STAT6 degraders and uses thereof

Abstract

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 thereof and methods of using said compositions in the treatment of various disorders.

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 / 686,593, filed August 23, 2025, 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). Activation of 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, thephosphorylation 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 The present application 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. 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 bindingmoiety to a ligand that binds STAT6 protein. It has now been found that compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are effective as degraders of STAT6 protein. Compounds of the present disclosure, 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.

[0007] Compounds provided by this disclosure 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 1. General Description of Certain Embodiments

[0008] Compounds of the present disclosure, and compositions thereof, are useful as degraders and / or inhibitors of STAT6 protein. In some embodiments, a provided compound degrades and / or inhibits STAT6. 2. Definitions

[0009] 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.

[0010] 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.

[0011] 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 unsaturationbut 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.

[0012] 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 is substituted 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:

[0013] 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.

[0014] 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)).

[0015] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0016] 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.

[0017] 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.

[0018] 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:

[0019] The term “halogen” means –F, –Cl, –Br, or .

[0020] 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.

[0021] 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 π 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).

[0022] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclicor 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.

[0023] 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, a heterocyclic 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.

[0024] 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.

[0025] 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 fortheir production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0026] 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 –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –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.

[0027] 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)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is 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.

[0028] 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, C1–6aliphatic 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. 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.

[0029] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is 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.

[0030] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group includeC(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic 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.

[0031] Suitable substituents on the aliphatic group of R†are independently halogen, – R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is 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.

[0032] 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)4salts. 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.

[0033] 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.

[0034] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0035] 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 IC50and / orbinding constant of less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0036] 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.

[0037] 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. 3. Description of Exemplary Embodiments Related to Methods of Use

[0038] Disclosed herein, in some embodiments, are methods of use related to a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof.

[0039] Disclosed herein, in some embodiments, are methods of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof, specifically affects, as its primary mechanism of action, the degradation of STAT6.

[0041] It will be understood that Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B cannot extend beyond the formulae described within this section (3) below and herein. It will be understood that all references to “defined and described herein” solely refer to this section (3) of the application. Additionally, all chemicalformulae and embodiments within section (3) can only apply to and can be combined with formulae and embodiments from this section (3).

[0042] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0043] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula II-A or Formula II-B:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0044] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula III-A or Formula III-B:Formula III-A Formula III-B, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0045] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula IV-A or Formula IV-B:Formula IV-A Formula IV-B, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein. STAT6 Binding Moiety (SBM)

[0046] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula I having a STAT6 Binding Moiety of:Formula I, or a pharmaceutically acceptable salt thereof, wherein: *ndicates bond to LE; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8- to 10- membered bicyclic 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; Rin ptionally substituted 5- to 6- memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein indicates bond to L; 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, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each RE4is, independently, hydrogen, or optionally substituted C1-C6 alkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; 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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1- C6 alkyl and C1-C6 alkoxy; RNGis hydrogen or optionally substituted C1-C6 alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, C3-C7 cycloalkyl, 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, RN6, RN7, and 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 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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; each RC1and RC2, is 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 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6 alkyl; m is 0 or 1; and p is 0 or 1.

[0047] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula II-A having a STAT6 Binding Moiety of:or or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0048] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula II-B having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein ndicates bond to L, and whereineach of the remaining variables is as defined herein.

[0049] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula III-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0050] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula III-B having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0051] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula IV-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, whereinindicates bond to L, and wherein each of the remaining variables is as defined herein.

[0052] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula IV-A having a STAT6 Binding Moiety ofor a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0054] In some embodiments, Ring E1 is optionally substituted phenyl. (E13

[0055] In some embodiments, Ring E1 is, wherein: 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-C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4.(*

[0056] In some embodiments, Ring E1 is , wherein: RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and 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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6 alkyl; and e1 is 0, 1, 2, 3, or 4.

[0057] 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.

[0058] 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.

[0059] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0060] 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 heteroatoms independently 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.#

[0061] In some embodiments, RE8is optionally substitutedIn some embodiments, RE8is optionally substituted

[0062] In some embodiments, RE8is o#

[0063] In some embodiments, RE8is

[0064] In some such embodiments, R° is hydrogen or C1-6aliphatic. #

[0065] In some embodiments, RE8is optionally substitutedwherein 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.

[0067] 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 partiallyunsaturated 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.

[0068] 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.

[0069] In some embodiments,R is 1-2 . In some embodiments, RE8is optionally substituted0-3 , where Wmis as described above and defined herein. In some embodiments,In some embodiments, RE8is optionally substituted In some emE8bodiments, R is

[0070] In some embodiments, RE8is an optionally substituted ring selected from: NN

[0071] In some embodiments, R is selected from: Nwherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0072] In some embodiments, RE8is:

[0073] 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.

[0074] In some embodiments, RE10is hydrogen. In some embodiments, RE10is C1-C6 alkyl.

[0075] In some embodiments, RE11is hydrogen. In some embodiments, RE11is C1-C6 alkyl.

[0076] In some embodiments, RE12is C1-C6alkyl. In some embodiments, RE11is C1-C6haloalkyl.

[0077] In some embodiments, 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-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.

[0078] 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-C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, or – NRN3C(O)RC3.

[0079] In some embodiments, Ring E1 is optionally substituted 8- to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is optionally substituted 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, Ring E1 is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is optionally substituted 5-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0081] In some embodiments, LEis –G–LE1–LE2–GS–. In some embodiments, LEis –GS–LE2–LE1– G–.

[0082] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G– wherein GSis absent

[0083] In some embodiments, G is –NRNG–.

[0084] In some embodiments, LE1is –C(O)–.

[0085] In some embodiments, LE2is –NRN6.

[0086] In some embodiments, 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. #

[0087] In some embodiments, LEis an optionally substituted1-4or1-4. In # some embodiments, LEis an optionally substitutedor . #

[0088] In some embodiments, LEis optionally substituted

[0090] In some such embodiments, R° is hydrogen or C1-6 aliphatic. O O O #

[0091] In some embodiments, LEis an optionally substituteO Og p y - ted 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.

[0093] 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.

[0094] 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.

[0095] In some embodiments,In some embodiments, LEis optionally substituted, where Wmis as described above and defined herein. In some embodiments, LEisEIn some embodiments, L is optionally substituted O O In some embodiments, In some embodiments, LEisO . In some embodiments,

[0096] In some embodiments, LEis an optionally substituted ring selected from:, , , , , , , wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0098] In some embodiments, LEis:. In some embodiments, Ring E2 is optionally substituted 5- to 6- memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, YE5is N. In some embodiments, YE5is CRE1.

[0101] In some embodiments, YE1is N. In some embodiments, YE1is CRE7.

[0102] In some embodiments, YE2is N. In some embodiments, YE2is CRE7.

[0103] In some embodiments, YE3is N. In some embodiments, YE3is CRE2;

[0104] In some embodiments, YE4is N. In some embodiment YE4i RE3#

[0105] In some embodiments, RE1is optionally substituted1-4or1-4. In some embodiments, RE1is optionally substituted 1-2 or 1-2. #

[0106] In some embodiments, RE1is optionally substituted,N, or

[0108] In some such embodiments, R° is hydrogen or C1-6 aliphatic. #

[0109] In some embodiments, RE1is optionally substitutedO Owherein 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.

[0111] 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 carbocyclylIn 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.

[0112] 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.

[0113] In some embodiments,R is . In some embodiments, RE1is optionally O substituted- , where Wmis as described above and defined herein. In some embodiments,In some embodiments, RE1is optionally substituted In some emboE1diments, R is O O

[0114] In some embodiments, RE1is an optionally substituted ring selected from: NN

[0115] In some embodiments, R is selected from:wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0116] In some embodiments, RE1is:

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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-C6haloalkyl.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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. O

[0126] In some embodiments, RE1 isorOO

[0127] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0128] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0129] 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.

[0130] 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. O

[0131] In some embodiments,

[0132] In some embodiments, RE1is CRC4RC5RC6.

[0133] 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-C4cycloalkylene.

[0134] In some embodiments, RC6is cyano or C1-C3 haloalkyl.

[0135] In some embodiments, RC4and RC5together formD2a D2bwherein R and R are each independently hydrogen and C1-C6 alkyl.

[0136] In some embodiments RC6is halogen

[0137] In some embodiments, RE1 is F3C , NC , or.

[0138] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0139] In some embodiments, RN1is 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.

[0140] In some embodiments, RN2is 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.

[0141] In some embodiments, 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 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0142] In some embodiments, 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.

[0143] In some embodiments, 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 monocyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 8- to 10- membered bicyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ligase Binding Moiety (LBM)

[0145] 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 WO2016 / 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, WO 2017 / 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.

[0146] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof, wherein LBM is a compound of formula 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 S(O)Ring B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 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.

[0147] In some embodiments, X1is a covalent bond. In some embodiments, X1is -CH2-. In some embodiments, X1is -C(O)-.

[0148] In some embodiments, LBM is selected from those depicted in Table 1. Linker (L)

[0149] As defined above and described herein, L is a bivalent moiety that connects SBM to LBM or SBM to DIM.

[0150] In some embodiments, 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; and 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.

[0151] 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)-, -, , or , wherein: 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 C1-6 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, and; each r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0152] 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-,orr .

[0153] In some embodiments, L is selected from the group consisting of:, each of Lx1and Lx2is, independently, O or NRbb; Rbbis H or C1-C6 alkyl; 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. Lr2

[0154] In some embodiments, L is selected from the group consisting of:Lr1Lr2r1 c1 c1 r21L2L1L1L4. Description of Exemplary Embodiments Related to Compounds and Compositions

[0155] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0156] Compounds of the present disclosure, and compositions thereof, are useful as degraders and / or inhibitors of STAT6 protein. In some embodiments, a provided compound degrades and / or inhibits STAT6.

[0157] Compounds disclosed herein, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, 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).

[0158] Compounds disclosed herein, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, 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.

[0159] It will be understood that Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B cannot extend beyond the formulae described within this section (4) below and herein. It will be understood that all references to “defined and described herein” solely refer to this section (4) of the application. Additionally, all chemical formulae and embodiments within section (4) can only apply to and can be combined with formulae and embodiments from this section (4). Compounds

[0160] 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 herein, and wherein L is not any one of the following structures:#represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4 aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6alkyl, -CR2ORL0, -OC1-6alkyl, C1-6haloalkyl, -OC1-6haloalkyl, or C3-6cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0161] Disclosed herein, in some embodiments, is a compound of Formula II-A or Formula II- B:RE1RE1Formula II-A Formula II-B, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, and wherein L is not any one of the following structures:#represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4 aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6alkyl, -CR2ORL0, -OC1-6alkyl, C1-6haloalkyl, -OC1-6haloalkyl, or C3-6cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] Disclosed herein, in some embodiments, is a compound of Formula III-A or Formula III-B:Formula III-A Formula III-B, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, and wherein L is not any one of the following structures: , ,wherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6cycloalkyl,or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] Disclosed herein, in some embodiments, is a compound of Formula IV-A or Formula IV- B:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein, and wherein L is not any one of the following structures:wherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6 cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. STAT6 Binding Moiety (SBM)

[0164] Disclosed herein, in some embodiments, is a compound of Formula I having a STAT6 Binding Moiety of:Formula I, or a pharmaceutically acceptable salt thereof, wherein:Ring E is p , wherein indicates bond to LE; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8- to 10- membered bicyclic 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; Rinptionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, whereinindicates bond to L; 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, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3;YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each RE4is, independently, hydrogen, or optionally substituted C1-C6 alkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; 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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1- C6 alkyl and C1-C6 alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6 alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and 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 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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; each RC1and RC2, is 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 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 RD2aRD2bRC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

[0165] 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 indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0166] 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 indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0167] Disclosed herein, in some embodiments, is a compound of Formula III-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0168] Disclosed herein, in some embodiments, is a compound of Formula III-B having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0169] Disclosed herein, in some embodiments, is a compound of Formula IV-A having a STAT6 Binding Moiety of:or a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein.

[0170] Disclosed herein, in some embodiments, is a compound of Formula IV-A having a STAT6 Binding Moiety ofor a pharmaceutically acceptable salt thereof, wherein indicates bond to L, and wherein each of the remaining variables is as defined herein. ** wherein indicates bond to LE.

[0172] In some embodiments, Ring E1 is optionall substituted phenyl.*

[0173] In some embodiments, Ring E1 is , wherein: 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-C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4.

[0174] In some embodiments, Ring E1 is , wherein: RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and 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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4.

[0175] 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.

[0176] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 14 heteroatoms independently selected from nitrogen oxygen and sulfuroptionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)NRE9RE10or –NRE11C(O)RE12.

[0177] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0178] 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 heteroatoms independently 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. #

[0179] In some embodiments, RE8is optionally substitutedIn some embodiments, RE8is optionally substituted#

[0180] In some embodiments, RE8is optionally substitutedor O

[0182] In some such embodiments, R is hydrogen or C1-6aliphatic. O #

[0183] In some embodiments, RE8is optionally substituted O O

[0184] In some embodiments, RE8is or , 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.

[0185] 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.

[0186] 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. O

[0187] In some embodiments,E8In some embodiments, R is optionally O substituted, where Wmis as described above and defined herein. In some O embodiments, In some embodiments, RE8is optionally substituted OO In some embodiments, RE8isE8N ,O, ,, orN.

[0189] In some embodiments, RE8is selected from:, , , , , , wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0190] In some embodiments, RE8is:

[0191] 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.

[0192] In some embodiments, RE10is hydrogen. In some embodiments, RE10is C1-C6 alkyl.

[0193] In some embodiments, RE11is hydrogen. In some embodiments, RE11is C1-C6alkyl.

[0194] In some embodiments, RE12is C1-C6alkyl. In some embodiments, RE11is C1-C6haloalkyl.

[0195] In some embodiments, 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-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.

[0196] 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.

[0197] In some embodiments, Ring E1 is optionally substituted 8- to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is optionally substituted 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0198] In some embodiments, Ring E1 is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is optionally substituted 5-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0199] In some embodiments, LEis –G–LE1–LE2–GS–. In some embodiments, LEis –GS–LE2–LE1– G–.

[0200] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent.

[0201] In some embodiments, G is –NRNG–.

[0202] In some embodiments, LE1is –C(O)–.

[0203] In some embodiments, LE2is –NRN6.

[0204] In some embodiments, 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. O O #

[0205] In some embodiments, LEis an optionally substituted nO O # some embodiments, LEis an optionally substitutedO O # # N NH N NH

[0206] In some embodiments, LEis optionally substituted,N, or O H .

[0207] In some embodiments,L

[0208] In some such embodiments, R° is hydrogen or C1-6ali h ti #

[0209] In some embodiments, LEis an optionally substitute, , ,E#

[0210] In some embodiments, L is 1wherein Ring Xa is 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.

[0211] 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.

[0212] 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.

[0213] In some embodiments, L In some embodiments, LEis optionally# substituted, where Wmis as described above and defined herein. In some # embodiments, LEis In some embodiments,EL is optionally substituted n some embodiments, Ls . In some embodiments, LEisn some embodiments,.

[0214] In some embodiments, LEis an optionally substituted ring selected from:, wherein each R is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0216] In some embodiments, LEis:

[0217] In some embodiments, Ring E2 is Y5. In some embodiments, Ring E2 is. In some embodiments, Ring E2 is optionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0218] In some embodiments, YE5is N. In some embodiments, YE5is CRE1.

[0219] In some embodiments, YE1is N. In some embodiments, YE1is CRE7.

[0220] In some embodiments, YE2is N. In some embodiments, YE2is CRE7.

[0221] In some embodiments, YE3is N. In some embodiments, YE3is CRE2;

[0222] In some embodiments, YE4is N. In some embodiments, YE4is CRE3.

[0223] In some embodiments,n some embodiments, RE1is optionally substitutedO #

[0224] In some embodiments, RE1is optionally substitutedor O, y g1-6p .#

[0227] In some embodiments, RE1is optionally substitutedE1#

[0228] In some embodiments, R iswherein 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.

[0229] 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.

[0230] 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.

[0231] In some embodiments, RE1In some embodE1iments, R is optionally substituted where Wmis as described above and defined herein. In someO embodiments, RE1isE1In some embodiments, R is optionally substituted0-3 In some embodiments RE1is 0-3 . In some embodiments, RE1is. In some embodiments, RE1is .

[0232] In some embodiments, RE1is an optionally substituted ring selected from:,, ,, o.

[0233] In some embodiments, RE1is selected from:wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0234] In some embodiments, RE1is: N

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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-C6haloalkyl.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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. O

[0245] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0246] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0247] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4 cycloalkylene.

[0248] 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.

[0249] In some embodiments, RE1isRN1orRN1.

[0250] In some embodiments, RE1is CRC4RC5RC6.

[0251] 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-C4cycloalkylene.

[0252] In some embodiments, RC6is cyano or C1-C3haloalkyl. D2a

[0253] In some embodiments, RC4and RC5together form , wherein RD2aand RD2bare each independently hydrogen and C1-C6alkyl.

[0254] In some embodiments, RC6is halogen.

[0256] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0257] In some embodiments, RN1is 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.

[0258] In some embodiments, RN2is 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.

[0259] In some embodiments, 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 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0260] In some embodiments, 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.

[0261] In some embodiments, 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 monocyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0262] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 8- to 10- membered bicyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ligase Binding Moiety (LBM)

[0263] 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, WO 2017 / 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.

[0264] Disclosed herein, in some embodiments, is a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof, wherein LBM is a compound of formula 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;RRing B is a fused ring selected from benzo or a 5-6 membered heteroaryl containing 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; and m is 0, 1, 2, 3 or 4.

[0265] In some embodiments, X1is a covalent bond. In some embodiments, X1is -CH2-. In some embodiments, X1is -C(O)-. Linker (L)

[0266] As defined above and described herein, L is a bivalent moiety that connects SBM to LBM or SBM to DIM.

[0267] Disclosed herein, in some embodiments, is a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, 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; andeach 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, wherein L is not any one of the following structures:#represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4 aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6alkyl, -CR2ORL0, -OC1-6alkyl, C1-6haloalkyl, -OC1-6haloalkyl, or C3-6cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0268] In some embodiments, L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50hydrocarbon 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–,, , or , wherein: 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 C1-6 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, and; each r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein L is not any one of the following structures: Hwherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6 cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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 C1-10 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)-, -C(O)NR-,wherein L is not any one of the following structures:wherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6 cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0269] Disclosed herein, in some embodiments, is a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, or Formula IV-B, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: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 selectedfrom nitrogen, oxygen, and sulfur and 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein L is not an one of the followin structures:wherein: # represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, -C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6alkyl, -CR2ORL0, -OC1-6alkyl, C1-6haloalkyl, -OC1-6 haloalkyl, or C3-6 cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0270] In some embodiments, L is selected from the group consisting of:11 2wherein L is not any one of the following structures:wherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6 cycloalkyl, or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Pharmaceutical Compositions

[0271] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) are administered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients.

[0272] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient (i.e., one or more pharmaceutically acceptable excipients).

[0273] The compounds disclosed herein are used in free base forms, salt forms, or solvate forms, or as prodrugs. All forms are within the compositions (e.g., pharmaceutical compositions) described herein. The disclosed compounds, or salts, solvates, or prodrugs thereof, are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.

[0274] Pharmaceutical compositions described herein are preferably formulated for administration to a subject (e.g., a human) in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) are useful for treating a disease or disorder, or symptoms thereof, described herein.

[0275] The dosage of the compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) in the pharmaceutical compositions, as well as the amount of the pharmaceutical composition administered to a subject, can vary depending on factors such characteristics of the subject (e.g., age, health, weight, and gender); the nature and extent of the symptoms; the frequency of treatment; the mode of administration of the pharmaceutical compositions; the solubility of the compounds in the pharmaceutical compositions; the potency and activity of the compounds; and the pharmacodynamic properties of the compound. The dosage of the compounds disclosed here (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) or compositions comprising compounds disclosed herein are varied to achieve a desired therapeutic response for a particular subject, composition, or mode of administration, without being toxic to the subject.

[0276] The present disclosure also provides kits including pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0277] Disclosed herein, in some embodiments, is a process for providing a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof).

[0278] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and FormulaIV-B, and subformulas thereof, as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0279] In some embodiments, the present disclosure provides a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament. Methods Treatment

[0280] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) and compositions comprising said compounds as described herein are generally useful for the degradation and / or inhibition of STAT6 protein activity.

[0281] Disclosed herein, in some embodiments, is a method of inhibiting or degrading STAT6 or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof), or a pharmaceutically acceptable salt thereof, or a composition comprising said compound, or pharmaceutically acceptable salt thereof.

[0282] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from a subject (e.g., a patient).

[0283] Inhibition and / or degradation of STAT6, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0284] Disclosed herein, in some embodiments, is a method of degrading and / or inhibiting STAT6, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound disclosed herein, or a pharmaceutically acceptable salt thereof, (e.g., compounds ofFormula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof), or a composition comprising said compound, or pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof, specifically affect, as their primary mechanism of action, the degradation of STAT6.

[0286] Disclosed herein, in some embodiments, is a method for treating a disease or disorder mediated by STAT6 or a mutant thereof, in a subject (e.g., a patient) in need thereof, the method comprising administering to said subject a compound disclosed herein, or a pharmaceutically acceptable composition thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof). Exemplary diseases and disorders are described in herein.

[0287] Disclosed herein, in some embodiments, is a method of degrading STAT6 in a subject, wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0288] Disclosed herein, in some embodiments, is a method of degrading STAT6 in a subject, wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to an untreated subject with the same STAT6- mediated disorder, disease, or condition. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0289] Disclosed herein, in some embodiments, is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the methodcomprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0290] In some embodiments, described herein is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to an untreated subject with the same STAT6-meditated disorder, disease, or condition. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0291] The activity of a compound disclosed herein as a degrader and / or inhibitor of STAT6 or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the activity and / or the subsequent functional consequences of activated STAT6 protein or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to STAT6 protein. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / STAT6 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with STAT6 protein bound to known radioligands. Detailed conditions for assaying a compound disclosed herein as a degrader and / or inhibitor of STAT proteins, or a mutant thereof, are set forth in the Examples below.

[0292] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic orother susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0293] Provided compounds are degraders and / or inhibitors of STAT6 protein and are therefore useful for treating one or more disorders associated with activity of STAT6 protein. Disclosed herein, in some embodiments, is a method for treating a STAT6-mediated disorder comprising the step of administering to a subject in need thereof (e.g., a patient), a compound disclosed herein, or a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof), or a pharmaceutically acceptable composition thereof.

[0294] As used herein, the term “STAT6-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which STAT6 or a mutant thereof, are known to play a role. Disclosed herein, in some embodiments, is a method of treating or lessening the severity of one or more diseases in which STAT6 or a mutant thereof, are known to play a role.

[0295] STAT6 functions as a transcription factor to induce gene expression and plays an important role in the IL-4 / IL-13 signaling pathway and thus is critical in IL-4 / IL-13 mediated biological responses including in human malignancies (e.g., Patel, B.K.R., et al. "Localization of the human stat6 gene to chromosome 12q13. 3–q14. 1, a region implicated in multiple solid tumors." Genomics 52.2 (1998): 192-200). The STAT6-mediated signaling pathway has been shown to be required for the development of T-helper type 2 (Th2) cells and Th2 immune response and plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma (e.g., Walford, H. H. and Doherty, T. A. “STAT6 and lung inflammation.” Jak-stat 2.4 (2013): e25301). It has been found that STAT6 induces the expression of BCL2L1 / BCL-X(L), which is responsible for the anti-apoptotic activity of IL-4 and is shown to play a prominent role in adaptive immunity such as providing innate immune signaling in response to virus infection (e.g., Chen, H., et al. “Activation of STAT6 by STING is critical for antiviral innate immunity.” Cell 147.2 (2011): 436-446). Knockout studies in mice have suggested the role STAT6 in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins. Activation of STAT6 signaling pathway is necessary in tumor-associated macrophages (TAMs) and is implicated in the treatment of cancers and atherosclerosis (e.g., Binnemars‐Postma, K., et al. “Targeting the Stat6 pathway in tumor‐ associated macrophages reduces tumor growth and metastatic niche formation in breast cancer.” The FASEB Journal 32.2 (2018): 969-978; Gong, M., et al. “STAT6 upregulation promotes M2 macrophage polarization to suppress atherosclerosis.” Medical science monitorbasic research 23 (2017): 240). STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation. STAT6 is also required for the development of IL-9-secreting T cells. STAT6 is also involved in IL4 signaling in B cells, and STAT6 determines the levels of CD20 on the surface of normal and malignant B lymphocytes (e.g., Sandova, V., et al. “IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3Kδ inhibitor idelalisib.” haematologica 106.11 (2021): 2995).

[0296] In some embodiments, biomarkers associated with the IL-4 / 13 pathway include IgE, Thymus and activation regulated chemokine (TARC), CD23, periostin, and eisinophils. TARC is a serum TH2 biomarker and chemoattractant for TH2 cell. CD23 is a B cell activation marker and correlates with IgE class switch. Periostin is a serum TH2 biomarker and ECM protein associated with tissue remodeling in atopic diseases.

[0297] In some embodiments, treatment with provided a compound results in lesser IL-4 induced TARC release compared to a reference or standard level. In some embodiments, treatment with provided a compound results in lesser IL-13 induced CD23 expression compared to a reference or standard level. In some embodiments, treatment with provided a compound results in lesser IL- 13 induced periostin release compared to a reference or standard level.

[0298] In some embodiments, treatment with provided a compound inhibits IL-4 induced TARC release. In some embodiments, treatment with provided a compound inhibits IL-13 induced CD23 expression. ISE, treatment with provided a compound inhibits IL-13 induced periostin release.

[0299] Disclosed herein, in some embodiments, is a method for treating one or more disorders, diseases, and / or conditions wherein the disorder, disease, or condition is a 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.

[0300] Diseases and conditions treatable according to the methods disclosed herein include, but are not limited to, cancer, cardiovascular disease, viral disease, autoimmune diseases, autoinflammatory syndromes, atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological disorders, metabolic syndrome, immunodeficiency disorders such as AIDS and HIV, destructive bone disorders, osteoarthritis, proliferative disorders, infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.In one embodiment, a human patient is treated with a compound disclosed herein and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably degrade and / or inhibit STAT6 or a mutant thereof

[0301] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present disclosure is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma exacerbated or induced following bacterial or viral infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[0302] Another aspect of the present disclosure relates to a method of treating an allergic or inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a compound disclosed herein to the subject. The disease may be a lung disease such as, e.g., asthma, airway hyperresponsiveness (AHR), an allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD), reactive airway disease, chronic rhinosinusitis, or essentially any other disease of the upper or lower airways that produces airflow obstruction.

[0303] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4 to 6 am, i.e., at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[0304] In some embodiments, STAT6, via its Src homology 2 (SH2) domain, is recruited to the phosphotyrosine residues and is phosphorylated on Tyr641. In some embodiments, STAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the nucleus, and participates in the expression of genes leading to asthma and airway hyperresponsiveness (AHR).

[0305] Disclosed herein, in some embodiments, is a method of treating asthma in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0306] Disclosed herein, in some embodiments, is a method of treating airway hyperresponsiveness (AHR) in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0307] Disclosed herein, in some embodiments, is a method of treating allergic rhinitis in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0308] Disclosed herein, in some embodiments, is a method of treating allergic asthma in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0309] Disclosed herein, in some embodiments, is a method of treating emphysema in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0310] Disclosed herein, in some embodiments, is a method of treating chronic rhinosinusitis (e.g., with nasal polyposis) in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0311] Disclosed herein, in some embodiments, is a method of treating atopic dermatitis in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0312] Disclosed herein, in some embodiments, is a method of treating COPD in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0313] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) can be used for other inflammatory or obstructive airways diseases and conditions, including, but not limited to acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith,emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) can also be used in the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0314] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds disclosed herein (e.g., compounds of Formula I, Formula II- A, Formula II-B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) are also useful in the treatment of eosinophil related disorders, e.g., eosinophilia, in particular eosinophil related disorders of the airways (e.g., involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and / or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, esophagitis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[0315] Disclosed herein, in some embodiments, is a method of treating eosinophilic esophagitis in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0316] Disclosed herein, in some embodiments, is a method of treating prurigo nodularis in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0317] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof), or are also useful in the treatment of inflammatory or allergic conditions of the skin. Disclosed herein, in some embodiments, is a method of treatinginflammatory or allergic conditions of the skin in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments the inflammatory disease of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0319] Compounds disclosed herein (e.g., compounds of Formula I, Formula II-A, Formula II- B, Formula III-A, Formula III-B, Formula IV-A, and Formula IV-B, and subformulas thereof, and pharmaceutically acceptable salts thereof) may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe,bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, prurigo nodularis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch- Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0320] Disclosed herein, in some embodiments, is a method of treating an autoimmune disease selected from encephalomyelitis, systemic sclerosis, idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, graft versus host disease (acute and chronic), and other tissue fibrosis diseases.

[0321] Disclosed herein, in some embodiments, is a method of treating idiopathic interstitial pneumonia(s) (IIPs), including any type of lung fibrosis, either interstitial lung disease associated with rheumatic disease (including SSc) or IPF itself, in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments the inflammatory disease which can be treated according to the methods disclosed herein is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), and osteoarthritis.

[0323] In some embodiments the inflammatory disease which can be treated according to the methods disclosed herein is a TH17 mediated disease or TH17-associated disease. In some embodiments the TH17 mediated disease or TH17-associated disease is selected from psoriasis, psoriatric arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis), or graft-versus-host disease.

[0324] In some embodiments the inflammatory disease which can be treated according to the methods disclosed herein is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0325] Disclosed herein, in some embodiments, is a method of treating an autoimmune disease or inflammatory disorder is selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic autoimmune hepatitis, progressive fibrosis associated interstitial lung disease, pulmonary arterial hypertension (PAH), immunoglobulin G4-related disease (IgG4-RD), chronic organ rejection (e.g., lung transplant), vasculitides (e.g., vasculitides), and STAT6 gain of function (GOF) mutations.

[0326] Disclosed herein, in some embodiments, is a method of treating STAT6 gain of function (GOF) mutations in a patient in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT6 GOF mutation is STAT6VT.

[0327] In some embodiments, the cardiovascular disease which can be treated according to the methods disclosed herein include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

[0328] In some embodiments, the neurodegenerative disease which can be treated according to the methods disclosed herein include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.

[0329] Disclosed herein, in some embodiments, is a method of treating, preventing or lessening the severity of Alzheimer’s disease comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt or composition thereof.

[0330] Disclosed herein, in some embodiments, is a method of treating a disease or condition commonly occurring in connection with transplantation. In some embodiments, the disease or condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease.

[0331] Disclosed herein, in some embodiments, is a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

[0332] Disclosed herein, in some embodiments, is a method of treating a viral disease. In some embodiments, the viral infection is HIV or COVID19 infection.

[0333] In some embodiments, the aberrant activation of STAT6 which can be treated according to the methods disclosed herein is a human cancer. In some embodiments, the human cancer which can be treated according to the methods disclosed herein include benign or malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkin’s and Non- Hodgkin’s, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, Smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[0334] Disclosed herein, in some embodiments, is a method of treating a cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve shealth tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC) including EGFR-mutant NSCLC, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes.

[0335] Disclosed herein, in some embodiments, is a method of treating a JAK-associated disease. In some embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma,Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia Such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example CTCLs include Sezary syndrome and mycosis fungoides.

[0336] Disclosed herein, in some embodiments, is a method of treating a hematologic malignancy selected from LGL leukemia (T and NK cell), cutaneous T cell lymphoma (CTCL), peripheral T cell lymphomas (PTCL, all subtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acute myelogenous leukemia, multiple myeloma, and myelofibrosis.

[0337] Furthermore, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation.

[0338] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0339] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0340] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof.

[0341] Disclosed herein, in some embodiments, is a method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0342] Disclosed herein, in some embodiments, is a method of treating a STAT-6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0343] In some embodiments, 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. EXAMPLES

[0344] The compounds disclosed may be prepared or isolated in general by synthetic and / or semi- synthetic methods known to those skilled in the art for analogous compounds. Example 1. STAT6 MSD Degradation Results

[0345] Degradation of STAT6 in cells is quantitatively measured using Meso Scale Discovery (MSD) technology. A549 cells are seeded in 96-well plates with a density of 1.5x10e4 to 5x10e5 cells per well in 100 μL fresh media. Compounds are then added to the assay plates with a final top concentration of up to 10 uM in a 1:3 dilution series with total of 9 doses. The assay plates are then incubated for 4 to 24 hours at 37oC under 5% CO2. The assay plates are then centrifuged for 5 minutes and the cell pellets are treated with 100 μl / well RIPA lysis buffer (Boston Bioproducts, BP-115D) with protease and phosphatase inhibitors (Roche, 05892791001 and 04906837001). To prepare the MSD assay plates (MSD, L15XA), the plates are coated with the capture antibody (Abnova, H00006778) in PBS, at 40 μL / well. The plates are then incubated overnight at 4oC, washed 1 time with 150 μL / well TBST buffer (Cell Signaling Technology, #9997S) and blocked with 150 μL / well blocking buffer (MSD, R93BA-4). Cell lysates are then added to MSD assay plates and the plates are incubated at room temperature for 1 hour. The plates are then washed 3 times with 150 μL / well TBST buffer and 25 μL / well primary detection antibody (Cell Signaling Technology, #5397S). The assay plates are then incubated at room temperature for 1 hour, washed 3 times with 150 μL / well TBST buffer, and 25 μL / well secondary detection antibody, SULFO- TAG anti-rabbit antibody (MSD, R32AB-1) are added. The assay plates are then incubated at roomtemperature for 1 hour, washed 3 times with 150 μL / well TBST buffer, and 150 μL / well MSD reading buffer (MSD, R92TC-2) are added. The plates are then analyzed by an MSD reader. The data is analyzed by GraphPad Prism, and the dose dependent STAT6 degradation is fit using the four-parameter inhibitor vs. response nonlinear regression. INCORPORATION BY REFERENCE

[0346] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[0347] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0348] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are intended to be within the scope of the following claims.

Claims

CLAIMS What is claimed:

1. 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 C1-50hydrocarbon 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: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 or a 5-6 membered heteroaryl containing 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; * Ring E isEindicates bond to L ; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8- to 10- membered bicyclic 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; Rings,, o a optionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, whereinindicates bond to L; 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, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each RE4is, independently, hydrogen, or optionally substituted C1-C6 alkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, whereinLE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; 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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1- C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6 alkyl; RNLis hydrogen or optionally substituted C1-C6 alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, 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, RN6, RN7, and 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 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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;each RC1and RC2, is 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 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 R s,independently, hydrogen or optionally substituted C1-C6 alkyl; m is 0 or 1; and p is 0 or 1, wherein L is not any one of the following structures:wherein:represents a bond to DIM; Ring L is an optionally substituted 4-10 membered saturated mono- or bicyclic carbocyclic or heterocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RL1is hydrogen, deuterium, halogen, –CN, –ORL0, –SRL0, –S(O)RL0, –S(O)2RL0, –N(RL0)2, or an optionally substituted C1-4aliphatic; RL2is a bivalent moiety selected from a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(RL0)2-, -CH(RL0)-, - C(F)2-, -N(RL0)-, -S-, -S(O)2- or -CRL0=CRL0-; each RL0is 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 RL0groups 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; represents a single bond or a double bond; and RL3is hydrogen, halo, -CN, -ORL0, oxo, C1-6 alkyl, -CR2ORL0, -OC1-6 alkyl, C1-6 haloalkyl, -OC1- 6 haloalkyl, or C3-6cycloalkyl,or two RL3groups on the same carbon atom combine to form, with the carbon atom from which the two v groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two RL3groups on two different carbon atoms combine to form, with the intervening atoms connecting the two v groups, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein the compound is of Formula II-A or Formula II-B:or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of Formula III-A or Formula III- B:Formula III-A Formula III-B, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein the compound is of Formula IV-A or Formula IV-Formula IV-A Formula IV-B, or a pharmaceutically acceptable salt thereof. * 5. The compound o *f claim 4, wherein*X , or ,* wherein indicates bond to LE.

6. The compound of any one of claims 1-5, wherein Ring E1 is optionally substituted phenyl. (7. The compound of claim 6, wherein Ring E1 is , wherein: 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-C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4. (RE131 8. The compound of claim 7, wherein Ring E1 is, wherein: RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and 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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6 alkyl; and e1 is 0, 1, 2, 3, or 4.

9. The compound of any one of claims 1-8, wherein Ring E1 is optionally substituted 8- to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

10. The compound of any one of claims 1-9, wherein R

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