8 cycloalkylene)N(H)(Ci-6 hydroxyalkyl), -(C3-8 cycloalkylene)N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)(CI-6 hydroxyalkyl), -N(H)C(O)N(H)(CI-6 hydroxyalkyl), - N(H)C(O)N(H)(CI-6 alkylene)-(Ci-6 alkoxy), -(C1-6 alkylene)-O-(Ci-6 alkylene)C(O)N(H)(Ci-6 alkyl), -(C1-6 alkylene)-O-(Ci-6alkylene)N(H)C(O)(Ci-6 alkyl), -O-(Ci-6 alkylene)C(O)N(H)(Ci-6alkyl), -N(CI-6 alkyl)(Ci-6 hydroxyalkyl), -N H)C(O)(CI-6 hydroxyalkyl), -N(CI-6 alkyl)C(O)(Ci-6 hydroxyalkyl), -(C1-6 alkylene)-heterocyclylene-(Ci-6 alkoxy), -(C1-6 alkylene)-O-(Ci-6 alkylene)-N(H)(Ci-6 alkyl), or -(C1-6 alkylene)-O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 alkyl), wherein the alkylene or alkyl is optionally substituted. In embodiments, the alkylene or alkyl is optionally substituted with -OH, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C1-6 alkoxy, -NH2, NRARB, -S(Ci-Ce alkyl), -S0(Ci-6 alkyl), -SO2(Ci-6 alkyl), -SO2N(CI-6 alkyl), -S02NRARB, carbocycle, heterocycle, aryl, or heteroaryl. In embodiments of the compound of formula (X-I), (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (I- C-3), (LC-4), (LD-1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)- N(CI-6 alkyl)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(0)N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)- N(CI-6 alkyl)C(O)N(Ci-6 alkyl)(Ci-6 alkoxy), -(C3-8 cycloalkylene)N(H)(Ci-6 hydroxyalkyl), - (C3-8 cycloalkylene)N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)(CI-6 hydroxyalkyl), -N(CI-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)C(0)(CI-6 hydroxyalkyl), or -N(CI-6 alkyl)C(O)(Ci-6 hydroxyalkyl), wherein the alkylene or alkyl is optionally substituted. In embodiments, the alkylene or alkyl is optionally substituted with -OH, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C1-6 alkoxy, -NH2, NRARB, -S(Ci-Ce alkyl), -SO(Ci-6 alkyl), - SO2(Ci-6 alkyl), -SO2N(CI-6 alkyl), -S02NRARB, carbocycle, heterocycle, aryl, or heteroaryl. In some embodiments, the alkylene or alkyl is optionally substituted with -OH or halogen.

[0105] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-NRARB. In some embodiments, L° is -C1-3 alkylene-NRARB. In some embodiments, each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene- NH2, or C1-6 alkylene-SH. In some embodiments, each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H, and RBis C1-6 hydroxyalkyl or C3-6 hydroxy cycloalkyl. In some embodiments, RBis -CH2CH2OH, -CH2CH(CH3)OH,3In some embodiments, L° is -, , , -CH2NHCH2CH(CH3)OH, orIn some embodiments, L° is -CH2NHCH2CH2OH.

[0106] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is C1-6 alkylene-NRA-Ci-6 alkylene-RB. In some embodiments, each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 alkoxy and L° is -(C1-6 alkylene)-NRA-(Ci-6 alkylene)-(Ci-6 alkoxy). In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RAis H. In some embodiments, L° is -(C1-3 alkylene)-NH-(Ci-3 alkylene)-(Ci-4 alkoxy). In some embodiments, L° is -CH2NHCH2CH2OCH(CH3)2 or -CH2NHCH2CH2OCH3.

[0107] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -(C1-6 alkylene)-NRA-(Ci-6 alkylene)-(Ci-6 alkoxy). In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RAis H. In some embodiments, L° is -(C1-3 alkylene)- NH-(CI-3 alkylene)-(C2-4 alkoxy). In some embodiments, L° is -CH2NHCH2CH2OCH(CH3)2.

[0108] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -(C1-6 alkylene)-O-(Ci-6 alkylene)-NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L° is -(C1-3 alkylene)-O-(Ci-3 alkylene)-NHRB. In some embodiments, L° is -(C1-6 alkylene)-O-(Ci-6 alkylene)-N(H)(Ci-6 alkyl). In some embodiments, RAis C1-6 alkyl. In some embodiments, L° is -(C1-6 alkylene)-O-(Ci-6 alkylene)- N(CI-6 alkyl)(Ci-6 alkyl). In some embodiments, RBis C1-3 alkyl. In some embodiments, RBis -CH3 or -CH(CH3)2. In some embodiments, L° is -CH2OCH2CH2NHCH3 or - CH2OCH2CH2NHCH(CH3)2. In some embodiments, RAis C1-3 alkyl. In some embodiments,RBis Ci-3 alkyl. In some embodiments, RAand RBare -CH3. In some embodiments, L° is - CH2OCH2CH2N(CH3)2.

[0109] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -(C1-6 alkylene)-O-(Ci-6 alkylene)-NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NLb, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L° is -(C1-3 alkylene)-O-(Ci-3 alkylene)-NHRB. In some embodiments, RBis -CH3 or -CH(CH3)2. In some embodiments, L° is -CH2OCH2CH2NHCH3 or -CH2OCH2CH2NHCH(CH3)2.

[0110] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C(O)NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene- NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, RBis C1-6 hydroxyalkyl. In some embodiments, L° is -C(O)NHCH2CH2OH.

[0111] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -NRAC(O)RB. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 hydroxyalkyl, and L°is -NRAC(O)CI-6 hydroxyalkyl. In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (I- B-l), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), or (I- D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is - NRAC(O)CI-6 hydroxyalkyl. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxy cycloalkyl, aryl, or heterocycle. In some embodiments, RAis H. In some embodiments, L° is -NHC(O)CI-3 hydroxyalkyl. In some embodiments, L° is - NHC(O)CH2CH2OH or -NHC(O)CH2OH.

[0112] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -Ci-6 alkylene-NRAC(O)NRARB. In some embodiments, each RAis independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, at least one RAis H. In some embodiments, L° is -C1-3 alkylene-NHC(O)NHRB. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 hydroxyalkyl. In some embodiments, L° is -CH2NHC(O)NHCH2CH2OH.

[0113] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-NRAC(O)NRARB. In some embodiments, L° is - C1-3 alkylene-NHC(O)NHRB. In some embodiments, L° is -CH2NHC(O)NHCH2CH2OH.

[0114] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C3-8 cycloalkylene-NRARB. In some embodiments, RAis H, Ci- 6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L° is -C3-5 cycloalkylene-NHRB. In some embodiments, RBis -CH2CH2OH. In some embodiments,

[0115] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -NRAC(O)NRARB. In some embodiments, each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxy cycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, eachRAis H. In some embodiments, L° is -NHC(O)NHRB. In some embodiments, RBis - CH2CH2OH. In some embodiments, L° is -NHC(O)NHCH2CH2OH.

[0116] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -O-C1-6 hydroxyalkylene-NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L° is -O-(C2-5 hydroxyalkylene)-NHRB. In some embodiments, RBis C1-3 alkyl. In some embodiments, RBis -CH(CH3)2. In some embodiments, L° is OCH2CH(OH)CH2NHCH(CH3)2.

[0117] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -O-C1-6 hydroxyalkylene-NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene- SH. In some embodiments, RAis H. In some embodiments, L° is -O-(C2-5 hydroxyalkylene)- NHRB. In some embodiments, RBis -CH(CH3)2. In some embodiments, L° is - OCH2CH(OH)CH2NHCH(CH3)2.

[0118] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -O-C1-6 alkylene-C(O)NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L° is -O-Ci-3 alkylene-C(O)NHRB. In some embodiments, L° is -O-(Ci-6 alkylene)C(O)N(H)(Ci-6 alkyl). In some embodiments, RBis C1-3 alkyl. In some embodiments, RBis -CH3. In some embodiments, L° is -OCH2CH2C(O)NHCH3.

[0119] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, ordeuterated form thereof, L° is -O-Ci-6 alkylene-C(O)NRARB. In some embodiments, RAis H, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NBfc, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, L°is -O-C1-3 alkylene-C(O)NHRB. In some embodiments, RBis -CH3. In some embodiments, L° is -OCH2CH2C(O)NHCH3.

[0120] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-O-Ci-6 alkylene-C(O)NRARB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, RBis C1-6 alkyl. In some embodiments, L° is - (C1-6 alkylene)-O-(Ci-6 alkylene)C(O)N(H)(Ci-6 alkyl). In some embodiments, L° is -C1-3 alkylene-O-Ci-3 alkylene-C(O)NHRB. In some embodiments, RBis C1-3 alkyl. In some embodiments, RBis -CH3. In some embodiments, L° is -CH2OCH2CH2C(O)NHCH3.

[0121] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-O-Ci-6 alkylene-NRAC(O)-RB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, RBis C1-6 alkyl. In some embodiments, L° is - (C1-6 alkylene)-O-(Ci-6 alkylene)N(H)C(O)(Ci-6 alkyl). In some embodiments, L° is -C1-3 alkylene-O-Ci-3 alkylene-NHC(O)-RB. In some embodiments, RBis C1-3 alkyl. In some embodiments, RBis -CH3. In some embodiments, L° is -CH2OCH2CH2NHC(O)CH3.

[0122] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-NRAC(O)-(Ci-6 hydroxy alkyl). In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RAis H. In some embodiments, L° is -(C1-3 alkylene)-NHC(O)-(CI-3 hydroxy alkyl). In some embodiments, L° is -CH2NHC(O)CH2OH, or -CH2NHC(O)CH2CH2OH.

[0123] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L°is -NRAC(O)NRA-CI-6 alkylene-Ci-6 alkoxy. In some embodiments, each RAis independently H, Ci-6 alkyl, Ci-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, each RAis H. In some embodiments, L° is - NHC(O)NH-(CI-3 alkylene)-(Ci-3 alkoxy). In some embodiments, L° isNHC(O)NHCH2CH2OCH3.

[0124] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-heterocyclylene-O-Ci-6 alkyl. In some embodiments, L° is -C1-3 alkylene-heterocyclylene-O-Ci-3 alkyl. In some embodiments, the heterocyclylene is 3-8 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, or S. In some embodiments, the heterocyclylene is 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, or O. In embodiments, the heterocyclene is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl. In some embodiments, the heterocyclyene is optionally substituted. In some embodiments, the heterocyclylene isor,

[0125] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -C1-6 alkylene-NRA-C3-8 cycloalkylene-RB. In some embodiments, RAis H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, RBis C1-6 alkyl, C1-6 hydroxyalkyl, C3-8 hydroxycycloalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH. In some embodiments, RAis H. In some embodiments, RBis C1-6 alkoxy. In some embodiments, L°is - C1-6 alkylene-NH-C3-8 cycloalkylene-RB. In some embodiments, L° is -C1-3 alkylene-NH-C3-8cycloalkylene-RB. In some embodiments, RBis C1-3 alkoxy. In some embodiments, RBis -OCH3. In some embodiments, the C3-8 cycloalkyleneIn some embodiments, the C3-8 cycloalkylene isIn some embodiments,

[0126] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is-CH2NHCH2CH2OH,-CH2NHCH2CH(CH3)OH,-CH(CH3)NHCH2CH2OH,-CH2NHCH2CH2OCH3,-CH2NHCH2CH2OCH(CH3)2,-CH2OCH2CH2NHCH3,-CH2OCH2CH2NHCH(CH3)2,-CH2OCH2CH2N(CH3)2,-C(O)NHCH2CH2OH,-NHC(O)CH2CH2OH,-NHC(O)CH2OH,-CH2NHC(O)NHCH2CH2OH,-NHC(O)NHCH2CH2OH,-OCH2CH(OH)CH2NHCH(CH3)2,-OCH2CH2C(O)NHCH3,-CH2OCH2CH2C(O)NHCH3,-CH2OCH2CH2NHC(O)CH3,-CH2NHC(O)CH2OH,-CH2NHC(O)CH2CH2OH, or-NHC(O)NHCH2CH2OCH3,

[0127] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is-CH2NHCH2CH2OH,-CH2NHCH2CH(CH3)OH,-CH(CH3)NHCH2CH2OH,-CH2NHCH2CH2OCH(CH3)2,-CH2OCH2CH2NHCH3,-CH2OCH2CH2NHCH(CH3)2,-C(O)NHCH2CH2OH,-NHC(O)CH2CH2OH,-NHC(O)CH2OH,-CH2NHC(O)NHCH2CH2OH,-NHC(O)NHCH2CH2OH,-OCH2CH(OH)CH2NHCH(CH3)2,-OCH2CH2C(O)NHCH3,-CH2NHC(O)CH2OH,-CH2NHC(O)CH2CH2OH, or-NHC(O)NHCH2CH2OCH3.

[0128] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -CH2NHCH2CH2OH, -CH2NHCH2CH(CH3)OH, - CH2OCH2CH2NHCH3, -OCH2CH(OH)CH2NHCH(CH3)2, -CH2OCH2CH2NHCH(CH3)2, or

[0129] In embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), or (LD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L° is -CH2NHCH2CH2OH.

[0130] In embodiments, the present disclosure provides a compound of formula (LA- La), (I- A-2-a), or (LA-3 -a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: each R1is independently Ci-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0131] In embodiments, the present disclosure provides a compound of formula (I-B-l-a), (I- B-2-a), or (I-B-3-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: each R1is independently Ci-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0132] In embodiments, the present disclosure provides a compound of formula(I-C-l-a) or (I- D-l-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein: each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0133] In embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A-l), (I- A-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD- 1), (LD-2), (LD-3), (LD-4), (LA- La), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (I- C-l-a), or (I-D-l-a), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, at least one H in L° is replaced by conjugate comprising a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid.

[0134] In embodiments, the present disclosure provides for components in which a linker is covalently attached to the compounds of (X-I), (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (I- D-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (LC-L a). The linker (e.g., L1disclosed herein) may be any moiety that is capable of covalently binding to the warhead and to the protein binding component (PBC). In embodiments, the present disclosure provides a compound of formula (X-II):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:ring W is 6,5-fused heteroaryl or 6,5-fused heterocycle ring, wherein each ring W contains 1, 2, or 3 heteroatoms selected from N, O, or S, and at least 1 of the heteroatoms is N or O;L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen, or two R2form an oxo;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0-2.

[0135] In embodiments, the present disclosure provides a compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; andb is an integer of 0 or 1.

[0136] In embodiments, the present disclosure provides a compound of formula (II-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0137] In embodiments, the present disclosure provides a compound of formula (II-A-1), (II- A-2), (II-A-3), or (II-A-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, andheterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen; each R1is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen; each R2is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0138] In embodiments, the present disclosure provides a compound of formula (II-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8 cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8 cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8 cycloalkyl)C(O)-, - N(H)C(0)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8 cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, andheterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen; each R1is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen; each R2is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0139] In embodiments, the present disclosure provides a compound of formula (II-B-1), (II- B-2), (II-B-3), or (II-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0140] In embodiments, the present disclosure provides a compound of formula (II-C) or (II-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4;each R4is independently halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0141] In embodiments, the present disclosure provides a compound of formula (II-C-1), (II- C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4):- - , or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)- , -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, - S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.L1

[0142] In embodiments of the compound of formula (X-II), (II), (II-A), (II-B), (II-C), (II-D), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)- , -S(O)2-, -S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8 cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8 cycloalkyl)C(O)-, -N(H)C(0)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, - N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8 cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally substituted. In embodiments, the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen. In embodiments, each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl.

[0143] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8 cycloalkyl)-, -O-, -C(O)-, - C(O)O-, -N(H)C(O)-, -N(C1-C6alkyl)C(O)-, -N(C3-C8 cycloalkyl)C(O)-, -C(O)N(H)-, - C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8 cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8 cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted. In some embodiments, each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz.

[0144] In embodiments of the compound of formula (X-II), (II), (ILA), (II-B), (ILC), (II-D), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2),(II-C-3), (ILC-4), (II-D-1), (II-D-2), (II-D-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1comprises -NH(CH2CH2O)m-(CH2)n-, wherein m is an integer of 1-12, and n is an integer of 0-12. In embodiments, m is an integer of 1-12, 1-6, or 1-4. In embodiments, n is an integer of 0-12, 0-8, or 0-3.

[0145] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C= CH, -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene-C=CH, -O-(Ci-6 alkylene)-CH(OH)- (Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH, -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- NH-C(O)O-(CI-6alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-(CH2)n- C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)- NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-C(O)O-(Ci-6alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m- (CH2)n-arylene-C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene-NH- C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-NH- C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-heteroarylene- C(O)O-(Ci-6alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA, -(Ci-6 alkylene)- NH(CH2CH2O)m-(CH2)n-C(O)-HETA, -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl), -O-(Ci-6 alkylene)- CH(OH)-(CI-6alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)- NH(CH2CH20)m-(CH2)n-0-C6-io aryl, -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-XH, -O- CH2CH(OH)-(CI-6alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH, or -(Ci-6 alkylene)- NH(CH2CH2O)m-(CH2)n-(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl), wherein HETAis a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N or O, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, Ci-6 alkyl, - (Ci-6 alkylene)-C=CH, -NH-C(O)O-(CI-6 alkyl), -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -Ci- 6 alkoxy, -(Ci-6 alkylene)-Ci-6 alkoxy, or -arylene-C(O)O-(Ci-6 alkyl); XHis halogen; each m is independently an integer of 1-12; and each n is independently an integer of 0-12. In embodiments, HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-Ce-io aryl, -(Ci-6 alkylene)-C=CH, -NH-C(O)O-(CI-6 alkyl), -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -O-Ci-6 alkyl, or -(Ci-6 alkylene)-O-(Ci-6 alkyl). In embodiments, m is an integer of 1-12, 1-6, or 1-4. In embodiments, n is an integer of 0-12, 0-8, or 0-3.

[0146] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C=CH. In some embodiments, L1is -(C1-3 alkylene)-NH-(CH2CH2O)m-(CH2)n-C=CH. In some embodiments, the alkylene is optionally substituted with 1 or 2 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-8. In some embodiments, L1is -CH2NH-(CH2CH2O)- (CH2)2-C=CH, -CH2NH-(CH2CH2O)-(CH2)5-C=CH, -CH2NH-(CH2CH2O)-(CH2)6-C=CH, - CH2NH-(CH2CH2O)-(CH2)8-C=CH, -CH2NH-(CH2CH2O)2-(CH2)-C=CH, -CH2NH- (CH2CH2O)2-(CH2)2-C=CH, -CH2NH-(CH2CH2O)3-(CH2)-C=CH, or -CH2NH-(CH2CH2O)3- (CH2)2-C=CH.

[0147] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C=CH. In some embodiments, L1is -(C1-3 alkylene)-NH-(CH2CH2O)m-(CH2)n-C=CH. In some embodiments, the alkylene is optionally substituted with 1 or 2 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-3. In some embodiments, L1is -CH2NH-(CH2CH2O)2-(CH2)2-C=CH or -CH2NH-(CH2CH2O)3- (CH2)2-C=CH.

[0148] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- arylene-C=CH. In some embodiments, L1is -(C1-3 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene- C=CH. In some embodiments, the arylene is optionally substituted phenylene. In some embodiments, the alkylene is optionally substituted with 1 or 2 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. Insome embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-3. In some embodiments,

[0149] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -O-(Ci-6 alkylene)-CH(OH)-(Ci-6 alkylene)- NH(CH2CH2O)m-(CH2)n-C=CH. In some embodiments, L1is -O-(Ci-3 alkylene)-CH(OH)-(Ci- 3 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH. In some embodiments, the alkylene is optionally substituted with 1 or 2 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-4. In some embodiments, n is an integer of 1-3. In some embodiments, L1is -O-CH2-CH(OH)-CH2-NH-(CH2CH2O)2-(CH2)2-C=CH.

[0150] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH- C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-8. In some embodiments, L1is -CH2NH-(CH2CH2O)-(CH2)2-NHC(O)OC(CH3)3, -CH2NH- (CH2CH2O)-(CH2)3-NHC(O)OC(CH3)3, -CH2NH-(CH2CH2O)-(CH2)5-NHC(O)OC(CH3)3, - CH2NH-(CH2CH2O)-(CH2)6-NHC(O)OC(CH3)3, -CH2NH-(CH2CH2O)-(CH2)8-NHC(O)OC(CH3)3, -CH2NH-(CH2CH2O)2-(CH2)2-NHC(O)OC(CH3)3, or -CH2NH- (CH2CH2O)3-(CH2)2-NHC(O)OC(CH3)3.

[0151] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(C1-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH- C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally andindependently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, L1is -CH2NH-[CH2CH2O]3-[CH2]2-NHC(O)OC(CH3)3.

[0152] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-NH-C(O)O-(Ci-6 alkyl) or -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene, cycloalkylene, or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, the C3-8 cycloalkylene isome embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-8. In some embodiments, L1is

[0153] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(C1-6 alkylene)-NH(CH2CH2O)m-(CH2)n- arylene-NH-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene, arylene, or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen. In some embodiments, the arylene is phenylene. In embodiments, the phenylene is / 2-phenylene, m-phenylene o-phenylene. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of0-12. In some embodiments, n is an integer of 0-6. In some embodiments, L1is

[0154] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci- 6 alkyl)-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, L1is -CH2NH-(CH2CH2O)3-(CH2)3-NCH?C(O)OC(CH3)3, or -CH2NH-(CH2CH2O)4-(CH2)3-NCH3C(O)OC(CH3)3.

[0155] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA, or -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)-HETA, wherein HETAis a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N or O, and is optionally substituted with -C(O)-(Ci-6alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-C6-io aryl, Ci-6 alkyl, -(Ci-6 alkylene)- C=CH, -NH-C(O)O-(CI-6alkyl), -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -Ci-6 alkoxy, -(Ci-6 alkylene)-Ci-6 alkoxy, or -arylene-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene is optionally substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In some embodiments, HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-O- C6-io aryl, -(Ci-6 alkylene)-C=CH, -NH-C(O)O-(CI-6 alkyl), -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -O-Ci-6 alkyl, or -(Ci-6 alkylene)-O-(Ci-6 alkyl). In some embodiments, HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -C(O)- (Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-Ce-io aryl. In some embodiments, HETAisazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -O-Ci-6 alkyl or -(Ci-6alkylene)-O-(Ci-6 alkyl). In some embodiments,In some embodiments,some embodiments, HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -(Ci-6 alkylene)-C=CH. In some embodiments,HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -NH-C(O)O-(CI-6 alkyl) or -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl). In some embodiments, HETAembodiments, L1isIn some embodiments, HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -arylene-C(O)O- (Ci-6 alkyl). In some embodiments, the arylene is optionally substituted phenylene. In some, p p y optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-Ce-io aryl.

[0156] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA, wherein HETAis a 4-10 membered heterocycle containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl. In some embodiments, the alkylene is optionally substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, HETAis piperidinyl optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-Ce-io aryl.

[0157] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH- (Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independentlysubstituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NHCH3. In some embodiments, L1is -CH2NH-[CH2CH2O]2-[CH2]2-NHCH3, -CH2NH-(CH2CH2O)2-(CH2)3- NHCH3, or -CH2NH-[CH2CH2O]3-[CH2]2-NHCH3.

[0158] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH- (Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NHCH3. In some embodiments, L1is -CH2NH-[CH2CH2O]2-[CH2]2-NHCH3, or -CH2NH-[CH2CH2O]3-[CH2]2- NHCH3.

[0159] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)NH-(CI-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In embodiments, L1is -(C1-3 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-CH3. In some embodiments, L1is -CH2NH-(CH2CH2O)2-(CH2)2-C(O)NH-CH3.

[0160] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)NH-(CH2)n-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In embodiments, L1is -(Ci-6alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-(CH2)n-C(O)OCH2CH3. In embodiments, L1is - CH2NH-(CH2CH2O)-(CH2)-C(O)NH-(CH2)-C(O)OCH2CH3.

[0161] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)O-(Ci-6 alkyl). In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)O-(Ci-4 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)OCH3 or -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)OC(CH3)3. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-8. In some embodiments, L1is - CH2NH-[CH2CH2O]2-[CH2]2-C(O)OCH3, -CH2NH-(CH2CH2O)3-(CH2)2-C(O)OCH3,CH2NH(CH2CH2O)-(CH2)-C(O)OC(CH3)3, -CH2NH(CH2CH2O)-(CH2)2-C(O)OC(CH3)3, - CH2NH(CH2CH2O)-(CH2)3-C(O)OC(CH3)3, -CH2NH(CH2CH2O)-(CH2)4-C(O)OC(CH3)3, - CH2NH(CH2CH2O)-(CH2)5-C(O)OC(CH3)3, -CH2NH(CH2CH2O)-(CH2)8-C(O)OC(CH3)3, or -CH2NH(CH2CH2O)2-(CH2)2-C(O)OC(CH3)3.

[0162] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)O-(Ci-6 alkyl). In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- C(O)O-(Ci-3 alkyl). In some embodiments, the alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)OCH3. In some embodiments, L1is -CH2NH-[CH2CH2O]2-[CH2]2-C(O)OCH3.

[0163] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -O-(Ci-6 alkylene)-CH(OH)-(Ci-6 alkylene)- NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl). In some embodiments, L1is -O-(Ci-3 alkylene)- CH(OH)-(CI-3 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-3 alkyl). In some embodiments,the alkylene is optionally substituted with 1 or 2 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-4. In some embodiments, n is an integer of 1-3. In some embodiments, L1is -O-CH2-CH(OH)-CH2NH-(CH2CH2O)-(CH2)2- C(O)OCH3.

[0164] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-O-C6- 10 aryl. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0- 6. In some embodiments, the alkylene or aryl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some

[0165] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- arylene-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene, arylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen. In some embodiments, the arylene is phenylene. In embodiments, the phenylene is / 2-phenylene, m-phenylene o-phenylene. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0- 12. In some embodiments, n is an integer of 0-6. In some embodiments, L1is

[0166] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3),(II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- heteroarylene-C(O)O-(Ci-6 alkyl). In some embodiments, the alkylene, heteroarylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently-OH, Ci-6 alkyl, or halogen. In some embodiments, the heteroarylene is pyridinylene. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In some embodiments,

[0167] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-XH, wherein XHis halogen. In some embodiments, XHis chloro or bromo. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In some embodiments, L1is -CH2NH-(CH2CH2O)2-(CH2)3-C1.

[0168] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (II-A-2), (II-A-3), (II-A-4), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (II-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -O-CH2CH(OH)-(CI-6 alkylene)- NH(CH2CH2O)m-(CH2)n-C=CH. In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In someembodiments, n is an integer of 0-6. In some embodiments, L1is -O-CH2CH(OH)-CH2- NH(CH2CH2O)2-(CH2)2-C=CH.

[0169] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -O-CH2CH(OH)-(CI-6 alkylene)- NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl). In some embodiments, m is an integer of 1-6. In some embodiments, m is an integer of 1-4. In some embodiments, n is an integer of 0-12. In some embodiments, n is an integer of 0-6. In some embodiments, L1is -O-CH2CH(OH)-CH2- NH(CH2CH2O)-(CH2)2-C(O)OCH3.

[0170] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L1is -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n- (CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl). In some embodiments, each m is independently an integer of 1-12; and each n is independently an integer of 0-12. In some embodiments, each m is an integer of 1-6, 1-4, or 2-3. In some embodiments, each n is an integer of 0-6, 1-5, or 2-3. In some embodiments, L1is -CH2NH(CH2CH2O)-(CH2)-(CH2CH2O)-(CH2)-C(O)OC(CH3)3.

[0171] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L1is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-O-(Ci-6alkylene)-CH(OH)-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl),-O-(Ci-6alkylene)-CH(OH)-(Ci-6alkylene)-NH(CH2CH2O)m-(CH2)11-C(O)O-(Ci-6 alkyl), or-(Ci-6 alkylene)-NH(CH2CH20)m-(CH2)n-0-C6-io aryl; wherein the alkylene, alkyl, or aryl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, Ci-6 alkyl, or halogen;HETAis a 4-10 membered heterocycle containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl; m is an integer of 1-12, 2-11, 3-10, 4-9, 5-9, 6-8, or 7; and n is an integer of 0-6, 1-5, 2-4, or 3.

[0172] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L1is:-CH2NH-(CH2CH2O)-(CH2)2-C=CH,-CH2NH-(CH2CH2O)-(CH2)5-C=CH,-CH2NH-(CH2CH2O)-(CH2)6-C=CH,-CH2NH-(CH2CH2O)-(CH2)8-C=CH,-CH2NH-(CH2CH2O)2-(CH2)-C=CH,-CH2NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-C=CH,-O-CH2-CH(OH)-CH2-NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)3-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)5-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)6-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)8-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)2-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)2-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)2-(CH2)3-NHCH3,-CH2NH-(CH2CH2O)3-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)2-(CH2)2-C(O)NH-CH3,-CH2NH-(CH2CH2O)-(CH2)-C(O)NH-(CH2)-C(O)OCH2CH3,-CH2NH-(CH2CH2O)2-(CH2)2-C(O)OCH3,-CH2NH-(CH2CH2O)3-(CH2)2-C(O)OCH3,-CH2NH(CH2CH2O)-(CH2)-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)2-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)3-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)4-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)5-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)8-C(O)OC(CH3)3,-CH2NH(CH2CH2O)2-(CH2)2-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)-(CH2CH2O)-(CH2)-C(O)OC(CH3)3,-O-CH2-CH(OH)-CH2NH-(CH2CH2O)-(CH2)2-C(O)OCH3,-CH2NH-(CH2CH2O)-(CH2)3-C1, or-O-CH2CH(OH)-CH2-NH(CH2CH2O)-(CH2)2-C(O)OCH3.

[0173] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L1is-CH2NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-C=CH,-O-CH2-CH(OH)-CH2-NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)3-(CH2)3-NCH3C(O)OC(CH3)3, -CH2NH-(CH2CH2O)4-(CH2)3-NCH3C(O)OC(CH3)3,-CH2NH-(CH2CH2O)2-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)3-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)2-(CH2)2-C(O)OCH3,-O-CH2-CH(OH)-CH2NH-(CH2CH2O)-(CH2)2-C(O)OCH3,

[0174] In embodiments of the compound of formula (II), (ILA), (II-B), (ILC), (II-D), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L1comprises a bivalent moiety selected from:

[0175] In embodiments of the compound of formula (II), (II-A), (II-B), (II-C), (II-D), (II-A- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L1comprises a bivalent moiety selected from:

[0176] In embodiments, a ligand (“A”) that binds to a protein, a protein aggregate, a protein complex, or a lipid that is targeted for degradation is covalently attached to the compounds of formula (X-II), (II), (ILA), (II-B), (ILC), (II-D), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), or (ILD-4). In embodiments, the present disclosure provides a compound of formula (X-III):or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:A is a ligand (e.g., a PBC) that binds to a protein, a protein aggregate, a protein complex, or a lipid; ring W is 6,5-fused heteroaryl or 6,5-fused heterocycle ring, wherein each ring W contains 1, 2, or 3 heteroatoms selected from N, O, or S, and at least 1 of the heteroatoms is N or O; each R1is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen; each R2is independently Ci-6 alkyl, Cs-Cs cycloalkyl, or halogen, or two R2form an oxo;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl)Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle a is an integer of 0-3; b is an integer of 0-2; andL2is a linker moiety that covalently binds ligand A to ring W.

[0177] In some embodiments, L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)-arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8 cycloalkyl)-, -O-, -C(O)-, - C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8 cycloalkyl)-, -N(H)C(O)- , -N(CI-C6alkyl)C(O)-, -N(C3-C8 cycloalkyl)C(O)-, -N(H)C(0)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8 cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen.

[0178] In embodiments, the present disclosure provides a compound of formula (III)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0179] In embodiments, the present disclosure provides a compound of formula (III-A): (III- A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0180] In embodiments, the present disclosure provides a compound of formula (III-A-1), (III- A-2), (III-A-3), or (III-A-4):wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0181] In embodiments, the present disclosure provides a compound of formula (III-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8 cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(0)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- Cs cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4;each R4is independently halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0182] In embodiments, the present disclosure provides a compound of formula (III-B-1), (III-or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

[0183] In embodiments, the present disclosure provides a compound of formula (III-C) or (III-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.

[0184] In embodiments, the present disclosure provides a compound of formula (III-A) formula (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3- C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3- C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; and a is an integer of 0-3.L2

[0185] In embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (ni-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)-arylene, wherein 1-25 methylene groupsof L2are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(Ci-C6alkyl)-, -S(O)2N(C3- C8cycloalkyl)-, -N(H)C(0)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - N(H)C(0)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted. In embodiments, the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, Ci-6 alkyl, or halogen.

[0186] In embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (ni-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, 1-25 methylene groups of L2are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, -O- , -C(O)-, -C(O)O-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted. In some embodiments, each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz, wherein each Rzis independently OH, Ci-6 alkyl, or halogen.

[0187] In embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III-C), (III- D), (in-A-1), (III-A-2), (III-A-3), (ni-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)-(Ci-6 alkylene)-O-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETB-, or-(Ci-6 alkylene)-N(H)(CH2CH2O)m-(CH2)n-HETB-(Ci-6 alkylene)-, wherein each alkylene or alkyl is optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, Ci-6 alkyl, or halogen;HETBis a 4-10 membered heterocyclylene containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl; m is an integer of 1-12; and n is an integer of 0-6.

[0188] In some embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III- C), (III-D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (ni-C-1), (III-C-2), (IILC-3), (ni-C-4), (III-D-1), (III-D-2), (IILD-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, L2is:-(CH2)-NH(CH2CH2O)-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)2-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NCH3-,-(CH2)-NH(CH2CH2O)3-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)4-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)3-,-(CH2)-NH(CH2CH2O)4-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-C(O)CH2-O-,-(CH2)-NH(CH2CH2O)3-(CH2)2-,-(CH2)-NH(CH2CH2O)3-(CH2)3-,

[0189] In some embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III- C), (III-D), (III-A-1), (III-A-2), (in-A-3), (in-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4),(ni-C-1), (ni-C-2), (ni-C-3), (III-C-4), (III-D-1), (Ill-D-2), (III-D-3), or (ni-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, L2is:-(CH2)-NH(CH2CH2O)-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)2-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-, or -(CH2)-NH(CH2CH2O)3-(CH2)2-NH-C(O)CH2-O-.

[0190] In some embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III- C), (III-D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (ni-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, L2is:

[0192] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (in-A-1), (III-A-2), (in-A-3), (ni-A-4), (in-B-1), (ni-B-2), (III-B-3), (in-B-4), (III-C-1), (ni-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, other linker moieties can be used as L2to covalently link A with ring W. Non-limiting examples of additional linker moiety as L2include the following:(i) -Ql-(CH2CH2O)ml-(CH2)nl-Pl-, -Ql-(CH2CH2CH2O)mi-(CH2)ni-Pl-, -Ql- (CH2CH2NH)mi-(CH2)ni-Pl-, and -Ql-(CH2CH2CONH)mi-(CH2)ni-Pl-, wherein QI is -NH-, -O-, =N-, or -N(CHs)-, which is a portion modified by binding to the moiety A; Pl is -NH-, -O-, -CH2-, -C(=0)-; mi is an integer of 0 to 4; and m is an integer of 0 to 3;(ii) -(CH2)n2-NH-C(=O)-, -(CH2)n3-NH-C(=O)-(CH2)n4-O-, -CH2-CH2-O-, -CH2-C(=O)-, wherein n2, ns, and are independently an integer of 1 to 7;ʼnllwherein m5 and n5 are each independently an integer of 0-6;(iv) -(CH2)m6-(OCH2CH2 )n6O(CH2)m6-, -O-(CH2)m6-(OCH2CH2)n6O-(CH2)m6O-, -NH-(CH2)m6-(OCH2CH2)n6O-(CH2)m6O-, -O-(CH2)m6-(OCH2CH2)n6O-(CH2)m6NH-, -O-(CH2)m6- NH-(CH2)m6-(OCH2CH2)n6O-(CH2)m6-, -O-(CH2)m6-NCH3-(CH2)m6-(OCH2CH2)n6O-(CH2)m6-, -O-(CH2)m6-NCH2CH3-(CH2)m6-(OCH2CH2)n6O-(CH2)p6-, -(CH2)m6-NH-(CH2)m6-(OCH2CH2)n6O-(CH2)p6-, -(CH2)m6-NCH3-(CH2)m6-(OCH2CH2)n6O-(CH2)p6-, and -(CH2)m6- NCH2CH3-(CH2)m6-(OCH2CH2)n6O-(CH2)p6-, wherein each m6 is independently an integer of 0-5, each n6 is independently an integer of 0- 7, and each p6 is independently an integer of 0-2.Ligand A (Protein Binding Component “PBC”)

[0193] In some embodiments of the compound of formula (X-III), (III), (III-A), (III-B), (III- C), (III-D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4),(ni-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, A is a ligand (e.g., a PBC) that binds to a protein. Once a protein targeted for degradation is identified, any ligand that binds to said target protein may be used in the compounds of (X-III), (III), (III- A), (III-B), (III-C), (III-D), (in-A-1), (III-A-2), (ni-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3),(ni-B-4), (in-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4) described herein. Such ligands may be covalently bound to the linker using a functional group found on the ligand, or the ligand may be modified to include an appropriate functional group to facilitate conjugation to the linker.

[0194] In some embodiments of the compound of (X-III), (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein is a protein that is associated with cancer. In some embodiments, the protein associated with cancer comprises a mutation or a fusion. In some embodiments, the protein associated with cancer is BRD4. In some embodiments, the protein associated with cancer is BRD4, and A isRvuis H, F, CF3, or Ci-6 alkyl.In some embodiments, R1Vis methyl.

[0195] Assays for assessing the binding of BRD4 with compounds having a corresponding ligand (e g., the compound of formula (III), (III- A), (III-B), (III-C), (III-D), (III-A-1), (III-A- 2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D- 1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary BRD4 binding assays include, but are not limited to, surface plasmon resonance (SPR) assay, fluorescence polarization (FP), and thermal shift assay (TSA). See e.g., ACS Chem. Biol. 2019, 14, 3, 361-368; JChem lnfModel. 2023, 63(17), 5408-5432; Structure 2023, 31(8), 912-923; SLAS Discovery 2015, 20(2), ISO- 189; Current Protocols in Pharmacology 2018, 80, 3.16.1-3.16.14, which are incorporated by reference herein in their entirety.

[0196] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein is a protein that is associated with a metabolic disease.

[0197] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein is a protein that is associated with inflammation.

[0198] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein is present in bacteria.

[0199] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceuticallyacceptable salt, a stereoisomer, or a deuterated form thereof, the protein is present in a virus particle.

[0200] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (in-A-1), (III-A-2), (III-A-3), (ni-A-4), (III-B-1), (ni-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, A is a ligand that binds to a protein aggregate. In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (ni-A-1), (III-A-2), (III-A-3), (ni-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III- C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein aggregate is a Tau protein aggregate, an alpha-synuclein protein aggregate, a mutant Huntingtin protein aggregate, a P-sheet aggregate, a mitochondrial protein aggregate, an amyloid protein aggregate, or a TDP-43 protein aggregate. In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (ni-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B- 2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein aggregate is an alpha-synuclein protein aggregate, a mutant Huntingtin protein aggregate, a P-sheet aggregate, an amyloid protein aggregate, or a TDP-43 protein aggregate.

[0201] In some embodiments, the protein aggregate is a Tau protein aggregate, and A iswherein: each R1is independently H or Ci-6 alkyl; and M is CH or N. In some embodiments, each R1is independently H or methyl.

[0202] Assays for assessing the binding of Tau with compounds having a corresponding ligand (e g., the compound of formula (III), (III- A), (III-B), (III-C), (III-D), (III-A-1), (III-A-2), (III- A-3), (III-A-4), (ni-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C- 4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary Tau binding assays include, but are not limited to, radioligand binding assay, surface plasmon resonance (SPR) assay, differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) titration. See e.g., Chembiochem. 2023 May 16;24(10):e202300163; JChemlnfModel. 2023, 63(17), 5408-5432; Alzheimer ’s Res Therapy 2017, 9, 96; Eur J Nucl Med Mol Imaging 2024, 51, 3960-3977; bioRxiv 2024.03.15.585148, which are incorporated by reference herein in their entirety.

[0203] In some embodiments, the protein aggregate is an alpha-synuclein protein aggregate,wherein: R1is H or Ci-6 alkyl; and M is CH or N. In some embodiments, R1is H or methyl.

[0204] Assays for assessing the binding of alpha-synuclein with compounds having a corresponding ligand (e.g., the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (III- A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C- 2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary alpha-synuclein binding assays include, but are not limited to, nuclear magnetic resonance (NMR) spectroscopy, surface plasmon resonance (SPR) assay, and radioligand binding assay. See e.g., Chembiochem. 2023 May 16;24(10):e202300163; J Chem Inf Model. 2023, 63(17), 5408-5432; Commun Biol 2Q &, , , JNeurochem. 2008, 105(4), 1428-37; Eur J Nucl Med Mol Imaging 2024, 51, 3960-3977, which are incorporated by reference herein in their entirety.

[0205] In some embodiments, the protein aggregate is a mutant Huntingtin protein aggregate

[0206] Assays for assessing the binding of mutant Huntingtin protein with compounds having a corresponding ligand (e.g., the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (ni-E), (III-F), (III-G), (III-A-1), (in-A-2), (III-A-3), (III-B-1), (III-C-1), (III-D-1), (III-E-1), (III-F-1), or (III-G-1), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary mutant Huntingtin protein binding assays include, but are not limited to, surface plasmon resonance (SPR) assay, differential scanning fluorimetry (DSF), and radioligand binding assay. See e.g., Chembiochem. 2023 May 16;24(10):e202300163; J Chem Inf Model. 2023, 63(17), 5408-5432; Structure 2023, 31(9), 1121-1131. e6; Sci Rep 2021, 11, 17977, which are incorporated by reference herein in their entirety.

[0207] In some embodiments, the protein aggregate is a P-sheet aggregate, and A is

[0208] Assays for assessing the binding of P-sheet aggregate with compounds having a corresponding ligand (e.g., the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (III- E), (III-F), (III-G), (III-A-1), (III-A-2), (III-A-3), (III-B-1), (III-C-1), (III-D-1), (III-E-1), (III- F-l), or (III-G-1), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary P-sheet aggregate binding assays include, but are not limited to, fluorescence spectroscopy, surface plasmon resonance (SPR) assay, differential scanning fluorimetry (DSF), nanoscale differential scanning fluorimetry (nanoDSF), and thermal shift assay (TSA). See e.g., Chembiochem. 2023 May 16;24(10):e202300163; J Chem Inf Model.2023, 63(17), 5408-5432; Anal Biochem. 2022, 654, 114828; Eur J Nucl Med Mol Imaging2024, 51, 3960-3977, which are incorporated by reference herein in their entirety.

[0209] In some embodiments, the protein is a mitochondrial protein, and A iswherein: R1is H or Ci-6 alkyl, and R11and R111are each independently a halogen or an alkyl. In some embodiments, R1is H or methyl, and R11and R111are each independently F, Cl, or Ci-6 alkyl.

[0210] Assays for assessing the binding of mitochondrial protein with compounds having a corresponding ligand (e.g., the compound of formula (III), (III-A), (III-B), (III-C), (III-D), (III- E), (III-F), (III-G), (III-A-1), (III-A-2), (III-A-3), (III-B-1), (III-C-1), (III-D-1), (III-E-1), (III- F-l), or (III-G-1), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof having the aforementioned A group) are generally known to a person of ordinary skill in the art. Exemplary mitochondrial protein binding assays include, but are not limited to, radioligand binding assay, surface plasmon resonance (SPR) assay, thermal shift assay (TSA), and X-ray crystallography. See e.g., Chembiochem. 2023 May 16;24(10):e202300163; J Chem Inf Model. 2023, 63(17), 5408-5432; Journal of Med. Chem. 2004, 47(7), 1852-1855; Biochemistry 2023, 62, 7, 1262-1273, which are incorporated by reference herein in their entirety.

[0211] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, the protein is an intracellular protein.

[0212] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, A is aryl, arylene-heteroaryl, arylene, heteroarylene, aryl, heteroarylene-aryl, heteroaryl ene-heteroaryl, heteroarylene- heteroarylene-heteroaryl, heterocyclylene-aryl, heterocyclylene-heteroaryl, heteroaryl ene- NC(O)-heteroaryl, heteroarylene-N=N-aryl, or arylene-(arylalkyl)-OC(O)-hetercyclyl- C(O)Ci-ealkylene-aryl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, Ci-6 alkyl, O-Ci-6 alkyl, NH2, NH(CI-6 alkyl), N(CI-6 alkyl)2, -(CH2)I-4C(O)NH2, -(CH2)I-4C(O)NH(CI-6 alkyl), or -(CH2)I-4C(O)N(CI-6 alkyl)2.

[0213] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, A iswherein: each R1is independently H or Ci-6 alkyl;R11and R111are each independently F, Cl, or Ci-6 alkyl;Rivis Ci-6 alkyl;Rvuis H, F, CF3, or C1-6 alkyl; and M is CH or N.

[0214] In some embodiments of the compound of formula ((III), (III-A), (III-B), (III-C), (III- D), (in-A-1), (III-A-2), (in-A-3), (ni-A-4), (in-B-1), (ni-B-2), (III-B-3), (in-B-4), (III-C-1),(ni-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, A isRvis H, F, CF3, or C1-6 alkyl.

[0215] In some embodiments of the compound of formula (III), (III-A), (III-B), (III-C), (III- D), (in-A-1), (III-A-2), (in-A-3), (ni-A-4), (in-B-1), (ni-B-2), (III-B-3), (ni-B-4), (III-C-1), (ni-C-2), (III-C-3), (III-C-4), (III-D-1), (ni-D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, other protein binding components (PBCs) that binds to a specific target protein, protein aggregates, protein complexes, lipids, or lipids can be used as ligand A. Non-limiting examples of the protein binding component include the following:wherein:Xo is O or C=O;Xi and Xii are each independently N or CH;Rviii is OH, O(CO)Rix, O-Ci-6 alkyl, wherein Rix is an alkyl or aryl group;Rix is H, OH, halogen, CN, CF3, SO2- C1-6 alkyl, O-C1-6 alkyl; andRxis H or halogen.

[0216] In some embodiments, the protein binding component is a derivative (e.g., a monovalent derivative that covalently bonded to linker L2) of one of the following compounds:

[0217] As a non-limiting example, a monovalent derivative of compound

[0218] In some embodiments, the protein binding component is an androgen receptor (AR) binding ligand. Non-limiting examples of androgen receptor binding ligand as protein binding component include:

[0219] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R1is independently optionally substituted Ci-6 alkyl, optionally substituted Cs-Cs cycloalkyl, or halogen. In some embodiments, each R1is independently optionally substituted C1-6 alkyl, C2-5 alkyl, or C3-4 alkyl. In some embodiments, each R1is independently optionally substituted C3-C8 cycloalkyl, C4-C7 cycloalkyl, or Cs-Ce cycloalkyl. In some embodiments, each R1is independent halogen.

[0220] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R1is -F, -Cl, -Br, or -I. In some embodiments, each R1is -F or -Cl. In some embodiments, each R1is -F. In some embodiments, each R1is -Cl.

[0221] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R1is C1-6 alkyl. In some embodiments, each R1is C1-3 alkyl. In some embodiments, each R1is methyl. a

[0222] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, a is an integer of 0-3. In some embodiments, a is 0, 1, 2, or 3. In some embodiments, a is 1 or 2. In some embodiments, a is 0 or 1. In some embodiments, a is 0. In some embodiments, a is 1.R2

[0223] In some embodiments of the compound of formula (I), (LA), (LB), (LA-1), (LA-2), (I- A-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB- 2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (III), (IILA), (IILB), (IILA-1), (IILA-2), (IILA-3), (IIL A-4), (IILB-1), (IILB-2), (IILB-3), or (IILB-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R2is independently optionally substituted Ci-6 alkyl, optionally substituted Cs-Cs cycloalkyl, or halogen. In some embodiments, each R2is independently optionally substituted Ci-6 alkyl, C2-5 alkyl, or C3-4 alkyl. In some embodiments, each R2is independently optionally substituted C3-C8 cycloalkyl, C4-C7 cycloalkyl, or Cs-Ce cycloalkyl. In some embodiments, each R2is independently halogen. In some embodiments, each R2is independently C1-6 alkyl, C2-5 alkyl, or C3-4 alkyl. In embodiments, each R2is independently optionally substituted C3-C8 cycloalkyl or halogen. In embodiments, R2is not optionally substituted C1-6 alkyl. In embodiments, R2is not methyl. In embodiments, R2is absent.

[0224] In some embodiments of the compound of formula (I), (LA), (LB), (LA-1), (LA-2), (I- A-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB- 2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (III), (IILA), (IILB), (IILA-1), (IILA-2), (IILA-3), (IIL A-4), (IILB-1), (IILB-2), (IILB-3), or (IILB-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R2is independently C1-3 alkyl (e.g., methyl, ethyl, w-propyl, isopropyl).

[0225] In some embodiments of the compound of formula (I), (I- A), (I-B), (I-A-l), (I-A-2), (I- A-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LA-l-a), (I-A-2-a), (I-A-3-a), (LB-l-a), (I-B- 2-a), (I-B-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (III), (IILA), (IILB), (IILA-1), (IILA-2), (IILA-3), (IIL A-4), (IILB-1), (IILB-2), (IILB-3), or (IILB-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, each R2is methyl. b

[0226] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA-l-a), (LA-2-a), (LA-3-a), (LB-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, b is an integer of 0-2. In some embodiments, b is 0, 1, or 2. In some embodiments, b is 1 or 2. In some embodiments, b is 0 or 1. In some embodiments, b is 0. In some embodiments, b is 1.Q

[0227] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA-l-a), (LA-2-a), (LA-3-a), (LB-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-, wherein the alkylene is optionally and independently substituted. In some embodiments, Q is a absent, Ci-4 alkylene, -(C1-3 alkylene)C(O)-, C3-6 cycloalkylene, -(C3-6 cycloalkylene)C(O)-, -C(O)-, or -S(O)2-, wherein the alkylene is optionally substituted. In some embodiments, Q is a absent. In embodiments, Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, or -S(O)2-,wherein the alkylene is optionally and independently substituted. In embodiments, Q is not - C(O)-.

[0228] In some embodiments, Q is C1-12 alkylene, C1-6 alkylene, C1-5 alkylene, Ci-4 alkylene, C1-3 alkylene, or C1-2 alkylene. In some embodiments, Q is -(C1-6 alkylene)C(O)-, -(C1-3 alkylene)C(O)-, -(C1-2 alkylene)C(O)-, or -CH2-C(O)-. In some embodiments, Q is C3-9 cycloalkylene, C3-6 cycloalkylene, C3-5 cycloalkylene, or C3-4 cycloalkylene. In some embodiments, Q is -(C3-9 cycloalkylene)C(O)-, -(C3-6 cycloalkylene)C(O)-, -(C3-5 cycloalkylene)C(O)-, or -(C3-4 cycloalkylene)C(O)-. In some embodiments, Q is -C(O)-. In some embodiments, Q is -S(O)2-.

[0229] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (D-C-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is a absent.

[0230] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (IILB-1), (ID-B-2), (IILB-3), (IILB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is -CH2-, -CH2CH2-, -CH(CH )-, or -C(CH3)2-. In some embodiments, Q is - CH2-. In some embodiments, Q is -CH2CH2-.

[0231] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4),(DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (III- D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is -C(O)-.

[0232] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is -S(O)2-.

[0233] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof,

[0234] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, Q is -CH2C(O)-.

[0235] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (LC-1 -a), (LD-1 -a), (II), (II- A), (II-B), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof,R3and R4

[0236] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (II-B), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted, Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl, and RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4, wherein each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or -C(O)O-(Ci-6 alkyl). In embodiments, R3is not a tetrazolyl.

[0237] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (II-B), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (DLA-1), (DLA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (DLB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (IIL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is C3-8 carbocycle, 3-10 membered heterocycle, Ce-io aryl, 5-10 membered heteroaryl, or -NRXRY, wherein the C3-8 carbocycle, 3-8 membered heterocycle, Ce-io aryl, and5-10 membered heteroaryl are each optionally substituted, and wherein Rxis H, Ci-6 alkyl, Ci- 6 haloalkyl, or Ci-6 hydroxyalkyl, and RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle. In some embodiments, the C3-8 carbocycle, 3-10 membered heterocycle, Ce-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 R4, and each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or -C(O)O-Ci-6 alkyl.

[0238] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is Ce-io aryl optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, C1-6 alkyl, C1-6 alkoxy, or -C(O)-NRXRY.

[0239] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (LC-1 -a), (LD-1 -a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (IILA-1), (IILA-2), (ID-A-3), (IILA-4), (IILB-1), (ID-B-2), (IILB-3), (IILB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (IILD-1), (IIL D-2), (IILD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is Ce-io aryl optionally substituted with -F, -Cl, C1-3 alkoxy, or -C(O)-NRXRY, wherein Rxis H or C1-6 alkyl, and RYis C1-6 alkyl. In some embodiments, R3i

[0240] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4),(LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (HI-D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is 5-10 membered heteroaryl optionally substituted with 1 or 2 R4; and wherein the heteroaryl contains 1 or 2 heteroatoms selected from N, S, or O. In some embodiments, R3

[0241] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4),(D-B-l), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (ILC-2), (II-C-3), (II-C-4), (II-D-1), (D-D-2), (II- D-3), (D-D-4), (III), (DLA), (III-B), (III-C), (III-D), (III-A-1), (III-A-2), (III-A-3), (III-A-4), (III-B-1), (III-B-2), (III-B-3), (III-B-4), (III-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III- D-2), (III-D-3), or (III-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is C3-8 carbocycle optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, -OH, Ci-6 alkyl, or Ci-6 alkoxy. In some embodiments, R3iseach optionally substituted with one or twoR4. In some embodiments, R4is halogen. In some embodiments, each R4is fluoro. In someembodiments, R3iseach optionally substituted with one R4. In some embodiments, R3is

[0242] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (n-B-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (D-C-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (DI), (DLA), (DLB), (ID-C), (DLD), (IILA-1), (IILA-2), (ID-A-3), (DLA-4), (DLB-1), (ID-B-2), (DLB-3), (IILB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (IILD-1), (DL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is 3-10 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, or S, and the heterocycle is optionally substituted with 1 or 2 R4, and wherein each R4is independently -OH, C1-6 alkyl, or -C(O)O-(Ci-6 alkyl). In some embodiments, each R4isindependently -OH, C1-3 alkyl, or -C(O)O-(Ci-s alkyl). In some embodiments, R3is

[0243] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (II- A), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, R3is -NRXRY, and wherein Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl, andRYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle.In some embodiments, Rxis H, or methyl, and RYis methyl, -CH(CH3)2,

[0244] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (D-C-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated

[0245] In some embodiments of the compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (D-D-4), (III), (IILA), (IILB), (IILC), (DI-D), (IILA-1), (IILA-2), (ID-A-3), (IILA-4), (IILB-1), (ID-B-2), (IILB-3), (IILB-4), (DLC-1), (DLC-2), (DLC-3), (DLC-4), (DLD-1), (DL D-2), (DLD-3), or (ID-D-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof,

[0246] In some embodiments of the compound of formula (I), (I-A), (I-B), (I-C), (I-D), (I-A- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (D-D-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IIL D-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt, stereoisomer, or deuterated

[0247] In embodiments, the compounds disclosed herein (e.g., compounds of formula (I), (I- A), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (I- C-l), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3- a), (I-B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (III- C-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (HI-D-4)), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof) have a molecular weight of up to 1,500 Daltons (Da), up to 1,200 Da, up to 1,000 Da, up to 900 Da, up to 800 Da, up to 700 Da, up to 600 Da, or up to 500 Da. In some embodiments, the compounds disclosed herein have a molecular weight ranging from about 100 Da to about 2,000 Da, from about 200 Da to about 1,800 Da, from about 400 Da to about 1,600 Da, from about 600 Da to about 1,200 Da, from about 700 Da to about 1,000 Da, or from about 800 Da to about 900 Da.

[0248] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0249] In embodiments, provided herein is a compound of formula (I), (I-A), (I-B), (I-C), (I- D), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC- 3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA- La), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2- a), (LB-3 -a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (II- A- 3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (D-D-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (III-B), (III-C), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (III-C-1), (IILC-2), (III-C-3), (IILC-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0250] In embodiments, provided herein is a stereoisomer of a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I- B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (II- A-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (III-B), (III-C), (III-D), (IILA-1), (IILA- 2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4). In embodiments, provided herein is a pharmaceutically acceptable salt of a compound of formula (I), (LA), (LB), (LC), (LD), (LA- 1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3- a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (II- D-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (III- D-2), (IILD-3), or (IILD-4). Further embodiments of the disclosure relate to a deuterated compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I- A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB- 4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or a pharmaceutically acceptable salt thereof.

[0252] In embodiments, provided herein is a compound in Table 1, 2, or 3, or a pharmaceutically acceptable salt thereof, racemic form thereof, or stereoisomer thereof.

[0253] In embodiments, provided herein is a compound in Table 1, 2, or 3, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.

[0254] In embodiments, provided herein is a compound in Table 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, provided herein is a compound set forth in Table 1, 2, or 3.

[0256] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound in Table 1, 2, or 3.

[0257] Table 1. Various compounds of the disclosure (series I)

[0258] Table 2. Various compounds of the disclosure (series II)

[0259] Table 3. Various compounds of the disclosure (series III)Compositions

[0260] The compounds of the present disclosure (e.g., a compound of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC- 2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA- La), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (LD-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (II- D-l), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (III-B), (IILC), (IILD), (IILA-1), (IILA-2), (III- A-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC- 4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or Table 1, 2, or 3, or a pharmaceuticallyacceptable salt, stereoisomer, or deuterated form thereof) may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound (active ingredient) is in association with pharmaceutically acceptable adjuvant(s), diluents(s), or carrier(s). Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0261] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of formula (I), (I-A), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (I- C-l), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3- a), (I-B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA- 1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (III- C-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or Table 1, 2, or 3) or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof.

[0262] Depending on the mode of administration, the pharmaceutical composition can comprise from 0.01 to 99 %wt (percent by weight), from 0.05 to 95 %wt, from 0.1 to 90 %wt, from 0.2 to 80 %wt, from 0.3 to 70 %wt, from 0.4 to 60 %wt, or from 0.5 to 50 %wt, of active ingredient (e.g., a compound of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (I- D-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (I-C-l-a), (LD-L a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (II- B-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof), all percentages by weight being based on total composition.

[0263] In embodiments, the present disclosure provides pharmaceutical composition(s) comprising one or more compounds of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (I- D-2), (LD-3), (LD-4), (I-A-l-a), (LA-2-a), (LA-3-a), (I-B-l-a), (LB-2-a), (LB-3-a), (LC-L a), (I-D-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (II-D-4), (III), (ni-A), (III-B), (III-C), (III-D), (III-A-1), (ni-A-2), (III-A-3), (III-A-4), (III-B-1), (ni-B-2), (in-B-3), (in-B-4), (III-C-1), (IILC-2), (III-C-3), (III-C-4), (in-D-1), (III-D-2), (III- D-3), or (III-D-4), or Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).

[0264] In some embodiments, the present disclosure provides pharmaceutical composition(s) comprising one or more compounds of Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, and pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).

[0265] The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, further comprise a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0266] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, transdermally, buccally, sublingually, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

[0267] In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.

[0268] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscularinjection). The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion.

[0269] In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler.Therapeutic Use

[0270] In embodiments, the compounds of the present disclosure are p62 modulators, and thus may be used in any disease area where p62 plays a role. In embodiments, the compounds of the present disclosure are NBR1 modulators, and thus may be used in any disease area where NBR1 plays a role. As such, in one aspect of the disclosure, a method of treatment is provided. The method of treatment, in one embodiment, comprises, administering to a subject in need thereof, a composition comprising an effective amount of a compound of formula (I), (I-A), (I- B), (I-C), (I-D), (LA-1), (LA-2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (I- C-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA-l-a), (LA-2-a), (LA-3-a), (LB-1- a), (LB-2-a), (LB-3-a), (LC-l-a), (LD-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA- 2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IIL C-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof. In embodiments, the composition is administered to the patient for an administration period.

[0271] In embodiments, a compound or composition of the present disclosure is used in a method for modulating autophagy. In some embodiments, the present disclosure provides methods of modulating autophagy. In some embodiments, the method comprises contacting p62 (e.g., one or more amino acids present in p62 protein) with compounds or compositions of the present disclosure (e.g., compounds of formula (I), (LA), (LB), (LC), (LD), (LA-1), (LA- 2), (LA-3), (LA-4), (LB-1), (LB-2), (LB-3), (LB-4), (LC-1), (LC-2), (LC-3), (LC-4), (LD-1), (LD-2), (LD-3), (LD-4), (LA-l-a), (LA-2-a), (LA-3-a), (LB-l-a), (LB-2-a), (LB-3-a), (LC- l-a), (LD-l-a), (II), (ILA), (ILB), (ILC), (ILD), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (ILB-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (II- D-4), (III), (IILA), (IILB), (IILC), (III-D), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IIL D-3), or (IILD-4), or Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof). In some embodiments, the compound increases activity of p62,thereby causing autophagy. In some embodiments, the compound decreases activity of p62, thereby reducing autophagy.

[0272] In some embodiments, the method comprises contacting NBR1 (e.g., one or more amino acids present in NBR1 protein) with compounds or compositions of the present disclosure (e.g., compounds of formula (I), (I-A), (I-B), (I-C), (I-D), (LA-1), (I-A-2), (LA-3), (LA-4), (I-B-l), (I-B-2), (I-B-3), (I-B-4), (I-C-l), (I-C-2), (I-C-3), (I-C-4), (I-D-l), (I-D-2), (I- D-3), (I-D-4), (I-A-l-a), (I-A-2-a), (I-A-3-a), (I-B-l-a), (I-B-2-a), (I-B-3-a), (I-C-l-a), (I-D-l- a), (II), (ILA), (ILB), (ILC), (II-D), (ILA-1), (ILA-2), (ILA-3), (ILA-4), (ILB-1), (ILB-2), (II- B-3), (ILB-4), (ILC-1), (ILC-2), (ILC-3), (ILC-4), (ILD-1), (ILD-2), (ILD-3), (ILD-4), (III), (IILA), (IILB), (IILC), (IILD), (IILA-1), (IILA-2), (IILA-3), (IILA-4), (IILB-1), (IILB-2), (IILB-3), (IILB-4), (IILC-1), (IILC-2), (IILC-3), (IILC-4), (IILD-1), (IILD-2), (IILD-3), or (IILD-4), or Table 1, 2, or 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof). In some embodiments, the compound increases activity of NBR1, thereby causing autophagy. In some embodiments, the compound decreases activity of NBR1, thereby reducing autophagy.

[0273] In embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for inducing autophagy. In some embodiments, the compound contacts p62, thereby inducing autophagy.

[0274] In embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for inducing autophagy. In some embodiments, the compound contacts NBR1, thereby inducing autophagy.

[0275] In embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for degrading target proteins, protein aggregates, protein complexes, lipids (e.g., lipid droplets), bacteria, or viruses. In some embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for reducing the quantity of target proteins, protein aggregates, protein complexes, lipids, bacteria, or viruses.

[0276] In embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for degrading a target protein. In some embodiments, a compound or composition of the present disclosure is administered to a subject in need thereof in a method for reducing the quantity of target proteins.

[0277] In embodiments, a compound or composition of the present disclosure is administered to a patient in a method for treating cancer (e.g., cancer metastasis), metabolic diseases, inflammation, neurodegenerative disorders, and infectious diseases.

[0278] In some embodiments, the cancer is a breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, urothelial cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, hematologic cancer, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, mesothelioma, endometrial cancer, and / or leukemia.

[0279] In some embodiments, the cancer is breast cancer (e.g. , ER negative breast cancer, triple negative breast cancer, basal-like breast cancers, HER2 -positive breast cancers), kidney cancer (e.g., renal cell carcinoma (RCC)), prostate cancer, glioblastoma, or leukemia (e.g., chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia).

[0280] In some embodiments, the neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, and / or Huntington's Disease.

[0281] In some embodiments, the infectious disease is a bacterial infection and / or a virus infection.NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0282] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.1. A compound of formula (I)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRAC(O)NRARB, -CI-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene- NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(O)NRA-Ci-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;each R2is independently Ci-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.2. The compound of embodiment 1, having a structure of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.3. The compound of embodiment 1, having a structure of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.4. The compound of embodiment 1, having a structure of formula (I-C) or (I-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.5. The compound of embodiment 1 or 2, having a structure of formula (I-A-l), (I-A-2), (LA-3), or (LA-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.6. The compound of embodiment 1 or 3, having a structure of formula (I-B-l), (I-B-2), (I-B-3), or (I-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.7. The compound of embodiment 1 or 4, having a structure of formula (I-C-l), (I-C-2), (I-C-3), (I-C-4), (I-D-l), (I-D-2), (I-D-3), or (I-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.8. The compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is -(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(Ci-6alkyl)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(O)N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(Ci-6 alkyl)C(O)N(Ci-6 alkyl)(Ci-6 alkoxy), -(C3-8 cycloalkylene)N(H)(Ci-6 hydroxyalkyl), -(C3-8 cycloalkylene)N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)(CI-6 hydroxyalkyl), -N(CI-6 alkyl)(Ci-6 hydroxyalkyl), or - N(H)C(0)(CI-6 hydroxyalkyl), -N(CI-6 alkyl)C(O)(Ci-6 hydroxyalkyl), wherein the alkylene or alkyl is optionally substituted with -OH or halogen.9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is-CH2NHCH2CH2OH,-CH2NHCH2CH(CH3)OH,-CH(CH3)NHCH2CH2OH,-CH2NHCH2CH2OCH(CH3)2,-CH2OCH2CH2NHCH3,-CH2OCH2CH2NHCH(CH3)2,-C(O)NHCH2CH2OH,-NHC(O)CH2CH2OH,-NHC(O)CH2OH,-CH2NHC(O)NHCH2CH2OH,-NHC(O)NHCH2CH2OH,-OCH2CH(OH)CH2NHCH(CH3)2,-OCH2CH2C(O)NHCH3,-CH2NHC(O)CH2OH,-CH2NHC(O)CH2CH2OH, or-NHC(O)NHCH2CH2OCH3.10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is -CH2NHCH2CH2OH, -CH2NHCH2CH(CH3)OH, -CH2OCH2CH2NHCH3, -OCH2CH(OH)CH2NHCH(CH3)2, -11. The compound of any one of embodiments 1, 2, 5, and 10, having a structure of formula (I-A-l-a), (I-A-2-a), or (I-A-3-a):(I-A-l-a),or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.12. The compound of any one of embodiments 1, 3, 6, and 10, having a structure of formula (I-B-l-a), (I-B-2-a), or (I-B-3-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.13. The compound of any one of embodiments 1, 4, 7, and 10, having a structure of formula (I-C-l-a) or (I-D-l-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.14. The compound of any one of the preceding embodiments, wherein at least one H in L° is replaced by conjugate comprising a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid.15. A compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8 cycloalkylene, or C3-C8 cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.16. The compound of embodiment 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ILA):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.17. The compound of embodiment 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ILB):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.18. The compound of embodiment 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (n-C) or (II-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.19. The compound of embodiment 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ILA-1), (ILA-2), (ILA-3), or (ILA-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.20. The compound of embodiment 17, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (n-B-1), (II-B-2), (II-B-3), or (II-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.21. The compound of embodiment 18, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (n-C-1), (II-C-2), (II-C-3), (II-C-4), (n-D-1), (n-D-2), (n-D-3), or (n-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.22. The compound of any one of embodiments 15-21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, - O-, -C(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz.23. The compound of any one of embodiments 15-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L1is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-O-(Ci-6alkylene)-CH(OH)-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl),-O-(Ci-6alkylene)-CH(OH)-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl), or-(Ci-6 alkylene)-NH(CH2CH20)m-(CH2)n-0-C6-io aryl; wherein HETAis a 4-10 membered heterocycle containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl; m is an integer of 1-12; and n is an integer of 0-6.24. The compound of embodiment 23, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein HETAis piperidinyl or piperazinyl optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-Ce-io aryl.25. The compound of embodiment 23 or 24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is an integer of 1-6.26. The compound of embodiment 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is an integer of 1-4.27. The compound of any one of embodiments 23-26, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein n is an integer of 0-3.28. The compound of embodiment 23, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L1is-CH2NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-C=CH,-O-CH2-CH(OH)-CH2-NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)3-(CH2)3-NCH3C(O)OC(CH3)3,-CH2NH-(CH2CH2O)4-(CH2)3-NCH3C(O)OC(CH3)3,30. A compound of formula (III)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by - N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, - N(C3-C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(Ci- C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, - C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.31. The compound of embodiment 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ni-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.32. The compound of embodiment 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula(ni-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.33. The compound of embodiment 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula(ni-C) or (III-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.34. The compound of embodiment 31, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ni-A-1), (III-A-2), (in-A-3), or (IILA-4):35. The compound of embodiment 32, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ni-B-1), (ni-B-2), (III-B-3), or (III-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.36. The compound of embodiment 33, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (ni-C-1), (III-C-2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4):- - ,or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.37. The compound of any one of embodiments 31-36, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein 1-25 methylene groups of L2are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, - O-, -C(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz.38. The compound of any one of embodiments 30-37, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)-(Ci-6 alkylene)-©-, or-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETB-, wherein HETBis a 4-10 membered heterocyclylene containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl; m is an integer of 1-12; and n is an integer of 0-6.39. The compound of any one of embodiments 30-38, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:-(CH2)-NH(CH2CH2O)-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)2-(CH2)2-NH-, -(CH2)-NH(CH2CH2O)3-(CH2)2-NH-, -(CH2)-NH(CH2CH2O)3-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)4-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)3-,-(CH2)-NH(CH2CH2O)4-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-C(O)CH2-O-,-(CH2)-NH(CH2CH2O)3-(CH2)2-,40. The compound of any one of embodiments 30-37, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:41. The compound of any one of embodiment 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein that is associated with cancer.42. The compound of embodiment 41, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein associated with cancer comprises a mutation or a fusion.43. The compound of embodiment 41 or 42, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein associated with cancer is BRD4.44. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein associated with a metabolic disease.45. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein associated with inflammation.46. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is present in bacteria.47. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is present in a virus particle.48. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein aggregate is an alpha- synuclein protein aggregate, a mutant Huntingtin protein aggregate, an amyloid protein aggregate, or a TDP-43 protein aggregate.49. The compound of any one of embodiments 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is an intracellular protein.50. The compound of any one of embodiments 30-40, wherein A is aryl, aryleneheteroaryl, arylene, heteroarylene, aryl, heteroarylene-aryl, heteroaryl ene-heteroaryl, heteroarylene-heteroarylene-heteroaryl, heterocyclylene-aryl, heterocyclylene-heteroaryl, heteroarylene-NC(O)-heteroaryl, heteroarylene-N=N-aryl, or arylene-(arylalkyl)-OC(O)- hetercyclyl-C(O)Ci-6alkylene-aryl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, Ci-6 alkyl, O-Ci-6 alkyl, NH2, NH(CI-6 alkyl), N(CI-6alkyl)2, -(CH2)I-4C(O)NH2, -(CH2)I-4C(O)NH(CI-6 alkyl), or -(CH2)I-4C(O)N(CI-6 alkyl)2.51. The compound of any one of embodiments 30-40 and 50, wherein A isRvis H, F, CF3, or C1-6 alkyl.52. The compound of any one of embodiments 1-51, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independent halogen.53. The compound of embodiment 52, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is -F or -Cl.54. The compound of any one of embodiments 1-51, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independently Ci-6 alkyl.55. The compound of embodiment 54, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independently C1-3 alkyl.56. The compound of embodiment 54 or 55, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is methyl.57. The compound of any one of embodiments 1-56, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein a is 0 or 1.58. The compound of any one of embodiments 1-57, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is independently C1-6 alkyl.59. The compound of embodiment 58, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is independently C1-3 alkyl.60. The compound of embodiment 58 or 59, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is methyl.61. The compound of any one of embodiments 1-60, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein b is 0 or 1.62. The compound of any one of embodiments 1-61, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is a absent, Ci-4 alkylene, -(C1-3 alkylene)C(O)-, C3-6 cycloalkylene, -(C3-6 cycloalkylene)C(O)-, -C(O)-, or -S(O)2-.63. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is a absent.64. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2-, -CH2CH2-, -CH(CH3)-, or - C(CH3)2-.65. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2-.66. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2CH2-.67. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -C(O)-.68. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -S(O)2-.69. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is70. The compound of embodiment 62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2C(O)-.71. The compound of embodiment 62, or a pharmaceutically acceptable salt, aO stereoisomer, or a deuterated form thereof, wherein Q is72. The compound of any one of embodiments 1-71, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is C3-8 carbocycle, 3-10 membered heterocycle, Ce-io aryl, 5-10 membered heteroaryl, or -NRXRY, wherein the C3-8 carbocycle, 3-8 membered heterocycle, Ce-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 R4, and each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or -C(O)O-Ci-6 alkyl, and wherein Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl, and RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle.73. The compound of embodiment 72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is Ce-io aryl optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, Ci-6 alkyl, Ci-6 alkoxy, or -C(O)- NRXRY.74. The compound of embodiment 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is Ce-io aryl optionally substituted with -F, -Cl, Ci-3 alkoxy, or -C(O)-NRXRY, wherein Rxis H or Ci-6 alkyl, and RYis Ci-6 alkyl.75. The compound of embodiment 73 or 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is76. The compound of embodiment 72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is 5-10 membered heteroaryl optionally substituted with 1 or 2 R4; and wherein the heteroaryl contains 1 or 2 heteroatoms selected from N, S, or O.77. The compound of embodiment 76, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is, each optionally substituted with one R4.78. The compound of embodiment 76 or 77, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is79. The compound of embodiment 72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is C3-8 carbocycle optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, -OH, C1-6 alkyl, or C1-6 alkoxy.80. The compound of embodiment 79, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is, each optionally substituted with one R4.81. The compound of embodiment 72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is 3-10 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, or S, and the heterocycle is optionally substituted with 1 or 2 R4, and wherein each R4is independently -OH, Ci-6 alkyl, or -C(O)O- (Ci-6 alkyl).82. The compound of embodiment 81, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R4is independently -OH, C1-3 alkyl, or -C(O)O-(Ci-5alkyl).83. The compound of embodiment 81 or 82, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is84. The compound of any one of embodiments 81-83, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is85. The compound of embodiment 72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is -NRXRY, and wherein Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl, and RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle.86. The compound of embodiment 85, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Rxis H, or methyl, and RYis methyl, -87. The compound of embodiment 85 or 86, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is88. The compound of any one of embodiments 1-63 and 72-87, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is absent, and R3is89. The compound of any one of embodiments 1-72, or a pharmaceutically acceptable90. The compound of any one of embodiments 1-72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein -Q-R3is91. The compound of any one of embodiments 1-72 and 89-90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein -Q-R3is92. The compound of any one of embodiments 1, 2, and 5, wherein the compound of formula (I) is:or a pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof.93. The compound of any one of embodiments 1, 3, and 6, wherein the compound of formula (I) is:or a pharmaceutically acceptable salt or deuterated form thereof.94. The compound of any one of embodiments 1, 4, and 7, wherein the compound of formula (I) is:or a pharmaceutically acceptable salt or deuterated form thereof.95. The compound of embodiment 15, wherein the compound of formula (II) isor a pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof.96. The compound of embodiment 30, wherein the compound of formula (III) isor a pharmaceutically acceptable salt, or deuterated form thereof.97. A method of modulating autophagy in a subject, comprising administering to the subject a compound of any one of the preceding claims.98. The method of embodiment 97, wherein the compound contacts p62.99. The method of embodiment 98, wherein the compound increases activity of p62, thereby causing autophagy.100. The method of embodiment 98, wherein the compound decreases activity of p62, thereby reducing autophagy.101. A method of degrading a target protein in a subject in need thereof, comprising administering a compound of any one of the preceding embodiments.102. A method of inducing autophagy in a subject in need thereof, comprising administering a compound of any one of the preceding embodiments.103. The method of embodiment 102, wherein the compound contacts p62, thereby inducing autophagy.EXAMPLES

[0283] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way.

[0284] In embodiments, compounds of the present disclosure can be synthesized using the following methods. General reaction conditions are given, and reaction products can be purified by generally known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0285] Abbreviations equiv. equivalence h hour(s) min minutesTHF tetrahydrofuranRT room temperatureTLC thin layer chromatographyEtOAc ethyl acetateEt2O di ethyl etherACN acetonitrileEDOHC1 (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride)HOBt 1 -hydroxybenzotriazoleFA formic acidTFA trifluoroacetic acid aq. aqueous br. broad sat. saturatedDIBAL-H diisobutylaluminum hydrideDMP Dess-Martin periodinaneDIPEA A,A-DiisopropylethylamineHATU Hexafluorophosphate Azabenzotriazole Tetramethyl UroniumNBS N-bromosuccinimide(BZO)2 Benzoyl peroxideNIS N-Iodosuccinimide(BOC)2O Di-tert-butyl decarbonateBn BenzylDCDMH 2,4-Dichloro-5,5-dimethylhydantoinIBCF Isobutyl chloroformateTs Tosyl dppp 1 ,3 -Bis(diphenylphosphino)propaneTBAB tetrabutylammonium bromideDMA dimethylacetamideFmoc-OSu 9-Fluorenylmethyl A-succinimidyl carbonateExample 1: Synthesis of synthesis of compound 2 via synthesis route A

[0286] Synthesis of methyl 2-phenylbenzofuran-6-carboxylate (A-3)

[0287] In a sealed tube, to a degassed solution of methyl 3-hydroxy-4-iodobenzoate A-l (1.00 g, 3.60 mmol, 1.0 equiv.) in THF (10 mL) at RT, was added EtiN (2.51 mL, 18.0 mmol, 5.0 equiv.), ethynylbenzene A-2 (0.40 mL, 3.60 mmol, 1.0 equiv.), Cui (68.6 mg, 0.36 mmol, 0.1 equiv.) and PdCh(PPh3)2 (126 mg, 0.18 mmol, 0.05 equiv.). The resultant mixture was stirred at 75 °C for 16 h. Upon the completion of reaction by TLC, the reaction mixture was diluted with water (80 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, evaporated, and purified by silica gel column (60-120 mesh) chromatography (elution with 10% EtOAc / hexane) to afford A-3 as a brown solid (485 mg, yield: 53%). TLC system: EtOAc / hexane (30:70), Revalue = 0.4;JH NMR (400 MHz, CDCh) 5 ppm: 8.22-8.21 (br. s, 1H), 7.95 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.90-7.88 (m, 2H), 7.60 (d, J= 8.0 Hz, 1H), 7.50-7.45 (m, 2H), 7.42-7.39 (m, 1H), 7.06 (s, 1H), 3.96 (s, 3H).

[0288] Synthesis of (2-phenylbenzofuran-6-yl)methanol (A-4)

[0289] To a stirred solution of A-3 (300 mg, 1.19 mmol, 1.0 equiv.) in CH2CI2 (6 mL) at 0 °C, was added IM DIBAL-H in toluene (4.76 mL, 4.76 mmol, 4.0 equiv.). The resultant mixture was allowed to warm to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with NH4Q solution (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated with n-pentane (20 mL), Et2O (20 mL), and dried under vacuum to afford A-4 as off-white solid (250 mg, yield: 94%). TLC system: EtOAc / hexane (30:70), Rfvalue = 0.4; 'HNMR (400 MHz, CDCh) 5 ppm: 7.88-7.86 (m, 2H), 7.57-7.55 (m, 2H), 7.48-7.44 (m, 2H), 7.37-7.34 (m, 1H), 7.25-7.23 (m, 1H), 7.01 (s, 1H), 4.81 (d, J = 6.0 Hz, 2H), 1.70 (t, J= 6.0 Hz, 1H).

[0290] Synthesis of 2-phenylbenzofuran-6-carbaldehyde (A-5)

[0291] To a stirred solution of A-4 (250 mg, 1.11 mmol, 1.0 equiv.) in CH2CI2 (10 mL) at 0 °C, was added Dess-Martin periodinane (708 mg, 1.67 mmol, 1.5 equiv.). The resultant mixture was stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture wasdiluted with water (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column (60-120 mesh) chromatography to afford A-5 as an off-white solid (225 mg, yield: 91%). TLC system: EtOAc / hexane (20:80), Rfvalue = 0.5; 'HNMR (400 MHz, CDCI3) 5 ppm: 10.07 (s, 1H), 8.03 (br. s, 1H), 7.93-7.90 (m, 2H), 7.79 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.45- 7.41 (m, 1H), 7.10 (d, J = 1.2 Hz, 1H).

[0292] Synthesis of 2-(((2-phenylbenzofuran-6-yl)methyl)amino)ethan-l-ol as formic acid salt (compound 2)

[0293] To a stirred solution of A-5 (225 mg, 1.01 mmol, 1.0 equiv.) in MeOH (7 mL) at RT, was added 2-aminoethan-l-ol (124 mg, 2.02 mmol, 2.0 equiv.) and AcOH (6 pL, 0.1 mmol, 0.1 equiv.). The reaction mixture was stirred at 80 °C for 3 h before the mixture was cooled to 0 °C and NaBH4 (76.4 mg, 2.02 mmol, 2.0 equiv.) was added portion-wise. The resultant mixture was stirred at RT for 1 h and upon the completion of reaction by TLC, reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (Grace column, elution with 30% MeCN / 0.02% FA in H2O) to afford compound 2 (formic acid salt) as a white solid (30 mg, yield: 9%). TLC system: MeOH / CH2Cl2(10:90), Rfvalue = 0.1; ‘H NMR (400 MHz, DMSO-tL) 5 ppm: 8.31 (br. s, 1H; HCOOH), 7.93-7.90 (m, 2H), 7.62 (s, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.43- 7.38 (m, 2H), 7.26 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 3.89 (s, 2H), 3.50 (t, J= 6.0 Hz, 2H), 2.63 (t, J= 6.0 Hz, 2H); LCMS (ESI) m / z 268.1 [C17H17NO2 + H]+.Example 2: Synthesis of compound 6 via synthesis route A

[0294] Synthesis of methyl 2-benzylbenzofuran-6-carboxylate (A-7)

[0295] Compound A-7 was obtained following the Pd-catalyzed benzofuran ring formation procedure similar to that for the synthesis of compound A-3, utilizing prop-2-yn-l-ylbenzene A-6 (1.0 equiv.) and reaction conditions of 75 °C for 16 h. Compound A-7 was obtained in 50% yield as yellow liquid following silica gel (60-120 mesh) column chromatography (elution with 10% EtOAc / hexane). TLC system: EtOAc / hexane (30:70), Rf value = 0.5; 'H NMR (400 MHz, CDCh) 5 ppm: 8.10 (s, 1H), 7.90 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.36-7.27 (m, 5H), 6.40 (s, 1H), 4.13 (s, 2H), 3.92 (s, 3H).

[0296] Synthesis of 2-benzylbenzofuran-6-carboxylic acid (A-8)

[0297] To a stirred solution of A-7 (300 mg, 1.13 mmol, 1.0 equiv.) in THF (4.5 mL) at RT, was added LiOH»H2O (299 mg, 7.12 mmol, 6.3 equiv., dissolved in 1.5 mL of H2O). The resultant mixture was stirred at RT for 6 h and upon the completion of reaction by TLC, the mixture was diluted with H2O (30 mL) and extracted with Et2O (2 x 30 mL) to remove unreacted starting material and non-polar impurities. The aqueous layer was then acidified with 2N HC1 (5 mL) and extracted with 10% MeOH in CH2CI2 (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford A-8 as yellow solid (230 mg, yield: 81%). TLC system: MeOH / CH2Ch (5:95), Rf value = 0.4; 'H NMR (400 MHz, CDCh) 5 ppm: 8.18 (s, 1H), 7.97 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.37-7.25 (m, 5H), 6.43 (s, 1H), 4.15 (s, 2H).

[0298] Synthesis of 2-benzyl-\-(2-hydroxyethyl)benzofur:in-6-carbox:imide (compound 6)

[0299] To a stirred solution of A-8 (200 mg, 0.79 mmol, 1.0 equiv.) in CHCh (2 mL) at 0 °C, was added 2-aminoethan-l-ol (121 mg, 1.98 mmol, 2.5 equiv.), EDC*HC1 (228 mg, 1.19 mmol, 1.5 equiv.), HOBt (161 mg, 1.19 mmol, 1.5 equiv.) and DIPEA (0.41 mL, 2.38 mmol, 3.0 equiv.). The resultant mixture was allowed to warm to RT and stirred at RT for 16 h. Upon the completion of reaction by TLC, H2O (10 mL) was added to the reaction mixture and the mixture was extracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by reverse phase column chromatography (Grace column, elution with 30% MeCN / 0.01% FA in H2O) to afford compound 6 as an off-white solid (25 mg, yield: 11%). TLC system: MeOH UCh (10:90), Rfvalue = 0.3; melting point range: 84-86 °C; 'H NMR (400 MHz, DMSO-tL) 5 ppm: 8.40 (t, .7= 5.6 Hz, 1H), 7.97 (s, 1H), 7.73 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.37- 7.32 (m, 4H), 7.28-7.25 (m, 1H), 6.66 (s, 1H), 4.71 (t, J= 5.6 Hz, 1H), 4.19 (s, 2H), 3.51 (q, J = 6.0 Hz, 2H), 3.34 (t, J= 5.6 Hz, 2H); LCMS (ESI) m / z 296.1 [C18H17NO3 + H]+.Example 3: Synthesis of compound 7 via synthesis route A

[0300] Synthesis of (2-benzylbenzofuran-6-yl)methanol (A-9)

[0301] To a stirred solution of A-7 (450 mg, 1.68 mmol, 1.0 equiv.) in CH2CI2 (5 mL) at 0 °C, was added DIBAL-H (25% in toluene) (3 mL, 5.04 mmol, 3.0 equiv.). The resultant mixture was warmed to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with aq. NH4Q solution (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel (60 - 120 mesh) column chromatography (gradient elution with 15-20%EtOAc / hexane) to afford A-9 as a yellow liquid (350 mg, yield: 87%). TLC system: EtOAc / hexane (20:80), Revalue = 0.2; 'HNMR (400 MHz, CDCh) 5 ppm: 7.45-7.43 (m, 2H), 7.35-7.28 (m, 5H), 7.18 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 6.35 (s, 1H), 4.76 (s, 2H), 4.11 (s, 2H), 1.65 (br. s, 1H).

[0302] Synthesis of 6-((allyloxy)methyl)-2-benzylbenzofuran (A-10)

[0303] To a stirred solution of A-9 (360 mg, 1.51 mmol, 1.0 equiv.) in DMF (3.6 mL) at 0 °C, was added NaH (60% dispersion in mineral oil) (121 mg, 3.02 mmol, 2.0 equiv.) slowly. The reaction mixture was stirred at 0 °C for 20 min before allyl bromide (261 pL, 3.02 mmol, 2.0 equiv.) was added. The resultant mixture was stirred at 0 °C for 4 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with ice-cold water and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse phase column chromatography (Grace column, elution with 43% MeCN / 0.1% FA in H2O) to afford A-10 (185 mg, yield: 44%) as a colourless oily liquid. TLC system: EtOAc / hexane (20:80), Rf value= 0.6;XH NMR (400 MHz, CDCI3) 5 ppm: 7.44-7.41 (m, 2H), 7.35-7.27 (m, 5H), 7.16 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.34 (s, 1H), 6.00-5.90 (m, 1H), 5.33-5.27 (m, 1H), 5.22-5.18 (m, 1H), 4.59 (s, 2H), 4.11 (s, 2H), 4.03-4.00 (m, 2H).

[0304] Synthesis of 3-((2-benzylbenzofuran-6-yl)methoxy)propane-l,2-diol (A-ll)

[0305] To a stirred solution of A-10 (180 mg, 0.65 mmol, 1.0 equiv.) in acetone (1.8 mL) and water (0.1 mL) at RT, was added K2[OsO2(OH)4] (47.9 mg, 0.13 mmol, 0.2 equiv.) and NMO (50% in water) (0.2 mL, 0.85 mmol, 1.3 equiv.). The resultant mixture was stirred at RT for 2 h. Upon the completion of reaction by TLC, water (20 mL) was added and the reaction was extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel (100-200 mesh) column chromatography (elution with 35% EtOAc / hexane) to afford A-ll (125 mg, crude) as a brown liquid. TLC system: EtOAc / hexane (50:50), Revalue = 0.3; 'H NMR (400 MHz, CDCI3) 5 ppm: 7.43 (d, J = 6.0 Hz, 1H), 7.38 (br. s, 1H), 7.35-7.27 (m, 4H— >5H), 7.14 (dd, J= 7.6 Hz, 1.2 Hz, 1H), 6.36 (s, 1H), 4.62 (s, 2H), 4.10 (s, 2H), 3.88 (br. s, 1H), 3.72-3.70 (m, 1H), 3.65-3.49 (m, 3H), 2.48 (br. s, 1H), 2.04 (br. s, 1H). Crude material was used in next step without further purification.

[0306] Synthesis of 2-((2-benzylbenzofuran-6-yl)methoxy)acetaldehyde (A-12)

[0307] To a stirred solution of A-ll (crude from previous step) (120 mg, 0.38 mmol, 1.0 equiv.) in MeOH (2.4 mL) and H2O (0.3 mL) at RT, was added NalCh (130 mg, 0.61 mmol, 1.6 equiv.). The resultant mixture was stirred at RT for 2 h and upon the completion of reaction by TLC, the reaction mixture was diluted with H2O (20 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel (100-200 mesh) column chromatography to afford A-12 (90 mg, yield: 49% over 2 steps) as a light green liquid. TLC system: EtOAc / hexane (50:50), Rfvalue = 0.5; 'H NMR (400 MHz, CDCI3) 5 ppm: 9.72 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.42 (s, 1H), 7.34-7.27 (m, 5H), 7.17 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 6.37 (s, 1H), 4.70 (s, 2H), 4.11 (s, 2H), 3.49 (s, 2H).

[0308] Synthesis of 7V-(2-((2-benzylbenzofuran-6-yl)methoxy)ethyl)propan-2-amine (compound 7)

[0309] To a stirred solution of A-12 (90 mg, 0.32 mmol, 1.0 equiv.) in MeOH (1 mL) at RT, was added isopropylamine (68.1 pL, 0.80 mmol, 2.5 equiv.) and AcOH (4 pL, 0.06 mmol, 0.2 equiv.). The reaction mixture was cooled to 0 °C and NaCNBH? (50.3 mg, 0.80 mmol, 2.5 equiv.) was added. The resultant mixture was warmed to RT and stirred at RT for 16 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with ice-cold water andextracted with CH2CI2. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude obtained was purified by reverse phase column chromatography (Grace column, elution with 35% MeCN / 0.1% FA in H2O) to afford compound 7 (30 mg, yield: 29%) as an off-white semi solid. TLC system: MeOH / CTfcCh (10:90), Revalue = 0.2; 'H NMR (400 MHz, DMSO-eL) 5 ppm: 7.52 (d, J= 8.0 Hz, 1H), 7.47 (s, 1H), 7.34-7.30 (m, 4H), 7.27-7.25 (m, 1H), 7.17 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 6.61 (s, 1H), 4.57 (s, 2H), 4.14 (s, 2H), 3.54 (t, J= 5.6 Hz, 2H), 2.98-2.92 (m, 1H), 2.87 (t, J= 5.6 Hz, 2H), 1.06 (d, J= 6.4 Hz, 6H); LCMS (ESI) m / z 324.3 [C21H25NO2 + H]+.Example 4: Synthesis of compound 36 via synthesis route Acompound 36

[0310] Synthesis of methyl 2-fluoro-5-hydroxy-4-iodobenzoate (A-14)

[0311] To a stirred solution of A-13 (1.75 g, 10.3 mmol, 1.0 equiv.) in 1 :1 ACOH / CH2CI2 (35 mL, 20 vol) at 0 °C, was added H2SO4 (0.7 mL, 0.4 vol) and NIS (2.79 g, 12.4 mmol, 1.2 equiv.). The reaction mixture was stirred at RT for 2 h and upon the completion of reaction by TLC, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude obtained was purified by reverse phase column chromatography (Grace column, elution with 28% MeCN / 0.1% FA in H2O) to afford A-14 (852 mg, yield: 28%) as a brown oil. TLC system: EtOAc / hexane (20:80), Revalue= 0.5;XH NMR (400 MHz, DMSO-tL) 5 ppm: 10.65 (s, 1H), 7.72 (d, J= 10 Hz, 1H), 7.31 (d, J= 6.4 Hz, 1H), 3.83 (s, 3H); LCMS (ESI) m / z 294.8 [CsHsFICh - H]’.

[0312] Synthesis of methyl 2-benzyl-5-fluorobenzofuran-6-carboxylate (A-15)

[0313] Compound A-15 was obtained following the Pd-catalyzed benzofuran ring formation procedure similar to that for the synthesis of compound A-3, utilizing prop-2-yn-l-ylbenzene A-6 (1.2 equiv.) and reaction conditions of 70 °C for 16 h. Compound A-15 was obtained in 65% yield as a brown oil following silica gel (60-120 mesh) column chromatography (elution with 5% EtOAc / hexane). TLC system: EtOAc / hexane (5:95), Revalue = 0.7; 'H NMR (400 MHz, CDCh) 5 ppm: 7.98 (d, J = 5.6 Hz, 1H), 7.37-7.30 (m, 5H), 7.17 (d, J= 10.8 Hz, 1H), 6.36 (s, 1H), 4.12 (s, 2H), 3.94 (s, 3H); LCMS (ESI) m / z 285.1 [C17H13FO3 + H]+.

[0314] Synthesis of (2-benzyl-5-fluorobenzofuran-6-yl)methanol (A-16)

[0315] Compound A-16 was obtained following the ester reduction procedure similar to that for the synthesis of compound A-4, utilizing DIBAL-H (2.0 equiv.) and reaction conditions of 0 °C - RT for 2 h. Compound A-16 was obtained as a crude and was used directly in the next step without further purification. TLC system: EtOAc / hexane (30:70), Revalue = 0.7; 'HNMR (400 MHz, CDCh) 5 ppm: 7.43 (d, J = 5.6 Hz, 1H), 7.35-7.28 (m, 5H), 7.12 (d, J = 9.6 Hz, 1H) 6.33 (s, 1H), 4.80 (s, 2H), 4.09 (s, 2H), 1.80 (br. s, 1H); LCMS (ESI) m / z 239.1 [C16H13FO2- OH]+.

[0316] Synthesis of 2-benzyl-5-fluorobenzofuran-6-carbaldehyde (A- 17)

[0317] Compound A-17 was obtained following the alcohol oxidation procedure similar to that for the synthesis of compound A-5, utilizing DMP (2.0 equiv.) and reaction conditions of 0 °C- RT for 2 h. Compound A-17 was obtained in 89% yield over 2 steps as a brown oil following silica gel (60-120 mesh) column chromatography (elution with 10% EtOAc / hexane). TLC system: EtOAc / hexane (20:80), Revalue = 0.4; 'H NMR (400 MHz, CDCh) 5 ppm: 10.36 (s, 1H), 7.88 (d, J= 5.2 Hz, 1H), 7.36-7.29 (m, 5H), 7.19 (d, J= 10.0 Hz, 1H) 6.40 (s, 1H), 4.13 (s, 2H); LCMS (ESI) m / z 255.1 [C16H11FO2 + H]+.

[0318] Synthesis of 2-(((2-benzyl-5-fluorobenzofuran-6-yl)methyl)amino)ethan-l-ol as formic acid salt (compound 36)

[0319] Compound 36 was obtained following the reductive amination procedure similar to that for the synthesis of compound 2, utilizing 2-aminoethan-l-ol (2.0 equiv.), AcOH (0.1 equiv.), NaBH4 (2.0 equiv.) and reaction conditions of 70 °C for 16 h for imine formation, and 0 °C to RT for 1 h for imine reduction. Compound 36 (formic acid salt) was obtained in 28% yield as a light brown semi-solid following reverse phase column chromatography (Grace column, elution with 17% MeCN / 0.1% FA in H2O). TLC system: MeOH / LCh (10:90), Rfvalue = 0.2; 'H NMR (400 MHz, DMSO-tL) 5 ppm: 8.22 (s, 1H, HCOOH), 7.56 (d, J= 6.0 Hz, 1H), 7.36-7.30 (m, 5H), 7.27-7.25 (m, 1H), 6.58 (s, 1H), 4.14 (s, 2H), 3.84 (s, 2H), 3.48 (t, J= 5.6 Hz, 2H), 2.62 (t, J= 5.6 Hz, 2H); LCMS (ESI) m / z 300.1 [C18H18FNO2 + H]+.Example 5: Synthesis of compound 9 via synthesis route B

[0320] Synthesis of 2-benzyl-6-methoxybenzofuran (B-2)

[0321] Compound B-2 was obtained following the Pd-catalyzed benzofuran ring formation procedure similar to that for the synthesis of compound A-3, utilizing prop-2-yn-l-ylbenzene A-6 (1.2 equiv.) and reaction conditions of 60 °C for 16 h. Compound B-2 was obtained semi- pure as a brown gum following silica gel (60-120 mesh) column chromatography (elution with 50% EtOAc / hexane). TLC system: EtOAc / hexane (20:80), Revalue = 0.3; 'H NMR (400 MHz, CDCh) 5 ppm: 7.35-7.29 (m, 6H), 6.96 (s, 1H), 6.81 (dd, J= 8.8 Hz, 2.4 Hz, 1H), 6.30 (s, 1H), 4.07 (s, 2H), 3.82 (s, 3H).

[0322] Synthesis of 2-benzylbenzofuran-6-ol (B-3)

[0323] To a stirred solution of B-2 (500 mg, 2.10 mmol, 1.0 equiv.) in CH2Ch (5 mL) at 0 °C, was added 1 M BBn in CH2CI2 (4.20 mL, 4.20 mmol, 2.0 equiv.). The resultant mixture was warmed to RT and stirred at RT for 16 h. Upon the completion of reaction by TLC, the reaction was quenched with aq. NaHCCh solution (30 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel (60-120 mesh) column chromatography (elution with 20% EtOAc / hexane) to afford B-3 as pale-yellow gum (380 mg, yield: 42% over 2 steps). TLC system: EtOAc / hexane (50:50), Rfvalue = 0.3; ‘HNMR (400 MHz, CDCh) 5 ppm: 7.39- 7.28 (m, 6H), 6.94 (d, J= 2.4 Hz, 1H), 6.75 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 6.32 (s, 1H), 4.89 (br. s, 1H), 4.10 (s, 2H).

[0324] Synthesis of 2-benzyl-6-(oxiran-2-ylmethoxy)benzofuran (B-4)

[0325] To a stirred solution of B-3 (370 mg, 1.65 mmol, 1.0 equiv.) in EtOH (4 mL) at 0 °C, was added 1.8 M aq. KOH solution (3.8 mL). The reaction mixture was stirred at 0 °C for 15 min before 2-(chloromethyl)oxirane (0.26 mL, 3.30 mmol, 2.0 equiv.) was added. The resultant mixture was warmed to RT and stirred at RT for 16 h. Upon the completion of reaction by TLC, the volatiles were removed, the residue was diluted with H2O (30 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude obtained was purified by silica gel (100-200 mesh) column chromatography (elution with 10% EtOAc / hexane) to afford B-4 as a brown gummy mass (160 mg, yield: 35%). TLC system: EtOAc / hexane (50:50), Revalue = 0.7; 'H NMR (400 MHz, CDCh) 5 ppm: 7.34-7.29 (m, 5H), 7.25-7.23 (m, 1H), 6.97 (d, J= 2.4 Hz, 1H), 6.84 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.29 (s, 1H), 4.24-4.21 (m, 1H), 4.07 (s, 2H), 3.99-3.95 (m, 1H), 3.39- 3.35 (m, 1H), 2.92-2.90 (m, 1H), 2.78-2.76 (m, 1H); LCMS (ESI) m / z 281.1 [CisHieCh + H]+.

[0326] Synthesis of l-((2-benzylbenzofuran-6-yl)oxy)-3-(isopropylamino)propan-2-ol as formic acid salt (compound 9)

[0327] To a stirred solution of B-4 (160 mg, 0.57 mmol, 1.0 equiv.) in EtOH (3.2 mL) at RT, was added isopropylamine (0.24 mL, 2.85 mmol, 5.0 equiv.). The resultant mixture was stirred at 80 °C for 16 h. Upon the completion of reaction by TLC, the volatiles were removed, and the crude obtained was purified by reverse phase column chromatography (Grace column, elution with 17% MeCN / 0.01% FA in H2O) to afford compound 9 (formic acid salt) as a light brown gum (51 mg, yield: 23%). TLC system: MeOH UCh (05:95), Revalue = 0.1; 'H NMR (400 MHz, DMSO-eL) 5 ppm: 8.34 (br. s, 1H; HCOOH), 7.41 (d, J = 8.4 Hz, 1H), 7.35-7.29 (m, 4H), 7.26-7.23 (m, 1H), 7.11 (s, 1H), 6.83 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 6.52 (s, 1H), 4.10 (s, 2H), 4.05-4.01 (m, 1H), 3.96-3.93 (m, 2H), 3.06-3.01 (m, 1H), 2.94-2.90 (m, 1H), 2.80- 2.75 (m, 1H), 1.13-1.11 (m, 6H); LCMS (ESI) m / z 340.3 [C21H25NO3 + H]+.Example 6: Synthesis of compound 11 via synthesis route C

[0328] Synthesis of 2-benzyl-6-nitrobenzofuran (C-2)

[0329] Compound C-2 was obtained following the Pd-catalyzed benzofuran ring formation procedure similar to that for the synthesis of compound A-3, utilizing prop-2-yn-l-ylbenzene A-6 (1.0 equiv.), piperidine (1.0 equiv.) and reaction conditions of 60 °C for 16 h. Compound C-2 was obtained in 57% yield as a brown gum following silica gel (100-200 mesh) column chromatography (elution with 5% EtOAc / hexane). TLC system: EtOAc / hexane (30:70), Rf value = 0.7; 'H NMR (400 MHz, CDCh) 5 ppm: 8.30 (s, 1H), 8.12 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.38-7.27 (m, 5H), 6.47 (s, 1H), 4.16 (s, 2H).

[0330] Synthesis of 2-benzylbenzofuran-6-amine (C-3)

[0331] To a stirred solution of C-2 (470 mg, 1.86 mmol, 1.0 equiv.) in 1 : 1 EtOH / H2O (4.60 mL) at RT, was added Fe powder (312 mg, 5.58 mmol, 3.0 equiv.) and NH4Q (298 mg, 5.58 mmol, 3.0 equiv.). The resultant mixture was stirred at 70 °C for 2 h. Upon the completion of reaction by TLC, the reaction mixture was filtered through a Celite bed, washing with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure, and triturated with n-pentane to afford C-3 as a brown solid (230 mg, yield: 55%). TLC system: EtOAc / hexane (30:70), Rfvalue = 0.1;XH NMR (400 MHz, CDCh) 5 ppm: 7.33-7.29 (m, 5H), 7.21(d, J= 8.0 Hz, 1H), 6.74 (s, 1H), 6.57 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 6.23 (s, 1H), 4.05 (s, 2H); LCMS (ESI) m / z 224.2 [C15H13NO + H]+.

[0332] Synthesis of 7V-(2-benzylbenzofuran-6-yl)-3-hydroxypropanamide (compound 11)

[0333] To a stirred solution of C-3 (185 mg, 0.83 mmol, 1.0 equiv.) in DMF (1.85 mL) at 0 °C, was added HATU (475 mg, 1.25 mmol, 1.5 equiv.) and DIPEA (0.29 mL, 1.66 mmol, 2.0 equiv.). The reaction mixture was warmed to RT and stirred at RT for 15 min before 3- hydroxypropanoic acid (30% in H2O) (0.41 mL, 4.98 mmol, 6.0 equiv.) was added. Theresultant mixture was stirred at 80 °C for 48 h. Upon the completion of reaction by TLC, the reaction was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude obtained was purified by reverse phase column chromatography (Grace column, gradient elution with 30-40% MeCN / 0.01% FA in FEO) to afford compound 11 as a white solid (28 mg, yield: 11%). TLC system: EtOAc / hexane (50:50), Rf value = 0.2; melting point range: 128-131 °C; 'H NMR (400 MHz, DMSO-tL) 5 ppm: 9.98 (s, 1H), 7.96 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 7.35-7.30 (m, 4H), 7.27-7.23 (m, 2H), 6.51 (s, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.11 (s, 2H), 3.71 (q, J = 5.6 Hz, 2H), 2.46 (t, J= 6.4 Hz, 2H); LCMS (ESI) m / z 296.1 [C18H17NO3 + H]+.Example 7: Synthesis of compound 13 via synthesis route D

[0334] Synthesis of ethyl 6-(bromomethyl)benzofuran-2-carboxylate (D-2)

[0335] To a solution of carboxylate D-l (6.70 g, 32.8 mmol, 1.0 equiv.) in CCI4 (140 mL) at RT, was added NBS (7.58 g, 42.6 mmol, 1.3 equiv.) and benzoic peroxyanhydride (795 mg, 3.28 mmol, 0.1 equiv.). The resultant mixture was stirred at 90 °C for 16 h and upon the completion of reaction by TLC, the mixture was diluted with H2O and extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated to afford D-2 as a brown solid (9.20 g, crude). TLC system: EtOAc / hexane (20:80), Rf value = 0.4;LCMS (ESI) m / z 283.0 [CnHnBrCh + H]+. The crude material was used in the next step without purification.

[0336] Synthesis of ethyl 6-(((2-((tert- butyldimethylsilyl)oxy)ethyl)amino)methyl)benzofuran-2-carboxylate (D-3)

[0337] To a stirred solution of D-2 (9.20 g, 32.5 mmol, 1.0 equiv.) in THF (100 mL) at RT, was added 2-((tert-butyldimethylsilyl)oxy)ethan-l -amine (7.40 mL, 35.8 mmol, 1.1 equiv.) and NEts (6.80 mL, 48.8 mmol, 1.5 equiv.). The resultant mixture was stirred at 60 °C for 16 h and upon the completion of reaction by TLC, the mixture was diluted with H2O and extracted with CH2CI2 (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude compound was purified by silica gel (60-120 mesh) column chromatography (elution with 20% EtOAc / hexane) to afford D-3 as a brown colour gum (4.70 g, yield: 38%). TLC system: EtOAc / hexane (20:80), Rfvalue = 0.3; ‘H NMR (400 MHz, CDCh) 5 ppm: 7.62 (d, J= 8.0 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J= 0.8 Hz, 1H), 7.30 (dd, J= 8.0 Hz, 1.2 Hz, 1H), 4.46 (q, J= 7.2 Hz, 2H), 3.96 (s, 2H), 3.75-3.68 (m, 2H), 2.76 (t, J= 5.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); LCMS (ESI) m / z 378.2 [C2oH3iN04Si + H]+.

[0338] Synthesis of ethyl 6-(((tert-butoxycarbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)methyl)benzofuran-2-carboxylate (D-4)

[0339] To a solution of D-3 (4.40 g, 11.7 mmol, 1.0 equiv.) in CH2CI2 (50 mL) at 0 °C, was added NEt3 (2.45 mL, 17.6 mmol, 1.5 equiv.) and (Boc)2O (3.49 mL, 15.2 mmol, 1.3 equiv.). The resultant mixture was warmed to RT and stirred at RT for 4 h. Upon the completion of reaction by TLC, the reaction mixture was diluted with H2O and extracted with CH2CI2 (2 x 70 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel (100-200 mesh) column chromatography (elution with 10% EtOAc / hexane) to afford D-4 as a pale-yellow oil (4.80 g, yield: 86%). TLC system: EtOAc / hexane (20:80), Rfvalue = 0.8; ‘H NMR (400 MHz, CDCh) 5 ppm : 7.61 (d, J= 8.4 Hz, 1H), 7.50 (s, 1H), 7.46 (br. s, 1H), 7.21-7.17 (m, 1H), 4.66 (d, J= 6.8 Hz, 2H), 4.44 (q, J= 7.2 Hz, 2H), 3.78-3.69 (m, 2H), 3.36-3.26 (m, 2H), 1.52-1.50 (d, 9H), 1.43 (t, J= 7.2 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H); LCMS (ESI) m / z 478.2 [C25H39NO6Si + H]+.

[0340] Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((2- (hydroxymethyl)benzofuran-6-yl)methyl)carbamate (D-5)

[0341] To a stirred solution of D-4 (4.50 g, 9.42 mmol, 1.0 equiv.) in CH2CI2 (50 mL) at 0 °C, was added DIBAL-H (25% in toluene) (15.9 mL, 23.6 mmol, 2.5 equiv.) drop-wise. Theresultant mixture was warmed to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with sat. NH4Q solution, filtered through a Celite bed and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by silica gel (60-120 mesh) column chromatography (elution with 15% EtOAc / hexane) to afford D-5 as a pale-yellow oil (2.90 g, yield: 66%). TLC system: EtOAc / hexane (30:70), Rfvalue = 0.3;JH NMR (400 MHz, CDCh) 5 ppm: 7.47 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.13-7.08 (m, 1H), 6.63 (s, 1H), 4.76 (s, 2H), 4.62 (s, 2H), 3.76-3.67 (m, 2H), 3.33-3.24 (m, 2H), 1.99 (br. s, 1H), 1.50-1.45 (d, 9H), 0.89 (s, 9H), 0.04 s, 6H); LCMS (ESI) m / z 436.2 [C23H37NO5Si + H]+.

[0342] Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((2- formylbenzofuran-6-yl)methyl)carbamate (D-6)

[0343] To a stirred solution of D-5 (1.50 g, 3.44 mmol, 1.0 equiv.) in CH2CI2 (30 mL) at 0 °C, was added Dess-Martin periodinane (2.92 g, 6.88 mmol, 2.0 equiv.). The resultant mixture was warmed to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with saturated aq. NaHCCh solution (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using silica gel (100-200 mesh) column (elution with 20% EtOAc / hexane) to afford D-6 as a colourless liquid (1.10 g, yield: 74%). TLC system: EtOAc / hexane (20:80), Rfvalue = 0.6;XH NMR (400 MHz, CDCh) 5 ppm: 9.88 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.28-7.26 (m, 1H), 4.71-4.69 (d, J = 6.8 Hz, 2H), 3.81-3.73 (m, 2H), 3.39-3.30 (m, 2H), 1.53-1.44 (d, 9H), 0.91 (s, 9H), 0.07 (s, 6H); LCMS (ESI) m / z 434.3 ^HssNOsSi + H]+.

[0344] Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((2-((4- chlorophenyl)(hydroxy)methyl)benzofuran-6-yl)methyl)carbamate (D-7)

[0345] To a stirred solution of D-6 (500 mg, 1.15 mmol, 1.0 equiv.) in THF (5 mL) at 0 °C, was added (4-chlorophenyl)magnesium bromide (1 M in THF, 3.45 mL, 3.45 mmol, 3 equiv.). The resultant mixture was warmed to RT and stirred at RT for 16 h. Upon the completion of reaction by TLC, the reaction mixture was diluted with H2O and extracted with CH2CI2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, filtered, and concentrated. The crude obtained was purified by silica gel (100-200 mesh) column chromatography (elution with 10% EtOAc / hexane) to afford D-7 as a gummy liquid (0.35 g, yield: 56%). TLC system: EtOAc / hexane (30:70), Rfvalue = 0.2;XH NMR (400 MHz,CDC13) 5 ppm: 7.45-7.42 (m, 3H), 7.36 (d, J= 8.8 Hz, 2H), 7.32-7.30 (m, 1H), 7.12-7.07 (m, 1H), 6.50 (s, 1H), 5.92 (d, J= 4.0 Hz, 1H), 4.61 (s, 2H), 3.75-3.67 (m, 2H), 3.31-3.23 (m, 2H), 2.57 (d, J= 4.4 Hz, 1H), 1.49-1.44 (d, 9H), 0.89 (s, 9H), 0.03 (s, 6H); LCMS (ESI) m / z 546.2 [C29H4oClN05Si + H]+.

[0346] Synthesis of 2-(((2-(4-chlorobenzyl)benzofuran-6-yl)methyl)amino)ethan-l-ol as formic acid salt (compound 13)

[0347] To a stirred solution of D-7 (350 mg, 0.64 mmol, 1.0 equiv.) in 1 : 1 MeCN / CTECh (7.0 mL) at - 40 °C, was added BF3*Et2O (0.13 mL, 1.15 mmol, 1.8 equiv.), followed by EtsSiH (0.3 mL, 1.92 mmol, 3 equiv.). The resultant mixture was allowed to stir at - 40 °C for 2 h. Upon the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (Grace column, elution with 17% MeCN / 0.1% FA in H2O) to afford the compound as a BF3 salt. This material was treated with isopropyl amine (5 equiv.) in THF (12 mL) at 40 °C and upon the absence of fluorine signal by 19F NMR, the mixture was concentrated and passed through a reverse phase column to afford compound 13 (formic acid salt) as an off-white solid (24 mg, yield: 10%). TLC system: MeOH / C^Ch (10:90), Revalue = 0.1; melting point range: 58-62 °C; 'H NMR (400 MHz, DMSO-tL) 5 ppm: 8.20 (s, 1H; HCOOH), 7.50-7.48 (m, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7.20 (d, J= 8.0 Hz, 1H), 6.60 (s, 1H), 4.15 (s, 2H), 3.89 (s, 2H), 3.49 (t, J= 5.6 Hz, 2H), 2.63 (t, J= 5.6 Hz, 2H); LCMS (ESI) m / z 316.2 [CisHisCINCh + H]+.Example 8: Synthesis of compound 33 via synthesis route Dcompound 33

[0348] Synthesis of tert-butyl ((2-(((3-hydroxycyclohexyl)amino)methyl)benzofuran-6- yl)methyl)(2-hydroxyethyl)carbamate (D-8)

[0349] Compound D-8 was obtained following the reductive amination procedure similar to that for the synthesis of compound 2, utilizing 3-aminocyclohexan-l-ol (1.5 equiv.) with NaBH4 (2.0 equiv.) and reaction conditions of 70 °C for 16 h for imine formation, and 0 °C toRT for 1 h for imine reduction. Compound D-8 was obtained in 45% yield as a brown liquid following reverse phase column chromatography (Grace column, gradient elution with 20-30% MeCN / 0.1% FA in H2O). TLC system: MeOH / CH2Cl2(10:90), Rfvalue = 0.2; LCMS (ESI) m / z 419.1 [C23H34N2O5+ H]+.

[0350] Synthesis of 3-(((6-(((2-hydroxyethyl)amino)methyl)benzofuran-2- yl)methyl)amino)cyclohexan-l-ol as bis-formic acid salt (compound 33)

[0351] To a stirred solution of D-8 (130 mg, 0.31 mmol, 1.0 equiv.) in 1,4-Dioxane (0.33 mL) at 0 °C, was added 4 M HCI in 1,4-Dioxane (0.33 mL). The resultant mixture was warmed to RT and and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (Grace column, gradient elution with 0-6% MeCN / 0.1% FA in H2O) to afford compound 33 (bis-formic acid salt) as an off-white gummy solid (52 mg, yield: 18% for 2 steps). TLC system: MeOH / CH2Cl2(10:90), Rfvalue = 0.1; 'HNMR (400 MHz, DMSO-tL) 5 ppm: 8.32 (br. s, 2H; HCOOH), 7.50-7.48 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 3.87-3.84 (m, 4H), 3.50 (t, J= 5.6 Hz, 2H), 3.36-3.31 (m, 1H), 2.86-2.84 (m, 1H), 2.67-2.63 (m, 2H), 2.44-2.40 (m, 1H), 1.82-1.73 (m, 1H), 1.65-1.62 (m, 1H), 1.49-1.37 (m, 2H), 1.18- 0.87 (m, 3H); LCMS (ESI) m / z 319.2 [Ci8H26N2O3 + H]+.Example 9: Synthesis of compound 49 via synthesis route D0 °C - RT, 2 h compound 49

[0352] Synthesis of tert-butyl (£7Z)-(2-((tert-butyldimethylsilyl)oxy)ethyl)((2-(4- fluorostyryl)benzofuran-6-yl)methyl)carbamate (D-9)

[0353] To a stirred solution of (4-fluorobenzyl)triphenylphosphonium bromide (1.17 g, 2.60 mmol, 2.5 equiv.) in dry toluene (4.5 mL) at 0 °C, was added NaH (60% in mineral oil) (104 mg, 2.60 mmol, 2.5 equiv.). The reaction mixture was warmed to RT and stirred at RT for 45 min before the reaction mixture was cooled back to 0 °C, and D-6 (450 mg, 1.04 mmol, 1.0 equiv.) was added. The resultant mixture was heated to 80 °C and stirred at 80 °C for 3 h. Upon the completion of reaction by TLC, the reaction mixture was diluted with H2O and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude obtained was purified by silica gel (60-120 mesh) column chromatography (elution with 10% EtOAc / hexane) to afford D-9 (mixture of E and Z isomers in 1 : 1 ratio) as a colourless liquid (380 mg, yield: 69%). TLC system: EtOAc / hexane (10:90), Rfvalue = 0.3; LCMS (ESI) m / z 526.4 [C3oH4oFN04Si + H]+.

[0354] Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((2-(4- fluorophenethyl)benzofuran-6-yl)methyl)carbamate (D-10)

[0355] To a stirred solution of D-9 (mixture of E and Z isomers) (300 mg, 0.57 mmol, 1.0 equiv.) in MeOH (3 mL) at 0 °C, was added NiCh’OELO (13.6 mg, 0.06 mmol, 0.1 equiv.) and NaBEL (64.7 mg, 1.71 mmol, 3.0 equiv.). The resultant mixture was warmed to RT and stirred at RT for 1 h. Upon the completion of reaction by TLC, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford D-10 as a colourless liquid (280 mg, crude). TLC system: EtOAc / hexane (10:90), Rf value = 0.3; LCMS (ESI) m / z 528.2 [C3oH42FN04Si + H]+. The crude material was taken forward to the next step without further purification.

[0356] Synthesis of 2-(((2-(4-fluorophenethyl)benzofuran-6-yl)methyl)amino)ethan-l-ol as formic acid salt (compound 49)

[0357] To a stirred solution of D-10 (270 mg, 0.51 mmol, 1.0 equiv.) in 1,4-Dioxane (3.0 mL) at 0 °C, was added 4 M HC1 in 1,4-Dioxane (1.4 mL). The resultant mixture was warmed to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the volatiles were removed and the crude obtained was purified by reverse phase column chromatography (Grace column, gradient elution with 20-25% MeCN / 0.1% FA in H2O) to afford compound 49 (formic acid salt) as an off-white solid (60 mg, yield: 33%). TLC system: MeOH / CELCh (10:90), Rfvalue = 0.2; melting point range: 49-51 °C; 'H NMR (400 MHz, DMSO-tL) 5 ppm: 8.24 (s, 1H; HCOOH), 7.51 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.19 (dd, J= 8.0 Hz, 0.8 Hz, 1H), 7.11-7.07 (m, 2H), 6.54 (s, 1H), 3.91 (s, 2H), 3.52 (t, J = 5.6 Hz, 2H),3.09-3.06 (m, 2H), 3.00-2.98 (m, 2H), 2.67 (t, J = 5.6 Hz, 2H); LCMS (ESI) m / z 314.3 [C19H20FNO2 + H]+.Example 10: Synthesis of compound 34 via synthesis route D

[0358] Synthesis of 6-(((tert-butoxycarbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)methyl)benzofuran-2-carboxylic acid (D-ll)

[0359] To a stirred solution of D-4 (300 mg, 0.63 mmol, 1.0 equiv.) in a mixture of 2: 1 : 1 THF / MeOH / H2O (2 mL) at 0 °C, was added LiOH»H2O (31.9 mg, 0.76 mmol, 1.2 equiv.). The resultant mixture was allowed to warm to RT and stirred at RT for 2 h. Upon the completion of reaction by TLC, the reaction mixture was neutralized with aq. citric acid solution and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford D-ll as a pale-yellow solid (267 mg) in its crude. TLC system: MeOH / CH2Cl2(10:90), Rfvalue = 0.4; LCMS (ESI) m / z 450.2 ^HssNOeSi + H]+. The crude compound was used in the next step without further purification.

[0360] Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)((2-(pip...

Claims

CLAIMSWhat is claimed is:

1. A compound of formula (I)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L° is -Ci-6 alkylene-NRARB, -Ci-6 alkylene-NRA-Ci-6 alkylene-RB, -Ci-6 alkylene- NRA-C3-8 cycloalkylene-RB, -Ci-6 alkylene-NRAC(O)NRARB, -Ci-6 alkylene-NRAC(O)-RB, - Ci-6 alkylene-O-Ci-6 alkylene-NRARB, -Ci-6 alkylene-O-Ci-6 alkylene-C(O)NRARB, -Ci-6 alkylene-O-Ci-6 alkylene-NRAC(O)-RB, -Ci-6 alkylene-heterocyclylene-O-Ci-6 alkyl, -C3-8 cycloalkylene-NRARB, -C(O)NRARB, -O-C1-6 alkylene-C(O)NRARB, -O-C1-6 alkylene- NRARB, -NRAC(O)RB, -NRAC(O)NRARB, or -NRAC(0)NRA-CI-6 alkylene-RB, wherein the alkylene is optionally substituted with -OH or halogen; each R1is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8 cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8 cycloalkylene, -C3-8 cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each RAis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; each RBis independently C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C3-8 hydroxycycloalkyl, C1-6 alkylene-NH2, or C1-6 alkylene-SH;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

2. The compound of claim 1, having a structure of formula (I-A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

3. The compound of claim 1, having a structure of formula (I-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

4. The compound of claim 1, having a structure of formula (I-C) or (I-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

5. The compound of claim 1 or 2, having a structure of formula (I-A-l), (I-A-2), (I-A-3), or (I-A-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

6. The compound of claim 1 or 3, having a structure of formula (I-B-l), (I-B-2), (I-B-3), or (I-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

7. The compound of claim 1 or 4, having a structure of formula (I-C-l), (I-C-2), (I-C-3), (I-C-4), (I-D-l), (I-D-2), (I-D-3), or (I-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is -(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -(Ci-6 alkylene)-N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)(Ci-6 alkylene)(Ci-6 alkoxy), -C(0)N(H)(CI-6 hydroxyalkyl), -(Ci-6 alkylene)-N(H)(C3-8 cycloalkylene)(Ci-6 alkoxy), -(Ci-6 alkylene)- N(CI-6 alkyl)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(Ci-6 alkyl)C(O)(Ci-6 alkoxy), -(Ci-6 alkylene)-N(H)C(O)N(H)(Ci-6 alkoxy), -(Ci-6 alkylene)- N(CI-6 alkyl)C(O)N(Ci-6 alkyl)(Ci-6 alkoxy), -(C3-8 cycloalkylene)N(H)(Ci-6 hydroxyalkyl), - (C3-8 cycloalkylene)N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(H)(Ci-6 hydroxyalkyl), -O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)(CI-6 hydroxyalkyl), -N(H)C(0)N(H)(CI-6 hydroxyalkyl), -N(H)C(0)N(H)(CI-6 alkylene)-(Ci-6 alkoxy), -(C1-6 alkylene)-O-(Ci-6 alkylene)C(O)N(H)(Ci-6 alkyl), -(C1-6 alkylene)-O-(Ci-6 alkylene)N(H)C(O)(Ci-6alkyl), -O-(Ci-6 alkylene)C(O)N(H)(Ci-6alkyl), -N(CI-6 alkyl)(Ci-6 hydroxyalkyl), -N(H)C(0)(CI-6 hydroxyalkyl), -N(CI-6 alkyl)C(O)(Ci-6 hydroxyalkyl), -(C1-6 alkylene)-heterocyclylene-(Ci-6 alkoxy), -(C1-6 alkylene)-O-(Ci-6 alkylene)-N(H)(Ci-6 alkyl), or -(C1-6 alkylene)-O-(Ci-6 alkylene)-N(Ci-6 alkyl)(Ci-6 alkyl), wherein the alkylene or alkyl is optionally substituted with -OH or halogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is-CH2NHCH2CH2OH,-CH2NHCH2CH(CH3)OH,-CH(CH3)NHCH2CH2OH,-CH2NHCH2CH2OCH3,-CH2NHCH2CH2OCH(CH3)2,-CH2OCH2CH2NHCH3,-CH2OCH2CH2NHCH(CH3)2,-CH2OCH2CH2N(CH3)2,-C(O)NHCH2CH2OH,-NHC(O)CH2CH2OH,-NHC(O)CH2OH,-CH2NHC(O)NHCH2CH2OH,-NHC(O)NHCH2CH2OH,-OCH2CH(OH)CH2NHCH(CH3)2,-OCH2CH2C(O)NHCH3,-CH2OCH2CH2C(O)NHCH3,-CH2OCH2CH2NHC(O)CH3,-CH2NHC(O)CH2OH,-CH2NHC(O)CH2CH2OH, or-NHC(O)NHCH2CH2OCH3,10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein L° is -CH2NHCH2CH2OH, - CH2NHCH2CH(CH3)OH, -CH2OCH2CH2NHCH3, -OCH2CH(OH)CH2NHCH(CH3)2, -11. The compound of any one of claims 1, 2, 5, and 10, having a structure of formula (I- A-l-a), (I-A-2-a), or (I-A-3-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

12. The compound of any one of claims 1, 3, 6, and 10, having a structure of formula (I-or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

13. The compound of any one of claims 1, 4, 7, and 10, having a structure of formula (I- C-l-a) or (I-D-l-a):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

14. The compound of any one of the preceding claims, wherein at least one H in L° is replaced by conjugate comprising a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid.

15. A compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:L1is C2-C50 alkylene-R5, C2-C25 alkenylene-R5, C2-C25 alkynylene-R5, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(CI-C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently -OH, C1-6 alkyl, or halogen; each R1is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently C1-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, C1-6 alkylene, -C1-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl); each R5is independently a bond, a leaving group, a protecting group, H, alkynyl, aryl, or heteroaryl;Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl;RYis C1-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

16. The compound of claim 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II- A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

17. The compound of claim 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

18. The compound of claim 15, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II-C) or (II-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

19. The compound of claim 16, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II-A-1), (II-A-2), (ILA-3), or (ILA-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

20. The compound of claim 17, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II-B-1), (II-B-2), (n-B-3), or (II-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

21. The compound of claim 18, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (II-C-1), (II-C-2), (II-C-3), (II-C-4), (II-D-1), (II-D-2), (II-D-3), or (ILD-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

22. The compound of any one of claims 15-21, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein 1-25 methylene groups of L1are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, - O-, -C(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz.

23. The compound of any one of claims 15-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L1is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene-C=CH,-O-(Ci-6alkylene)-CH(OH)-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)NH-(CH2)n- C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene-C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-arylene-NH-C(O)O-(Ci-6 alkyl), -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-NH-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(C3-8 cycloalkylene)-(Ci-6 alkylene)-NH- C(O)O-(Ci-6alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-heteroarylene-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETA,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)-HETA,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl),-O-(Ci-6alkylene)-CH(OH)-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl),-(Ci-6 alkylene)-NH(CH2CH20)m-(CH2)n-0-C6-io aryl,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-XH,-O-CH2CH(OH)-(CI-6alkylene)-NH(CH2CH2O)m-(CH2)n-C=CH, or -(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-(CH2CH2O)m-(CH2)n-C(O)O-(Ci-6 alkyl), wherein HETAis a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N or O, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-C6-io aryl, Ci-6 alkyl, -(Ci-6 alkylene)-C=CH, -NH-C(O)O-(CI-6 alkyl), -(Ci-6 alkylene)-NH-C(O)O-(Ci-6 alkyl), -Ci-6 alkoxy, -(Ci-6 alkylene)-Ci-6 alkoxy, or -arylene- C(O)O-(Ci-6alkyl);XHis halogen; each m is independently an integer of 1-12; and each n is independently an integer of 0-12.

24. The compound of claim 23, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein HETAis azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or oxetanyl optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), or -(Ci-6 alkyl)-0-C6-io aryl, -(Ci-6 alkylene)-C=CH, -NH-C(0)0-(CI-6 alkyl), -(Ci-6 alkylene)-NH- C(O)O-(Ci-6 alkyl), -O-Ci-6 alkyl, or -(Ci-6 alkylene)-O-(Ci-6 alkyl).

25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is an integer of 1-6.

26. The compound of claim 25, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein m is an integer of 1-4.

27. The compound of any one of claims 23-26, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein n is an integer of 0-8.

28. The compound of claim 23, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L1is-CH2NH-(CH2CH2O)-(CH2)2-C=CH,-CH2NH-(CH2CH2O)-(CH2)5-C=CH,-CH2NH-(CH2CH2O)-(CH2)6-C=CH,-CH2NH-(CH2CH2O)-(CH2)8-C=CH,-CH2NH-(CH2CH2O)2-(CH2)-C=CH,-CH2NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)3-(CH2)-C=CH,-CH2NH-(CH2CH2O)3-(CH2)2-C=CH,-O-CH2-CH(OH)-CH2-NH-(CH2CH2O)2-(CH2)2-C=CH,-CH2NH-(CH2CH2O)-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)3-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)5-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)6-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)-(CH2)8-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)2-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)3-(CH2)2-NHC(O)OC(CH3)3,-CH2NH-(CH2CH2O)3-(CH2)3-NCH3C(O)OC(CH3)3,-CH2NH-(CH2CH2O)4-(CH2)3-NCH3C(O)OC(CH3)3,-CH2NH-(CH2CH2O)2-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)2-(CH2)3-NHCH3,-CH2NH-(CH2CH2O)3-(CH2)2-NHCH3,-CH2NH-(CH2CH2O)2-(CH2)2-C(O)NH-CH3,-CH2NH-(CH2CH2O)-(CH2)-C(O)NH-(CH2)-C(O)OCH2CH3,-CH2NH-(CH2CH2O)2-(CH2)2-C(O)OCH3,-CH2NH-(CH2CH2O)3-(CH2)2-C(O)OCH3,-CH2NH(CH2CH2O)-(CH2)-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)2-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)3-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)4-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)5-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)8-C(O)OC(CH3)3,-CH2NH(CH2CH2O)2-(CH2)2-C(O)OC(CH3)3,-CH2NH(CH2CH2O)-(CH2)-(CH2CH2O)-(CH2)-C(O)OC(CH3)3,-O-CH2-CH(OH)-CH2NH-(CH2CH2O)-(CH2)2-C(O)OCH3,-CH2NH-(CH2CH2O)-(CH2)3-C1, or-O-CH2CH(OH)-CH2-NH(CH2CH2O)-(CH2)2-C(O)OCH3.

29. The compound of any one of claims 15-22, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L1comprises a bivalent moiety selected from:or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof, wherein:A is a ligand that binds to a protein, a protein aggregate, a protein complex, or a lipid;L2is C2-C50 alkylene, C2-C25 alkenylene, C2-C25 alkynylene, or -(C2-C50 alkylene)- arylene, wherein 1-25 methylene groups of L2are optionally and independently replaced by -N(H)-, -N(CI-C6alkyl)-, -N(C3-C8cycloalkyl)-, -O-, -C(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2-, - S(O)2N(CI-C6alkyl)-, -S(O)2N(C3-C8cycloalkyl)-, -N(H)C(O)-, -N(CI-C6alkyl)C(O)-, - N(C3-C8cycloalkyl)C(O)-, -N(H)C(O)N(H)-, -N(CI-C6alkyl)C(O)N(H)-, -N(H)C(O)N(Ci- C6alkyl)-, -N(CI-C6alkyl)C(O)N(Ci-C6alkyl)-, -C(O)N(H)-, -C(O)N(CI-C6alkyl)-, - C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, C3-C8cycloalkylene, or C3-C8cycloalkenylene, wherein the alkylene, alkenylene, alkynylene, alkyl, arylene, heteroarylene, and heterocyclylene are each optionally and independently substituted with 1, 2, or 3 Rz, wherein each Rzis independently OH, Ci-6 alkyl, or halogen; each R1is independently Ci-6 alkyl, C3-C8cycloalkyl, or halogen; each R2is independently Ci-6 alkyl, C3-C8cycloalkyl, or halogen;X1is O or S; one of X2or X3is C-Q-R3and the other is CH, C, or N as permitted by valency;Q is absent, Ci-6 alkylene, -Ci-6 alkylene-C(O)-, C3-8cycloalkylene, -C3-8cycloalkylene-C(O)-, -C(O)-, or -S(O)2-;R3is carbocycle, heterocycle, aryl, heteroaryl, or -NRXRY, wherein the carbocycle, heterocycle, aryl, and heteroaryl are each optionally substituted with 1, 2, or 3 R4; each R4is independently halogen, -OH, Ci-6 alkyl, Ci-6 alkoxy, -C(O)-NRXRY, or - C(O)O-(Ci-6alkyl);Rxis H, Ci-6 alkyl, Ci-6 haloalkyl, or Ci-6 hydroxyalkyl;RYis Ci-6 alkyl, C3-8cycloalkyl, C3-8hydroxycycloalkyl, aryl, or heterocycle; a is an integer of 0-3; and b is an integer of 0 or 1.

31. The compound of claim 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III- A):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

32. The compound of claim 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III-B):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

33. The compound of claim 30, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III-C) or (III-D):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

34. The compound of claim 31, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III-A-1), (III-A- 2), (III-A-3), or (III-A-4):

35. The compound of claim 32, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III-B-1), (III-B- 2), (III-B-3), or (III-B-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

36. The compound of claim 33, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the compound has a structure of formula (III-C-1), (III-C- 2), (III-C-3), (III-C-4), (III-D-1), (III-D-2), (III-D-3), or (III-D-4):or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof.

37. The compound of any one of claims 31-36, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein 1-25 methylene groups of L2are optionally and independently replaced by -N(H)-, -N(Ci-Ce alkyl)-, -N(C3-C8cycloalkyl)-, - O-, -C(O)-, -C(O)O-, -N(H)C(O)-, -N(C1-C6alkyl)C(O)-, -N(C3-C8cycloalkyl)C(O)-, - C(O)N(H)-, -C(O)N(Ci-Ce alkyl)-, -C(O)N(C3-C8cycloalkyl)-, arylene, heteroarylene, heterocyclylene, or C3-C8cycloalkylene, wherein each arylene or heteroarylene is optionally and independently substituted with 1 or 2 Rz.

38. The compound of any one of claims 30-37, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-N(Ci-6 alkyl)-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-NH-C(O)-(Ci-6 alkylene)-©-,-(Ci-6 alkylene)-NH(CH2CH2O)m-(CH2)n-HETB-, or-(Ci-6 alkylene)-N(H)(CH2CH2O)m-(CH2)n-HETB-(Ci-6 alkylene)-, wherein HETBis a 4-10 membered heterocyclylene containing 1-3 N, and is optionally substituted with -C(O)-(Ci-6 alkyl), -C(O)O-(Ci-6 alkyl), -(Ci-6 alkyl)-0-Ce-io aryl, or Ci-6 alkyl; m is an integer of 1-12; and n is an integer of 0-6.

39. The compound of any one of claims 30-38, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:-(CH2)-NH(CH2CH2O)-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)2-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NCH3-,-(CH2)-NH(CH2CH2O)3-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)4-(CH2)3-NCH3-,-(CH2)-NH(CH2CH2O)3-,-(CH2)-NH(CH2CH2O)4-,-(CH2)-NH(CH2CH2O)3-(CH2)2-NH-C(O)CH2-O-,-(CH2)-NH(CH2CH2O)3-(CH2)2-,-(CH2)-NH(CH2CH2O)3-(CH2)3-,40. The compound of any one of claims 30-37, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein L2is:

41. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein that is associated with cancer.

42. The compound of claim 41, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein associated with cancer comprises a mutation or a fusion.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein associated with cancer is BRD4.

44. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein associated with a metabolic disease.

45. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a protein associated with inflammation.

46. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is present in bacteria.

47. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is present in a virus particle.

48. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein aggregate is a Tau protein aggregate, an alpha-synuclein protein aggregate, a P-sheet protein aggregate, a mutant Huntingtin protein aggregate, an amyloid protein aggregate, or a TDP-43 protein aggregate.

49. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is a mitochondrial protein.

50. The compound of any one of claims 30-40, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein the protein is an intracellular protein.

51. The compound of any one of claims 30-40, wherein A is aryl, arylene-heteroaryl, arylene, heteroarylene, aryl, heteroarylene-aryl, heteroarylene-heteroaryl, heteroarylene- heteroarylene-heteroaryl, heterocyclylene-aryl, heterocyclylene-heteroaryl, heteroarylene- NC(O)-heteroaryl, heteroarylene-N=N-aryl, or arylene-(arylalkyl)-OC(O)-hetercyclyl- C(O)Ci-ealkylene-aryl, each of which is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, Ci-6 alkyl, O-Ci-6 alkyl, NH2, NH(CI-6 alkyl), N(CI-6 alkyl)2, -(CH2)I-4C(O)NH2, -(CH2)I-4C(O)NH(CI-6 alkyl), or -(CH2)I-4C(O)N(CI-6 alkyl)2.

52. The compound of any one of claims 30-40 and 51, wherein A iseach R1is independently H or Ci-6 alkyl;R11and R111are each independently F, Cl, or Ci-6 alkyl;R1Vis Ci-6 alkyl;Rvuis H, F, CF3, or C1-6 alkyl; and M is CH or N.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independent halogen.

54. The compound of claim 53, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is -F or -Cl.

55. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independently Ci-6 alkyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is independently C1-3 alkyl.

57. The compound of claim 55 or 56, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R1is methyl.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein a is 0 or 1.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is independently C1-6 alkyl.

60. The compound of claim 59, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is independently C1-3 alkyl.

61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R2is methyl.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein b is 0 or 1.

63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is absent, Ci-4 alkylene, -(C1-3 alkylene)C(O)-, C3-6 cycloalkylene, -(C3-6 cycloalkylene)C(O)-, -C(O)-, or -S(O)2-.

64. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is absent.

65. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2-, -CH2CH2-, -CH(CH3)-, or -C(CH3)2-.

66. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2-.

67. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2CH2-.

68. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -C(O)-.

69. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -S(O)2-.

70. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is71. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is -CH2C(O)-.

72. The compound of claim 63, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is C3-8 carbocycle, 3-10 membered heterocycle, Ce-io aryl, 5-10 membered heteroaryl, or -NRXRY, wherein the C3-8 carbocycle, 3- 8 membered heterocycle, Ce-io aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 R4, and each R4is independently halogen, -OH, C1-6 alkyl, C1-6 alkoxy, -C(O)-NRXRY, or -C(O)O-Ci-6 alkyl, and wherein Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6hydroxyalkyl, and RYis Ci-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle.

74. The compound of claim 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is Ce-io aryl optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, Ci-6 alkyl, Ci-6 alkoxy, or -C(O)-NRXRY.

75. The compound of claim 74, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is Ce-io aryl optionally substituted with -F, -Cl, C1-3 alkoxy, or -C(O)-NRXRY, wherein Rxis H or C1-6 alkyl, and RYis C1-6 alkyl.

76. The compound of claim 74 or 75, or a pharmaceutically acceptable salt, a77. The compound of any one of claims 74-76, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is78. The compound of claim 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is 5-10 membered heteroaryl optionally substituted with 1 or 2 R4; and wherein the heteroaryl contains 1 or 2 heteroatoms selected from N, S, or O.

79. The compound of claim 78, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3isoptionally substituted with one R4.

80. The compound of claim 78 or 79, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is81. The compound of claim 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is C3-8 carbocycle optionally substituted with 1 or 2 R4, and wherein each R4is independently halogen, -OH, C1-6 alkyl, or C1-6 alkoxy.

82. The compound of claim 81, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is, each optionally substituted with one or two R4.

83. The compound of claim 81 or 82, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein84. The compound of claim 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is 3-10 membered heterocycle containing 1 or 2heteroatoms selected from N, O, or S, and the heterocycle is optionally substituted with 1 or 2 R4, and wherein each R4is independently -OH, C1-6 alkyl, or -C(O)O-(Ci-6 alkyl).

85. The compound of claim 84, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein each R4is independently -OH, C1-3 alkyl, or -C(O)O-(Ci-s alkyl).

86. The compound of claim 84 or 85, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is87. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is88. The compound of claim 73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is -NRXRY, and wherein Rxis H, C1-6 alkyl, C1-6 haloalkyl, or C1-6 hydroxyalkyl, and RYis C1-6 alkyl, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, aryl, or heterocycle.

89. The compound of claim 88, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Rxis H, or methyl, and RYis methyl, -CH(CH3)2,90. The compound of claim 88 or 89, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein R3is91. The compound of any one of claims 1-64 and 73-90, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein Q is absent, and R3is92. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt, a93. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein -Q-R3is94. The compound of any one of claims 1-73 and 92-93, or a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof, wherein -Q-R3is95. The compound of any one of claims 1, 2, and 5, wherein the compound of formula (I)or a pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof.

96. The compound of any one of claims 1, 3, and 6, wherein the compound of formula (I)or a pharmaceutically acceptable salt or deuterated form thereof.

97. The compound of any one of claims 1, 4, and 7, wherein the compound of formula (I)or a pharmaceutically acceptable salt or deuterated form thereof.

98. The compound of claim 15, wherein the compound of formula (II) isor a pharmaceutically acceptable salt, a stereoisomer, or deuterated form thereof.

99. The compound of claim 30, wherein the compound of formula (III) isor a pharmaceutically acceptable salt, or deuterated form thereof.

100. A method of modulating autophagy in a subject, comprising administering to the subject a compound of any one of the preceding claims.

101. The method of claim 100, wherein the compound contacts p62.

102. The method of claim 101, wherein the compound increases activity of p62, thereby causing autophagy.

103. The method of claim 101, wherein the compound decreases activity of p62, thereby reducing autophagy.

104. The method of claim 100, wherein the compound contacts NBR1.

105. The method of claim 104, wherein the compound increases activity of NBR1, thereby causing autophagy.

106. The method of claim 104, wherein the compound decreases activity of NBR1, thereby reducing autophagy.

107. A method of degrading a target protein in a subject in need thereof, comprising administering a compound of any one of the preceding claims.

108. A method of inducing autophagy in a subject in need thereof, comprising administering a compound of any one of the preceding claims.

109. The method of claim 108, wherein the compound contacts p62, thereby inducing autophagy.

110. The method of claim 108, wherein the compound contacts NBR1, thereby inducing autophagy.

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