STAT6 degraders and uses thereof

Abstract

The present disclosure provides compounds, compositions, and methods of using the same.

Description

STAT6 DEGRADERS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 684,019, filed August 16, 2024; U.S. Provisional Application No. 63 / 767,549, filed March 5, 2025; and U.S. Provisional Application No. 63 / 767,560, filed March 5, 2025, each of which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to compounds and methods useful for the modulation of signal transducer and activator of transcription 6 (“STAT6”) via ubiquitination and / or degradation by compounds according to the present disclosure. The present disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present disclosure and methods of using said compositions in the treatment of various disorders. BACKGROUND

[0003] Ubiquitin-Proteasome Pathway (UPP) or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews, C., Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth, J.S. Jr., Chembiochem, 2005, 6(l):40-46).

[0005] Signal transducer and activator of transcription 6 (STAT6 or Interleukin-4-Stat / IL4-STAT) is an undruggable transcription factor belonging to the structurally conserved Signal Transducer and Activator of Transcription (STAT) family of proteins (STAT1 through STAT6). Activationof STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

[0006] STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4 / IL- 13-mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells (Hebenstreit et al. "Signaling mechanisms, interaction partners, and target genes of STAT6." Cytokine & growth factor reviews 17.3 (2006): 173-188; Chapoval et al. "Regulation of the T helper cell type 2 (Th2) / T regulatory cell (Treg) balance by IL‐4 and STAT6." Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin-4 (IL4) and interleukin-13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema (Goenka and Kaplan. "Transcriptional regulation by STAT6." Immunologic research 50.1 (2011): 87-96.). There is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases and cancers (Glosson et al. "Wheezing and itching: The requirement for STAT proteins in allergic inflammation." Jak-Stat 1.1 (2012): 3-15; Loh et al. "Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication." Frontiers in oncology 9 (2019): 48). As such, small molecule compounds that leverage E3 ligase mediated protein degradation to target disease-associated proteins such as STAT6 hold promise as therapeutic agents. SUMMARY

[0007] The present disclosure relates to novel bifunctional compounds, which function to recruit STAT6 protein to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of STAT6 protein, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. Also provided are monovalent compounds, which find utility as inducers of targeted ubiquitination of STAT6 protein, which are then degraded and / or otherwise inhibited by the monovalent compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of STAT6 protein. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as inflammatory disorders.

[0008] The present application further relates to targeted degradation of STAT6 protein through the use of bifunctional molecules, including bifunctional molecules that link a cereblon or VHL binding moiety to a ligand that binds STAT6 protein.

[0009] Compounds described herein, and pharmaceutically acceptable compositions thereof, are effective as degraders of STAT6 protein.

[0010] Disclosed herein, in some embodiments, is a compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0011] Disclosed herein, in some embodiments, is a compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] Disclosed herein, in some embodiments, is a compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0013] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0014] Disclosed herein, in some embodiments, is a compound of Formula II:Formula II, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0015] Disclosed herein, in some embodiments, is a compound of Formula III:Formula III, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0016] Disclosed herein, in some embodiments, is a compound of Formula IV:Formula IV, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0017] Disclosed herein, in some embodiments, is a compound of Formula V:Formula V, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0018] Disclosed herein, in some embodiments, is a compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0019] Disclosed herein, in some embodiments, is a compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0020] Disclosed herein, in some embodiments, is a compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0021] Disclosed herein, in some embodiments, is a compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0022] Disclosed herein, in some embodiments, is a compound of Formula M-II:Formula M-II, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0023] Disclosed herein, in some embodiments, is a compound of Formula M-III:Formula M-III, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0024] Disclosed herein, in some embodiments, is a compound of Formula M-IV:Formula M-IV, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0025] Disclosed herein, in some embodiments, is a compound of Formula M-V:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0026] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0027] Compounds disclosed herein are also useful for the study of STAT6 protein in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new STAT6 inhibitors or STAT6 degraders or other regulators of cell cycling, metastasis, angiogenesis, and immune cell evasion, in vitro or in vivo. DETAILED DESCRIPTION

[0028] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’- A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, Formula M-V, and subformulas thereof, and compounds of Table 1, and compounds of Table 2, and pharmaceutically acceptable salts thereof), compositions comprising said compounds, and methods useful for treating diseases or disorders (e.g., cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone- related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder).

[0029] Compounds disclosed herein, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, Formula M-V, and subformulas thereof, and compounds of Table 1, and compounds of Table 2, and pharmaceutically acceptable salts thereof), and compositions comprising said compounds are useful as degraders and / or inhibitors of STAT6 protein. In some embodiments, a provided compound degrades STAT6. In someembodiments, a provided compound inhibits STAT6. In some embodiments, a provided compound degrades and inhibits STAT6. Definitions

[0030] As used herein, the following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0031] Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0032] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is substituted or unsubstituted and is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0033] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge and issubstituted or unsubstituted. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0034] The term “lower alkyl” refers to a C1-4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0035] The term “haloalkyl” refers to a C1-6 straight or branched alkyl group that is substituted with one or more halogen atoms and “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms. The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0036] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0037] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0038] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0039] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:.

[0040] The term “halogen” means –F, –Cl, –Br, or –I.

[0041] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl). Unless otherwise specified, an aryl is optionally substituted with one or more substituents.

[0042] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0043] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). Unless otherwise specified, a heterocyclyl is optionally substituted with one or more substituents.

[0044] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, aheterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0045] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0046] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned in the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0047] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4S R°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; –(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – (CH2)0–4P(O)2R°; –(CH2)0–4P(O)R°2; –(CH2)0–4OP(O)R°2; –(CH2)0–4OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2,wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0048] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2Rl, –(haloRl), –(CH2)0–2OH, –(CH2)0–2ORl, –(CH2)0–2CH(ORl)2; -O(haloRl), –CN, –N3, –(CH2)0–2C(O)Rl, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)ORl, –(CH2)0–2SRl, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHRl, –(CH2)0–2NRl2, –NO2, –SiRl3, –OSiRl3, -C(O)SRl, –(C1–4 straight or branched alkylene)C(O)ORl, or –SSRlwherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0049] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Suitable substituents on the aliphatic group of R*include halogen, –Rl, -(haloRl), -OH, – ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or –NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include , – C(O)CH2wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the aliphatic group of R†are independently halogen, – Rl, -(haloRl), –OH, –ORl, –O(haloRl), –CN, –C(O)OH, –C(O)ORl, –NH2, –NHRl, –NRl2, or -NO2, wherein each Rlis unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0054] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0055] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0056] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits STAT6 protein with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0057] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in STAT6 protein activity between a sample comprising a compound of the present disclosure, or composition thereof, and STAT6 protein, and an equivalent sample comprising STAT6 protein, in the absence of said compound, or composition thereof.

[0058] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. In some embodiments, a “reference” sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant comparison. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.Compounds

[0059] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0060] Compounds disclosed herein, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, Formula M-V, and subformulas thereof, and compounds of Table 1, and compounds of Table 2, and pharmaceutically acceptable salts thereof), and compositions comprising said compounds are useful for treating diseases or disorders (e.g., cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder).

[0061] Compounds disclosed herein, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, Formula M-V, and subformulas thereof, and compounds of Table 1, and compounds of Table 2, and pharmaceutically acceptable salts thereof), and compositions comprising said compounds are useful as degraders and / or inhibitors of STAT6 protein. In some embodiments, a provided compound degrades STAT6. In some embodiments, a provided compound inhibits STAT6. In some embodiments, a provided compound degrades and inhibits STAT6. Formula I’’-A’’ and Related Formulas Formula I’’-A’’

[0062] Disclosed herein, in some embodiments, is a compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms;Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4. Formula I’-A’

[0063] Disclosed herein, in some embodiments, is a compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2;Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4. Formula I’

[0064] Disclosed herein, in some embodiments, is a compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms;Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4. Formula I

[0065] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6 haloalkyl;each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1;y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6. Formula II

[0001] Disclosed herein, in some embodiments, is a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-A

[0002] Disclosed herein, in some embodiments, is a compound of Formula II-A:Formula II-A, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-A-1

[0003] Disclosed herein, in some embodiments, is a compound of Formula II-A-1:Formula II-A-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-A-2

[0004] Disclosed herein, in some embodiments, is a compound of Formula II-A-2:Formula II-A-2, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-A-3

[0005] Disclosed herein, in some embodiments, is a compound of Formula II-A-3:Formula II-A-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-A-4

[0006] Disclosed herein, in some embodiments, is a compound of Formula II-A-4:Formula II-A-4, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula II-B

[0007] Disclosed herein, in some embodiments, is a compound of Formula II-B:Formula II-B, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula III

[0008] Disclosed herein, in some embodiments, is a compound of Formula III:Formula III, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula IV

[0009] Disclosed herein, in some embodiments, is a compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula V

[0010] Disclosed herein, in some embodiments, is a compound of Formula V:Formula V, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. STAT6 Binding Moiety (SBM)

[0011] Disclosed herein, in some embodiments, is a compound of Formula I’’-A’’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] Disclosed herein, in some embodiments, is a compound of Formula I’-A’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0013] Disclosed herein, in some embodiments, is a compound of Formula I’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0014] Disclosed herein, in some embodiments, is a compound of Formula I having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0015] Disclosed herein, in some embodiments, is a compound of Formula II having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0016] Disclosed herein, in some embodiments, is a compound of Formula III having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0017] Disclosed herein, in some embodiments, is a compound of Formula IV having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0018] Disclosed herein, in some embodiments, is a compound of Formula V having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0019] Disclosed herein, in some embodiments, is a compound of Formula II-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0020] Disclosed herein, in some embodiments, is a compound of Formula II-A-1 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0021] Disclosed herein, in some embodiments, is a compound of Formula II-A-1 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0022] Disclosed herein, in some embodiments, is a compound of Formula Formula II-A-2 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0023] Disclosed herein, in some embodiments, is a compound of Formula II-A-2 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0024] Disclosed herein, in some embodiments, is a compound of Formula II-A-3 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0025] Disclosed herein, in some embodiments, is a compound of Formula II-A-4 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0026] Disclosed herein, in some embodiments, is a compound of Formula II-B having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. LE

[0027] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent.

[0028] In some embodiments, G is –NRNG–.

[0029] In some embodiments, RN6and RNGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0030] In some embodiments, G is –(CRC7RCG)1-2.

[0031] In some embodiments, RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. RE1

[0032] In some embodiments, RE1is optionally substituted monocyclic ring selected from 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)-NRN1RN2, or –NRN3C(O)RC1.

[0033] In some embodiments, RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6cycloalkoxy, C1-C6amine, and C1-C6haloalkyl.

[0034] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, or – NRN3C(O)RC1, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0035] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0036] In some embodiments, RE1is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0037] In some embodiments, RE1is 6-membered heteroaryl with 1-3 nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from C1-C6 alkyl, and C1-C6haloalkyl.

[0038] In some embodiments, RE1is 5-membered heterocyclyl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0039] In some embodiments, RE1is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0040] In some embodiments, RE1is 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0041] In some embodiments, RE1is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0042] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, – C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3NRN3C(O)NRN1RN2.

[0043] In some embodiments,.

[0044] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl.

[0045] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0047] In some embodiments, Ring F2 is selected from the group consisting of 4- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0048] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0049] In some embodiments, Ring F2 is selected from the group consisting of 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0050] In some embodiments, d is 0. In some embodiments, d is 1, 2, 3, 4, 5, or 6. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5. In some embodiments, d is 6.

[0051] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)- NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0052] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)- NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0053] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0054] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0055] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0056] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0057] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0058] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0059] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0060] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0061] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0062] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0063] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0064] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0065] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0066] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0067] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0068] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0069] In some embodiments,is selected from the group consisting of ,,,d.

[0070] In some embodiments,is selected from the group consisting of

[0072] In some embodiments,is selected from the group consisting of,

[0073] In some embodiments,is selected from the group consisting of,,

[0075] In some embodiments,is selected from the group consisting of,

[0076] In some embodiments,is selected from the group consisting of,[.some embodiments,some embodiments, RE1is. , .

[0088] In some embodiments, RE1is:.

[0089] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0090] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0091] In some embodiments,.

[0092] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4cycloalkylene.

[0093] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form 3- to 5-membered heterocyclylene with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments,.

[0095] In some embodiments, RE1is CRC4RC5RC6.

[0096] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C4 cycloalkylene.

[0097] In some embodiments, RC6is cyano or C1-C3haloalkyl.

[0098] In some embodiments, RC4and RC5together form, wherein RD2aand RD2bare each independently hydrogen and C1-C6alkyl.

[0099] In some embodiments, RC6is halogen.

[0101] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0102] In some embodiments, RE1is optionally substituted. In some embodiments, RE1is optionally substituted.

[0103] In some embodiments, RE1is optionally substituted , , or.

[0104] In some embodiments,

[0105] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0106] In some embodiments, RE1is optionally substituted, ,wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0108] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0109] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, RE1. In some embodiments, RE1is optionally substituted, where Wmis as described above and defined herein. In some embodiments,. In some embodiments, RE1is optionally substituted . In some embodiments, RE1is . In some embodiments, RE1is. so e e o e s, s .

[0111] In some embodiments, RE1is an optionally substituted ring selected from:

[0112] In some embodiments, RE1is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0113] In some embodiments, RE1is:Ring E2

[0114] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0115] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0116] In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0117] In some embodiments, Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

[0118] In some embodiments, Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl. In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is optionally substituted pyridinyl.

[0119] In some embodiments, Ring, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; represents a bond to Ring E; a is 0, 1, 2, 3, 4, 5, or 6; and each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0120] In some embodiments, Ring E2 is phenyl.

[0121] In some embodiments, Ring E2 is 6-membered monocyclic carbocyclyl.

[0122] In some embodiments, Ring E2 is 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 5-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0123] In some embodiments, Ring E2 is 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms.

[0124] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0125] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0126] In some embodiments, Ring E2 is selected from the group consisting of phenyl, cyclohexyl, cyclohexenyl, pyrazole, and pyridinyl.

[0127] In some embodiments, a is 0.

[0128] In some embodiments, a is 1, 2, 3, or 4. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0129] In some embodiments, each RAis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1.

[0130] In some embodiments, each RAis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0131] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0132] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0133] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0134] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0135] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0136] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0137] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0138] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et,or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0139] In some embodiments, each RAis independently selected from the group consisting of –F, cyano, and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0140] In some embodiments, each RAis independently selected from the group consisting of –F and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0141] In some embodiments,, wherein represents a bond to Ring E.,wherein represents a bond to Ring E.

[0143] The compound of any one of claims 1-15, wherein Ring,w ere n represents a bond to Ring E . Ring E

[0144] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0145] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, Ring E is optionally substituted phenyl. In some embodiments, Ring E is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0147] In some embodiments, Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl.

[0148] In some embodiments, Ring, wherein Ring E is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;represents a bond to LE; b is 0, 1, 2, 3, 4, 5, or 6; each RBis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –(C1-C6 alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1; or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0149] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0150] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0151] In some embodiments, Ring E is phenyl. In some embodiments, Ring E is 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0152] In some embodiments, Ring E is selected from the group consisting of phenyl, pyridinyl, and piperidinyl.

[0153] In some embodiments, b is 0.

[0154] In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4.

[0155] In some embodiments, each RBis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0156] In some embodiments, each RBis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0157] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0158] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0159] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0160] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0161] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0162] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0163] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0164] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and – CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0165] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0166] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0167] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0168] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et,or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0169] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et.

[0170] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et. r ,,r, wherein represents a bond to LE.wherein represents a bond to LE. ,,wherein represents a bond to LE.wherein represents a bond to LE.y2

[0179] In some embodiments, y2 is 0. In some embodiments, y2 is 1. e2

[0180] In some embodiments, e2 is 0. In some embodiments, e2 is 1. In some embodiments, e2 is 2. In some embodiments, e2 is 3. In some embodiments, e2 is 4. In some embodiments, e2 is 5. In some embodiments, e2 is 6. RE14

[0181] In some embodiments, each RE14is independently halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy.

[0182] In some embodiments, each RE14is independently halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy.

[0183] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0184] In some embodiments, each each RE14is independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1- C6 hydroxyalkyl, –(C1-C6 alkyl)-NRN1RN2, and –(C1-C6 alkyl)-ORO1.

[0185] In some embodiments, each RE14is independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0186] In some embodiments, each RE14is independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0187] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0188] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0189] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0190] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0191] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3.

[0192] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and –CH2CF3.

[0193] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0194] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0195] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0196] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0197] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0198] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et. y1

[0199] In some embodiments, y1 is 0. In some embodiments, y1 is 1. Ring E1

[0201] In some embodiments, Ring E1, along with its RE8and R13substituents,.

[0202] In some embodiments, Ring E1, along with its RE8and R13substituents, is ,,, , , ,,,

[0203] In some embodiments, Ring E1, along with its RE8and R13substituents, is ,or.

[0204] In some embodiments, Ring E1, along with its RE8and R13substituents, is

[0205] In some embodiments, e1 is 0. In some embodiments, e1 is 1. In some embodiments, e1 is 2. In some embodiments, e1 is 3. In some embodiments, e1 is 4. RE8

[0206] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)NRE9RE10or –NRE11C(O)RE12.

[0207] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0208] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 3- to 7- membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0209] In some embodiments, RE8is optionally substituted. In someembodiments, RE8isoptionally substituted.

[0210] In some embodiments, RE8is optionally substituted, , or

[0212] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0213] In some embodiments, RE8is optionally substituted, ,, wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0215] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0216] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0217] In some embodiments, RE8is. In some embodiments, RE8is optionally substituted, where Wmis as described above and defined herein. In some embodiments,. In some embodiments, RE8is optionally substituted. , . In some embodiments, RE8is. , .

[0218] In some embodiments, RE8is an optionally substituted ring selected from: ,

[0219] In some embodiments, RE8is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0220] In some embodiments, RE8is:RE9

[0221] In some embodiments, RE9is hydrogen. In some embodiments, RE9is C1-C6 alkyl. In some embodiments, RE9is optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0222] In some embodiments, RE10is hydrogen. In some embodiments, RE10is C1-C6alkyl. RE11

[0223] In some embodiments, RE11is hydrogen. In some embodiments, RE11is C1-C6 alkyl. RE12

[0224] In some embodiments, RE12is C1-C6alkyl. In some embodiments, RE12is C1-C6haloalkyl.

[0225] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, – S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0226] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, – S(O)2NRN1RN2, –NRN3S(O)2RC2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, or – NRN3C(O)RC3. RN1and RN2

[0227] In some embodiments, each of RN1and RN2is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0228] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0229] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0230] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6haloalkyl.

[0231] In some embodiments, RN1is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0232] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0233] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0234] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0235] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0236] In some embodiments, RN1is hydrogen or –Me.

[0237] In some embodiments, RN1is hydrogen.

[0238] In some embodiments, RN1is –Me.

[0239] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0240] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0241] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0242] In some embodiments, RN2is selected from the group consisting of hydrogen and C1-C6alkyl.

[0243] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0244] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0245] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0246] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0247] In some embodiments, RN2is hydrogen or –Me.

[0248] In some embodiments, RN2is hydrogen.

[0249] In some embodiments, RN2is –Me.

[0250] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0251] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0252] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0253] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0254] In some embodiments, RN3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0255] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0256] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0257] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0258] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0259] In some embodiments, RN3is hydrogen or –Me.

[0260] In some embodiments, RN3is hydrogen.

[0261] In some embodiments, RN3is –Me. RN4

[0262] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0263] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0264] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0265] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6haloalkyl.

[0266] In some embodiments, RN4is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0267] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0268] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0269] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0270] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0271] In some embodiments, RN4is hydrogen or –Me.

[0272] In some embodiments, RN4is hydrogen.

[0273] In some embodiments, RN4is –Me. RN5

[0274] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0275] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0276] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0277] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6haloalkyl.

[0278] In some embodiments, RN5is selected from the group consisting of hydrogen and C1-C6alkyl.

[0279] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0280] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0281] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0282] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0283] In some embodiments, RN5is hydrogen or –Me.

[0284] In some embodiments, RN5is hydrogen.

[0285] In some embodiments, RN5is –Me. RN7

[0286] each of RN1, RN2, RN3, and RN4is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0287] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0288] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0289] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0290] In some embodiments, RN7is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0291] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0292] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0293] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0294] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0295] In some embodiments, RN7is hydrogen or –Me.

[0296] In some embodiments, RN7is hydrogen.

[0297] In some embodiments, RN7is –Me.RC3

[0298] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0299] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0300] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0301] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0302] In some embodiments, RC3is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0303] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0304] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0305] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0306] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0307] In some embodiments, RC3is hydrogen or –Me.

[0308] In some embodiments, RC3is hydrogen.

[0309] In some embodiments, RC3is –Me. RD1

[0310] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0311] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0312] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0313] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0314] In some embodiments, RD1is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0315] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0316] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0317] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0318] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0319] In some embodiments, RD1is hydrogen or –Me.

[0320] In some embodiments, RD1is hydrogen.

[0321] In some embodiments, RD1is –Me. Ligase Binding Moiety (LBM)

[0322] In some embodiments, DIM is LBM. In some embodiments, LBM is an E3 ligase ligand well known to one of ordinary skill in the art including those described in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017 / 176708, US 2017 / 0281784, WO 2017 / 161119, WO 2017 / 176957, WO 2017 / 176958, WO 2015 / 160845, US 2015 / 0291562, WO 2016 / 197032, WO 2016 / 105518, US 2018 / 0009779, WO 2017 / 007612, 2018 / 0134684, WO 2013 / 106643, US 2014 / 0356322, WO 2002 / 020740, US 2002 / 0068063, WO 2012 / 078559, US 2014 / 0302523, WO 2012 / 003281, US 2013 / 0190340, US 2016 / 0022642, WO 2014 / 063061, US 2015 / 0274738, WO 2016 / 118666, US 2016 / 0214972, WO 2016 / 149668, US 2016 / 0272639, WO 2016 / 169989, US 2018 / 0118733, WO 2016 / 197114, US 2018 / 0147202, WO 2017 / 011371, US 2017 / 0008904, WO 2017 / 011590, US 2017 / 0037004, WO 2017 / 079267, US 2017 / 0121321, WO 2017 / 117473, WO 2017 / 117474, WO 2013 / 106646, WO 2014 / 108452, WO 2017 / 197036, US 2019 / 0076540, WO 2017 / 197046, US 2019 / 0076542, WO2017 / 197051, US 2019 / 0076539, WO 2017 / 197055, US 2019 / 0076541, and WO 2017 / 197056, the entirety of each of which is herein incorporated by reference.

[0323] In certain embodiments, the present disclosure provides a compound of Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula II-A, Formula II-A-1, Formula II-A-2, Formula II-A-3, Formula II-A-4, Formula II-B, Formula III, Formula IV, or Formula V, wherein LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; and m is 0, 1, 2, 3 or 4.

[0324] As defined above and described herein, X1is a covalent bond, -CR2-, -SO2-, -S(O)-, -In some embodiments, X1is a covalent bond. In some embodiments, X1is -CR2-. In some embodiments, X1is -SO2-. In some embodiments, X1is -S(O)-. In some embodiments, X1is -P(O)R-. In some embodiments, X1is - P(O)OR-. In some embodiments, X1is -P(O)N(R)2-. In some embodiments, X1is -C(O)-. In someembodiments, X1is -C(S)-, or . In some embodiments, X1is -CH2-. In some embodiments, X1is -C(O)-.

[0325] In some embodiments, LBM is selected from the groups depicted in the compounds in Table 1.

[0326] In some embodiments, LBM is selected from the groups depicted in the compounds in Table 2.

[0327] In some embodiments, LBM is selected from the group consisting of:Linker (L)

[0328] As defined above and described herein, L is a bivalent moiety that connects SBM to LBM or SBM to DIM.

[0329] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, - C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0330] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur, and;each r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0331] In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, saturated or partially unsaturated, straight or branched C1-50, C1-40, C1-30, C1-20, or C1-10hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, - NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, –NRC(O)O-,.

[0332] In some embodiments, L is selected from the group consisting of:wherein each of Lx1and Lx2is, independently, O or NRbb; Rbbis H or C1-C6alkyl; each of Lx3and Lx4is, independently, optionally substituted phenylenyl; each of Lc1, Lc2, and Lc3is, independently, C1-C3 alkylene, C2-C5 alkenylene, or C2-C5 alkynylene; and each of Lr1and Lr2is, independently, an optionally substituted bivalent ring selected from 4-6 membered saturated or partially unsaturated monocyclic carbocyclylenyl, 4-6 membered saturated or partially unsaturated monocyclic heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0333] In some embodiments, L is selected from the group consisting of:,.

[0334] In some embodiments, L is. In some embodiments, L is. , . In some embodiments, L is. In some embodiments, L is. , . some embodiments, L is. In some embodiments, L is, . ,. so e e o e s, s . In some. ,In some embodiments, L is. In some embodiments, L is. In someembodiments, L is. In some embodiments, L is. , . In somesome embodiments, L is. In some embodiments, L isIn some embodiments, L is. In some embodiments, L is. so e e o e s, s . In some. ,some embodiments,. In some embodiments, L isIn some embodiments, L is. In some embodiments, L is. , . In some embodiments, L is. In some embodiments, L issome embodiments, L is. In some embodiments, L is. , . In some embodiments,. some embodiments,. n some em o mens, s. , . In some embodiments, L is. In some embodiments, L is. , . In someembodiments, L is. In some embodiments, L issome embodiments,. In some embodiments, L issome embodiments,. In some embodiments, L issome embodiments, L is. In some embodiments, L isIn. In some embodiments, L is. In some embodiments, L is. In someembodiments, L is. In some embodiments, L isIn some embodiments, L is. In some embodiments, L is. In someembodiments, L is . In some embodiments, L is . In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. so e e o e s, s . In some embodiments,In some embodiments, L is. In some embodiments, L is. , . In some embodiments,embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. , . In some embodiments,In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L isIn some embodiments, L is . In some embodiments, L issome embodiments, L is. In some embodiments, L is. n some emo mens, s . In some embodiments,In some embodiments, L is. In some embodiments, L is. In some embodiments, L is . In some embodiments, L is. In some embodiments, L is. n some em o mens, s . In some embodiments, L is. In some embodiments,.some embodiments, L is. In some embodiments, L issome embodiments, L is. In some embodiments, L issome embodiments, L is. In some embodiments, L isembodiments, L is . In some embodiments, L isembodiments,. In some embodiments, L isIn some embodiments, L is. In some embodiments, L isIn some embodiments, L is. In some embodiments, L isIn some embodiments, L is . In some embodiments, L is. so e e o e s, s . In someembodiments, L is. In some embodiments, L is. so e e o e s, s . In some embodiments, L is. In some embodiments, L isembodiments, L is. In some embodiments,is. , . In some embodiments, L is. In some embodiments, L isIn some embodiments,. In some embodiments, L is. , . In some embodiments,. some embodiments, L issome embodiments, L is . In some embodiments, L isembodiments, L is . In some embodiments, L issome embodiments, L is . In some embodiments, L is. , . some embodiments, L is. In some embodiments, L is. ,some embodiments, L is. In some embodiments, L isIn some embodiments, L is. In some embodiments, L is. , . In someembodiments, L is. In some embodiments, L is. , . In some embodiments, L is. In some embodiments, L is. , . some embodiments,.

[0335] In some embodiments, L is. In some embodiments, L isIn some embodiments, L is. In some embodiments, L isembodiments,. In some embodiments, L is. In. In some embodiments, L is. , . embodiments, L is. In some embodiments, L is. , . e embodiments, L is. In some embodiments, L is. so e e o e s, s . In someembodiments, L is. In some embodiments, L is. , . In some embodiments, L is. In some embodiments, L isembodiments,. In some embodiments, L isembodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is. In some embodiments, L is, .

[0337] In some embodiments, L is selected from the group consisting of: , , nd, wherein Lx1is, independently, –O– or –NRX–; each of Lc1and Lc2is, independently, selected from C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene,, wherein each of Lc1and Lc2is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RC; each of Lr1and Lr2is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of Lr1and Lr2is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR; each RXis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)Rxa; each RCis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, –C(O)Rca, –ORcb, and –N(Rcc)2, or two RCgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RRis, independently, selected from the group consisting of halo, C1-C6 alkyl, and C1-C6 haloalkyl, –C(O)Rra, –ORrb, and –N(Rrc)2, or two RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rxais, independently, selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl; each Rcais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1- C6 haloalkyl; each Rccis, independently, selected from the group consisting of hydrogen, C1-C6 alkyl, and C1- C6haloalkyl; each Rrais, independently, selected from the group consisting of C1-C6 alkyl, and C1-C6 haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, C1-C6 alkyl, and C1- C6haloalkyl; and each Rrcis, independently, selected from the group consisting of hydrogen, C1-C6 alkyl, and C1- C6 haloalkyl.

[0338] In some embodiments, each of Lc1and Lc2is, independently, selected from C1-C6alkylene, C2-C6alkenylene, and C2-C6alkynylene,wherein each of Lc1and Lc2is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RC.

[0339] In some embodiments, each RCis, independently, selected from halo, C1-C6alkyl, and C1- C6 haloalkyl.

[0340] In some embodiments, each RCis, independently, –F, –Cl, –Br, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, or –CH2CF3.

[0341] In some embodiments, each of Lr1and Lr2is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of Lr1and Lr2is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0342] In some embodiments, each of Lr1and Lr2is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, and 3-8 membered monocyclic heterocyclylene having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of Lr1and Lr2is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0343] In some embodiments, Lx1is –O–. In some embodiments, Lx1is –NRX–.

[0344] In some embodiments, Lx2is –O–. In some embodiments, Lx2is –NRX–.

[0345] In some embodiments, each RXis, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl. In some embodiments, each RXis, independently, selected from the group consisting of C1-C6alkyl and –C(O)Rxa. In some embodiments, each RXis, independently, selected from the group consisting of C1-C6 alkyl. In some embodiments, each RXis, independently, selected from the group consisting of C1-C6 haloalkyl. In some embodiments, each RXis, independently, selected from the group consisting of –C(O)Rxa.

[0346] In some embodiments, each RCis, independently, selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)Rca, –ORcb, and –N(Rcc)2.

[0347] In some embodiments, two RCgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0348] In some embodiments, each RRis, independently, selected from halo, C1-C6alkyl, and C1- C6haloalkyl.

[0349] In some embodiments, each RRis, independently, –F, –Cl, –Br, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, or –CH2CF3.

[0350] In some embodiments, two RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0351] In some embodiments, each Rxais, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rxais, independently, selected from the group consisting of C1-C6 haloalkyl.

[0352] In some embodiments, each Rcais, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rcais, independently, selected from the group consisting of C1-C6 haloalkyl.

[0353] In some embodiments, each Rcbis, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rcbis, independently, selected from the group consisting of C1-C6 haloalkyl.

[0354] In some embodiments, each Rccis, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rccis, independently, selected from the group consisting of C1-C6 haloalkyl.

[0355] In some embodiments, each Rrais, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rrais, independently, selected from the group consisting of C1-C6haloalkyl.

[0356] In some embodiments, each Rrbis, independently, selected from the group consisting of C1-C6alkyl. In some embodiments, each Rrbis, independently, selected from the group consisting of C1-C6haloalkyl.

[0357] In some embodiments, each Rrcis, independently, selected from the group consisting of C1-C6 alkyl. In some embodiments, each Rrcis, independently, selected from the group consisting of C1-C6haloalkyl.

[0358] In some embodiments, Lx1is selected from the groups depicted in the linkers of the compounds in Table 1.

[0359] In some embodiments, Lx1is selected from the groups depicted in the linkers of the compounds in Table 2.

[0360] In some embodiments, each of Lc1and Lc2is, independently, selected from the groups depicted in the linkers of the compounds in Table 1.

[0361] In some embodiments, each of Lc1and Lc2is, independently, selected from the groups depicted in the linkers of the compounds in Table 2.

[0362] In some embodiments, each of Lr1and Lr2is, independently, selected from the groups depicted in the linkers of the compounds in Table 1.

[0363] In some embodiments, each of Lr1and Lr2is, independently, selected from the groups depicted in the linkers of the compounds in Table 2.

[0364] In some embodiments, L is selected from the linkers depicted in the compounds in Table 1.

[0365] In some embodiments, L is selected from the linkers depicted in the compounds in Table 2. Exemplary Compounds

[0366] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary CompoundsFormula M-I’’-A’’ and Related Formulas Formula M-I’’-A’’

[0367] Disclosed herein, in some embodiments, is a compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 memberedbicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which thetwo R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0368] In some embodiments, Ring, wherein: XE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6 alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0369] In some embodiments, the compound is a compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen,and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6; G is –NRNG– or –(CRC7RCG)1-2; GSis absent;RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. Formula M-I’-A’

[0370] Disclosed herein, in some embodiments, is a compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclicring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6 alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring;y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0371] In some embodiments, Ring, wherein: XE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0372] In some embodiments, the compound is a compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturatedcarbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6; G is –NRNG– or –(CRC7RCG)1-2; GSis absent;RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; and RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. Formula M-I’

[0373] Disclosed herein, in some embodiments, is a compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which thetwo R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6 alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0374] In some embodiments, Ring, wherein: XE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0375] In some embodiments, the compound is a compound of Formula M-I’’-A’’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturatedcarbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1-C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; andRN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. Formula M-I

[0376] Disclosed herein, in some embodiments, is a compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6 alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6.

[0377] In some embodiments, Ring, wherein: XE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0378] In some embodiments, the compound is a compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6 alkoxy; RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; y2 is 0 or 1; and e2 is 0, 1, 2, 3, 4, 5 or 6. Formula M-II

[0379] Disclosed herein, in some embodiments, is a compound of Formula M-II:Formula M-II, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A

[0380] Disclosed herein, in some embodiments, is a compound of Formula M-II-A:Formula M-II-A, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-1

[0381] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-1:Formula M-II-A-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-2

[0382] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-2:Formula M-II-A-2, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-3

[0383] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-3:Formula M-II-A-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-4

[0384] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-4:Formula M-II-A-4, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B

[0385] Disclosed herein, in some embodiments, is a compound of Formula M-II-B:Formula M-II-B, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-III

[0386] Disclosed herein, in some embodiments, is a compound of Formula M-III:Formula M-III, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-IV

[0387] Disclosed herein, in some embodiments, is a compound of Formula M-IV:Formula M-IV, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-V

[0388] Disclosed herein, in some embodiments, is a compound of Formula M-V:Formula M-V, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. STAT6 Binding Moiety (SBM)

[0389] Disclosed herein, in some embodiments, is a compound of Formula M-I’’-A’’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0390] Disclosed herein, in some embodiments, is a compound of Formula M-I’-A’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0391] Disclosed herein, in some embodiments, is a compound of Formula M-I’ having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0392] Disclosed herein, in some embodiments, is a compound of Formula M-I having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0393] Disclosed herein, in some embodiments, is a compound of Formula M-II having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0394] Disclosed herein, in some embodiments, is a compound of Formula M-III having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0395] Disclosed herein, in some embodiments, is a compound of Formula M-IV having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0396] Disclosed herein, in some embodiments, is a compound of Formula M-V having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0397] Disclosed herein, in some embodiments, is a compound of Formula M-II-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0398] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-1 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0399] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-1 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0400] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-2 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0401] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-2 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0402] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-3 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0403] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-4 having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0404] Disclosed herein, in some embodiments, is a compound of Formula M-II-B having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. LE

[0405] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent.

[0406] In some embodiments, G is –NRNG–.

[0407] In some embodiments, RN6and RNGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0408] In some embodiments, G is –(CRC7RCG)1-2.

[0409] In some embodiments, RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. RE1

[0410] In some embodiments, RE1is optionally substituted monocyclic ring selected from 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)-NRN1RN2, or –NRN3C(O)RC1.

[0411] In some embodiments, RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 cycloalkoxy, C1-C6 amine, and C1-C6 haloalkyl.

[0412] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, or – NRN3C(O)RC1, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0413] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0414] In some embodiments, RE1is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0415] In some embodiments, RE1is 6-membered heteroaryl with 1-3 nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6 haloalkyl.

[0416] In some embodiments, RE1is 5-membered heterocyclyl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0417] In some embodiments, RE1is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0418] In some embodiments, RE1is 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0419] In some embodiments, RE1is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0420] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and – NRN3C(O)NRN1RN2.

[0421] In some embodiments,.

[0422] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl.

[0423] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0424] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0425] In some embodiments, Ring F2 is selected from the group consisting of 4- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0426] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring F2 is selected from the group consisting of 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0427] In some embodiments, d is 0. In some embodiments, d is 1, 2, 3, 4, 5, or 6. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5. In some embodiments, d is 6.

[0428] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0429] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0430] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0431] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0432] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0433] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0434] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0435] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0436] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0437] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0438] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0439] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0440] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0441] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0442] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0443] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0444] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3,or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0445] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0446] In some embodiments,is selected from the group consisting of ,,,d.

[0447] In some embodiments,is selected from the group consisting of ,, , , , ,.

[0448] In some embodiments,is selected from the group consisting of,

[0449] In some embodiments,is selected from the group consisting of,

[0450] In some embodiments,is selected from the group consisting of,,

[0452] In some embodiments,is selected from the group consisting of,.

[0453] In some embodiments,is selected from the group consisting of,

[0454] In some embodiments,is selected from the group consisting of,, , , , , , ,.,, , , , , , ,In some embodiments,some embodiments, RE1is. , .

[0465] In some embodiments, RE1is:.

[0466] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0467] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0468] In some embodiments,.

[0469] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4cycloalkylene.

[0470] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form 3- to 5-membered heterocyclylene with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0471] In some embodiments,.

[0472] In some embodiments, RE1is CRC4RC5RC6.

[0473] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C4 cycloalkylene.

[0474] In some embodiments, RC6is cyano or C1-C3haloalkyl.

[0475] In some embodiments, RC4and RC5together form, wherein RD2aand RD2bare each independently hydrogen and C1-C6alkyl.

[0476] In some embodiments, RC6is halogen.

[0477] In some embodiments,

[0478] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0479] In some embodiments, RE1is optionally substituted.embodiments, RE1isoptionally substituted.

[0480] In some embodiments, RE1is optionally substituted, , or.

[0481] In some embodiments,

[0482] In some such embodiments, R° is hydrogen or C1-6aliphatic. ,

[0484] In some embodiments,, wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0485] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0486] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0487] In some embodiments, RE1is. In some embodiments, RE1is optionally substituted , where Wmis as described above and defined herein. In some embodiments,. In some embodiments, RE1is optionally substituted. so e e o e s, s .

[0488] In some embodiments, RE1is an optionally substituted ring selected from:

[0489] In some embodiments, RE1is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0490] In some embodiments, RE1is:Ring E2

[0491] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0492] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0493] In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0494] In some embodiments, Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

[0495] In some embodiments, Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl. In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is optionally substituted pyridinyl.

[0496] In some embodiments, Ring, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; represents a bond to Ring E; a is 0, 1, 2, 3, 4, 5, or 6; and each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0497] In some embodiments, Ring E2 is phenyl.

[0498] In some embodiments, Ring E2 is 6-membered monocyclic carbocyclyl.

[0499] In some embodiments, Ring E2 is 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 5-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0500] In some embodiments, Ring E2 is 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms.

[0501] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0502] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0503] In some embodiments, Ring E2 is selected from the group consisting of phenyl, cyclohexyl, cyclohexenyl, pyrazole, and pyridinyl.

[0504] In some embodiments, a is 0.

[0505] In some embodiments, a is 1, 2, 3, or 4. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0506] In some embodiments, each RAis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1.

[0507] In some embodiments, each RAis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0508] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0509] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0510] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0511] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0512] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0513] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0514] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0515] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et,or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0516] In some embodiments, each RAis independently selected from the group consisting of –F, cyano, and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0517] In some embodiments, each RAis independently selected from the group consisting of –F and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0518] In some embodiments,, wherein represents a bond to Ring E.,wherein represents a bond to Ring E.

[0520] In some embodiments, wherein Ring E2, , , whereinrepresents a bond to Ring E . Ring E

[0521] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0522] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0523] In some embodiments, Ring E is optionally substituted phenyl. In some embodiments, Ring E is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0524] In some embodiments, Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl.

[0525] In some embodiments, Ring, wherein Ring E is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; represents a bond to LE; b is 0, 1, 2, 3, 4, 5, or 6;each RBis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –(C1-C6 alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1; or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0526] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0527] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0528] In some embodiments, Ring E is phenyl. In some embodiments, Ring E is 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0529] In some embodiments, Ring E is selected from the group consisting of phenyl, pyridinyl, and piperidinyl.

[0530] In some embodiments, b is 0.

[0531] In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4.

[0532] In some embodiments, each RBis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl.

[0533] In some embodiments, each RBis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0534] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0535] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0536] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0537] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0538] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0539] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3,or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0540] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0541] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and – CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0542] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0543] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0544] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0545] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0546] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et.

[0547] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et.

[0548] In some embodiments, wherein. , or ,,r, whereinrepresents a bond to LE.,,wherein represents a bond to LE. ,,wherein represents a bond to LE.

[0552] In some embodiments, Ring E is

[0553] In some embodiments, Ring E isy2

[0556] In some embodiments, y2 is 0. In some embodiments, y2 is 1. e2

[0557] In some embodiments, e2 is 0. In some embodiments, e2 is 1. In some embodiments, e2 is 2. In some embodiments, e2 is 3. In some embodiments, e2 is 4. In some embodiments, e2 is 5. In some embodiments, e2 is 6. RE14

[0558] In some embodiments, each RE14is independently halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy.

[0559] In some embodiments, each RE14is independently halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy.

[0560] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0561] In some embodiments, each each RE14is independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1- C6 hydroxyalkyl, –(C1-C6 alkyl)-NRN1RN2, and –(C1-C6 alkyl)-ORO1.

[0562] In some embodiments, each RE14is independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0563] In some embodiments, each RE14is independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0564] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0565] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0566] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0567] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0568] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3.

[0569] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and –CH2CF3.

[0570] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0571] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0572] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0573] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0574] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0575] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et. Ring E1

[0576] In some embodiments, Ring.

[0577] In some embodiments, Ring.

[0578] In some embodiments, Ring E1.

[0579] In some embodiments, Ring E1, , .

[0580] In some embodiments, Ring E1.

[0581] In some embodiments, Ring E1 is selected from the groups depicted in the compounds in Table 2.

[0582] In some embodiments, XE1is N. In some embodiments, XE1is CRE18.

[0583] In some embodiments, XE1is selected from the groups depicted in the compounds in Table 2. RE15

[0584] In some embodiments, RE15is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0585] In some embodiments, RE15is hydrogen.

[0586] In some embodiments, RE15is selected from the groups depicted in the compounds in Table 2.RE16

[0587] In some embodiments, RE16is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0588] In some embodiments, RE16is hydrogen.

[0589] In some embodiments, RE16is selected from the groups depicted in the compounds in Table 2.

[0590] In some embodiments, RE17is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1-C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0591] In some embodiments, RE17is hydrogen.

[0592] In some embodiments, RE17is selected from the groups depicted in the compounds in Table 2. RE18

[0593] In some embodiments, RE18is hydrogen or C1-C6 alkyl.

[0594] In some embodiments, RE18is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0595] In some embodiments, RE18is hydrogen or –Me.

[0596] In some embodiments, RE18is hydrogen.

[0597] In some embodiments, RE18is selected from the groups depicted in the compounds in Table 2. RN1and RN2

[0598] In some embodiments, each of RN1and RN2is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0599] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0600] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0601] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0602] In some embodiments, RN1is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0603] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0604] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0605] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0606] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0607] In some embodiments, RN1is hydrogen or –Me.

[0608] In some embodiments, RN1is hydrogen.

[0609] In some embodiments, RN1is –Me.

[0610] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0611] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0612] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0613] In some embodiments, RN2is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0614] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0615] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0616] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0617] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0618] In some embodiments, RN2is hydrogen or –Me.

[0619] In some embodiments, RN2is hydrogen.

[0620] In some embodiments, RN2is –Me.

[0621] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0622] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0623] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0624] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6haloalkyl.

[0625] In some embodiments, RN3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0626] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0627] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0628] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0629] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0630] In some embodiments, RN3is hydrogen or –Me.

[0631] In some embodiments, RN3is hydrogen.

[0632] In some embodiments, RN3is –Me. RN4

[0633] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0634] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0635] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0636] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6haloalkyl.

[0637] In some embodiments, RN4is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0638] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0639] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0640] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0641] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0642] In some embodiments, RN4is hydrogen or –Me.

[0643] In some embodiments, RN4is hydrogen.

[0644] In some embodiments, RN4is –Me. RN5

[0645] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0646] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0647] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0648] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0649] In some embodiments, RN5is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0650] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0651] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0652] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0653] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0654] In some embodiments, RN5is hydrogen or –Me.

[0655] In some embodiments, RN5is hydrogen.

[0656] In some embodiments, RN5is –Me. RN7

[0657] each of RN1, RN2, RN3, and RN4is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0658] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0659] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and –C(O)-C1-C6 alkyl.

[0660] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6 haloalkyl.

[0661] In some embodiments, RN7is selected from the group consisting of hydrogen and C1-C6 alkyl.

[0662] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0663] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0664] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0665] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0666] In some embodiments, RN7is hydrogen or –Me.

[0667] In some embodiments, RN7is hydrogen.

[0668] In some embodiments, RN7is –Me. RC3

[0669] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0670] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0671] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0672] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0673] In some embodiments, RC3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0674] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0675] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0676] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0677] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0678] In some embodiments, RC3is hydrogen or –Me.

[0679] In some embodiments, RC3is hydrogen.

[0680] In some embodiments, RC3is –Me.

[0681] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0682] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6 haloalkyl, –C(O)-C1-C6 alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0683] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0684] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0685] In some embodiments, RD1is selected from the group consisting of hydrogen and C1-C6alkyl.

[0686] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0687] In some embodiments, RD1is selected from the group consisting of hydrogen...

Claims

1. CLAIMS What is claimed:

1. A compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3-to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; ande1 is 0, 1, 2, 3, or 4.

2. A compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6 alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; and RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

3. A compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms;Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6 alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6 alkyl; and RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

4. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 memberedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6 alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl;each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6 alkyl, C1-C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6 alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; ande2 is 0, 1, 2, 3, 4, 5 or 6.

5. The compound of any one of claims 1-4, wherein y2 is 0.

6. The compound of any one of claims 1-5, wherein y1 is 1.

7. The compound of any one of claims 1-6, wherein Ring.

8. The compound of any one of claims 1-7, wherein Ring E1, along with its RE8and R139. The compound of any one of claims 1-8, wherein Ring E1, along with its RE8and R13.

10. The compound of any one of claims 1-9, wherein RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of claims 1-10, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-3 substituents, each independently selected from oxo, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl12. The compound of any one of claims 1-11, wherein,13. The compound of any one of claims 1-12, wherein,14. The compound of any one of claims 1-12, wherein RE1is.

15. The compound of any one of claims 1-14, wherein RE1is .

16. The compound of any one of claims 1-15, wherein Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl.

17. The compound of any one of claims 1-16, wherein Ring E2 is,represents a bond to R , andrepresents a bond to Ring E.

18. The compound of any one of claims 1-17, wherein Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl. .The compound of any one of claims 1-18, wherein Ring21. A compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ringhaving 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2; , , ,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’,-CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms;Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; and RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

22. A compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, –P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 memberedheterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent;RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

23. A compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2, -S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, or -OC1-6 haloalkyl; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which the two R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; V is Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–; LE1is –C(O)–; LE2is –NRN6–; G is –NRNG– or –(CRC7RCG)1-2–; GSis absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1-C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6 alkyl)-ORO1, –(C1-C6 alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl;each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, – C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; andRN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

24. A compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein: L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, -CHF-, -CF2-, -O-, -NR-, –SiR2–, –Si(OH)R–, –Si(OH)2–, –P(O)OR–, –P(O)R–, – P(O)NR2–, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or –NRC(O)O-; each –Cy– is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM); LBM is a compound of formula I-aa-1:I-aa-1 or a pharmaceutically acceptable salt thereof, wherein: X1is a bivalent moiety selected from -CH2- or -C(O)-; X2is N or CH; L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, -NR’-, -O-, -S-, or -S(O)2;,Ring B is a fused ring selected from benzo, a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1is independently RA, halogen, -CN, -NO2, -OR’, -SR’, -NR’2, - SiR’3, -S(O)2R’, -S(O)2NR’2,-S(O)R’, -C(O)R’, -C(O)OR’, -C(O)NR’2, -C(O)N(R’)OR’, -CR’2N(R’)C(O)R’, -CR’2N(R’)C(O)NR’2, -CFR’2, -CF2R’, -CF3, -CR’2(OR’), - CR’2(NR’2), -OC(O)R’, -OC(O)NR’2, -OP(O)R’2, -OP(O)(OR’)2, -OP(O)(OR’)NR’2, - OP(O)(NR’2)2, -N(R’)C(O)OR’, -N(R’)C(O)R’, -N(R’)C(O)NR’2, -N(R’)S(O)2R’, - N(R’)P(O)R’2, -N(R’)P(O)(OR’)2, -N(R’)P(O)(OR’)NR’2, -N(R’)P(O)(NR’2)2, or - N(R’)S(O)2R’; R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6haloalkyl; each RAis independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3- 10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R’ is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R’ groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms, in addition to the carbon or nitrogen from which thetwo R’ groups are attached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6 alkyl)-NRN1RN2, –(C1-C6 alkyl)-NRN1RN2, –O-(C1-C6 alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6 alkyl; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen,oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y2 is 0 or 1; and e2 is 0, 1, 2, 3, 4, 5 or 6.

25. The compound of any one of claims 21-24, wherein y2 is 0.

26. The compound of any one of claims 21-25, wherein Ring.

27. The compound of any one of claims 21-25, wherein Ring E1, , or..

28. The compound of any one of claims 21-26, wherein Ring E1.

29. The compound of any one of claims 21-28, wherein RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

30. The compound of any one of claims 21-28, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-3 substituents, each independently selected from oxo, C1-C6alkyl, C1-C6alkoxy and C1-C6haloalkyl 31. The compound of any one of claims 21-28, wherein,32. The compound of any one of claims 21-28, wherein RE1is, ,33. The compound of any one of claims 21-28, wherein RE1iso .

34. The compound of any one of claims 21-28, wherein RE1is.

35. The compound of any one of claims 21-34, wherein Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl.

36. The compound of any one of claims 21-34, wherein Ring E2 is,represents a bond to R , andrepresents a bond to Ring E.

37. The compound of any one of claims 21-361, wherein Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl.

38. The compound of any one of claims 21-361, wherein Ring40. A compound selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

41. A compound selected from any one of the compounds of Table 2, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

43. A method of modulating STAT6 in a subject or a biological sample, wherein the method 20 comprises administering to the subject a compound of any one of claims 1-41, or a pharmaceutical composition of claim 42.

44. A method of degrading STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or contacting the biological sample with a compound of any one of claims 1-41, or a pharmaceutical composition of claim 42.

45. A method of treating a STAT6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of claims 1- 41, or a pharmaceutical composition of claim 42.

46. The method of claim 45, wherein the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

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