STAT6 degraders and uses thereof

Abstract

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

Description

PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOSTAT6 DEGRADERS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application No.63 / 633,659, filed April 12, 2024; U. S. Provisional Application No. 63 / 633,664, filed April 12, 2024; U. S. Provisional Application No. 63 / 633,666, filed April 12, 2024; U. S. Provisional Application No. 63 / 660,237, filed June 14, 2024; U. S. Provisional Application No. 63 / 660,240, filed June 14, 2024; U. S. Provisional Application No. 63 / 660,238, filed June 14, 2024; U. S. Provisional Application No. 63 / 681,713, filed August 9, 2024; and U. S. Provisional Application No. 63 / 767,176, filed March 5, 2025, each of which is incorporated herein by reference in its entirety.TECHNICAL 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 removing1IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOpathogenic or oncogenic proteins (Crews, C., Chemistry & Biology, 2010, 17(6):551-555; Schnekloth, J. S. Jr., Chembiochem, 2005, 6(1):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, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

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

[0007] The present 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 2IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOand / or otherwise inhibited by the bifunctional compounds as described herein. Also provided are monovalent compounds, which find utility as inducers of targeted ubiquitination of STAT6 protein, which are then degraded and / or otherwise inhibited by the monovalent compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of STAT6 protein. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as inflammatory disorders.

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

[0009] It has now been found that compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are effective as degraders of STAT6 protein.

[0010] 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.

[0011] 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 OF CERTAIN EMBODIMENTS / . General Description of Certain Embodiments:

[0012] 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. Compounds and Definitions:

[0013] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements,3IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOCAS 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.

[0014] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is substituted or unsubstituted and is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) 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.

[0015] 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 4IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOaliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:H

[0016] The term “lower alkyl” refers to a Ci-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0017] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0018] 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 quatemized 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)).

[0019] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0020] As used herein, the term “bivalent Ci-s (or Ci-s) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0021] 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 a5IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOpolymethylene 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.

[0022] 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.

[0023] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group ofthe following structure:

[0024] The term “halogen” means F, Cl, Br, or I.

[0025] 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 of the present disclosure, “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 nonaromatic 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.

[0026] 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 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 quatemized 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,6IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor 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-quinol izinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,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).

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A-substituted pyrrolidinyl). Unless otherwise specified, a heterocyclyl is optionally substituted with one or more substituents.

[0028] 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, 3 / / -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 (=0) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl,7IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0029] 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.

[0030] 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 by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)o- 0R°; -0(CH2)o R°, -O-(CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O- SR°; -(ClUjo^Ph, which may be substituted with R°; -(CH2)o- 0(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)O- 0(CH2)O-I -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O^N(R0)2; -(CH2)O^N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)O^N(R°)C(0)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o^C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O^C(0)SR°; -(CH2)o^C(0)OSiR°3; -(CH2)o^OC(0)R°; -OC(0)(CH2)O^S R°; -(CH2)O- SC(0)R°; -(CH2)O^C(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O- 0C(0)NR02; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O^SSR°; -(CH2)O^S(0)2R°; -(CH2)O^S(0)20R°; -(CH2)O^OS(0)2R°; -S(O)2NR°2; -(CH2)O^S(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CH2)O^P(0)2R°; -(CH2)O- P(0)R02; -(CH2)O-40P(0)R°2; -(CH2)O-40P(0)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; orstraight 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, -CH2PI1, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6- 8IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered 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.

[0032] 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)o~2R‘, -(haloR*), -(CH2)O-2OH, -(CH2)O-2OR*, -(CH2)O-2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)O-2C(0)R‘, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR‘, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR‘, -(CH2)O-2NR*2, -NO2, -SiR’3, -OSiR*3, -C(O)SR* -(Ci^ 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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, 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 =0 and =S.

[0033] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0. =S. =NNR“2. =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR“. =NC)R\ -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci~6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] 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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected9IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOfrom nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rf, -NRf2, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, C(O)CH2C(O)Rt, -S(O)2Rf, -S(O)2NRf2, -C(S)NRf2, -C(NH)NRf2, or -NCR R1; wherein each R' is independently hydrogen, Ci~6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R'. taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] 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 Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] 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 of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate,10IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmaleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci^alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. 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.

[0039] 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 disclosed herein 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 this 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.

[0040] As used herein, the term “about” refers to within 20% of a given value. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0041] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.11IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3. Description of Exemplary Embodiments Related to Methods ofVse:

[0042] Disclosed herein, in some embodiments, are methods of use related to a compound of formulae 11", 1-1’, 1-1, l-II, l-III, 1-IV, 2-1 ", 2-1", 2-1, 2-II, 2-III, 2 IV, 3-A’, 3-A, 3-1 ", 3-I", 3-1, 3-II ", 3-II", 3-II, 3-111', 3-III, 3-IV, 3 IV, 3-V, 3-V, 3-VI", 3-VI, 3-VII", 3-VII, 3-VIII", or 3- VIII, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound of formulae 1-1", 1-1", 1-1, l-II, l-III, 1-IV, 2-I", 2-1", 2-1, 2-II, 2-III, 2 IV, 3-A", 3-A, 3-1 ", 3-1", 3-1, 3-II ", 3-II", 3-II, 3-III", 3-III, 3 -IV, 3-IV, 3-V, 3-V, 3-VI", 3-VI, 3-VII", 3-VII, 3- VIII", or 3- VIII, or a pharmaceutically acceptable salt thereof, specifically effects, as its primary mechanism of action, the degradation of STAT6.

[0044] It will be understood that formulae 1-1", 1-1’, 1-1, l-II, l-III, 1-IV, 2-1", 2-1", 2-1, 2-II, 2-III, 2 IV, 3-A", 3-A, 3-1 ", 3-1", 3-1, 3-II ", 3-II", 3-II, 3-III", 3-III, 3-IV, 3-IV, 3-V, 3-V, 3-VI', 3-VI, 3-VII', 3-VII, 3- VIII', or 3- VIII 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 chemical formulae and embodiments within section (3) can only apply to and can be combined with formulae and embodiments from this section (3).Formula 1-1' ', 1-1', 1-1, l-II, l-III, and 1-IV

[0045] Disclosed herein, in some embodiments, are methods of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1", 1-1", 1-1, l-II, l-III, or 1-IV, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula 1-1", 1-1", 1-1, l-II, l-III, or 1-IV, or a pharmaceutically acceptable salt thereof, specifically affects, as its primary mechanism of action, the degradation of STAT6.Formula 1-1"

[0047] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1":12IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, p, q, Xa, Xb, Xc, Xd, Ring SI, and Ring S2 are as defined 5 and described herein;RS1L is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 1-1'10

[0048] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1':13IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO1-1’or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, Xc, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;RS1L is a bivalent moiety that connectsXs3Xs4to DIM; andDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 1-110

[0049] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1:14IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, wherein:RS1, RS2, RS3, LS1, LS2, Xs1, Xs2, Xs3, Xs4, YS1, YS2, and Ring SI are as defined and described 5 herein;RS1RS2RS3X°' N - 1Xs2 / >— LS1\\ vS3 v 'S'4 \ \ [A A|_S2 _ / S1 )L is a bivalent moiety that connectsto DIM; andDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula l-II10

[0050] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula l-II:15IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;L is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula l-III10

[0051] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula l-III:16IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORS1or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;RS1yS1 yS3 yS2 yS4XcXs1Xa— XbXs3Xd— LsL is a bivalent moiety that connectsXs4to DIM; andDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 1-IV10

[0052] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-IV:17IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO1 IVor a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;L is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 2-1", 2-1', 2-1, 2-II, 2-III, and 2-IV10

[0053] Disclosed herein, in some embodiments, are methods of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1", 2-1', 2-1, 2-II, 2-III, or 2-IV, or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the compound of formula 2-1", 2-1', 2-1, 2-II, 2-III, or 2-IV, or18IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOa pharmaceutically acceptable salt thereof, specifically affects, as its primary mechanism of action, the degradation of STAT6.Formula 2-1"

[0055] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant 5 thereof, comprising administering a compound of formula 2-1":or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, p, q, Xa, Xb, Xc, Xd, Ring SI, and Ring S2 are as defined 10 and described herein;L is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 2-F15

[0056] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1':19IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORS1or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, Xc, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;DIM; andDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).10 Formula 2-1

[0057] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1:20IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO2-1or a pharmaceutically acceptable salt thereof, wherein:RS1, RS2, RS3, RS4, LS1, LS2, Xs1, Xs2, Xs3, Xs4, YS1, YS2, and Ring SI are as defined and described herein;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 2-II

[0058] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant 10 thereof, comprising administering a compound of formula 2- II:2-IIor a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and 15 described herein;21IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOSyS3LsXS5Xd Y$2 XbXs4X*1xaL is a bivalent moiety that connectsXXS6 ^XS3to DIM; andDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 2-IH

[0059] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2- III:10 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;22IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WODIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 2-IV

[0060] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-IV:10 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;23IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsandDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3-A ', 3-A, 3-1", 3-1', 3-1, 3-H", 3-H', 3-H, 3-HI', 3-III, 3-IV, 3-IV, 3- V, 3-V, 3-VI', 3-VI, 3-VII', 3-VII, 3-VIII', and3-VIII

[0061] Disclosed herein, in some embodiments, are methods of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-A', 3-A, 3-1”, 3-1', 3-1, 3-II", 3- II', 3-II, 3-III', 3-III, 3-IV, 3-IV, 3-V, 3-V, 3-VI', 3-VI, 3-VII', 3-VII, 3-VIII', or 3-VIII, 10 or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound of formula 3-A', 3-A, 3-1", 3-1', 3-1, 3-II", 3-II', 3-II, 3-III', 3-III, 3-IV, 3-IV, 3-V, 3-V, 3-VI', 3-VI, 3-VII', 3-VII, 3-VIII', or 3-VIII, or a pharmaceutically acceptable salt thereof, specifically affects, as its primary mechanism of action, the degradation of STAT6.15 Formula 3-A'

[0063] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-A':3-A',24IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, wherein Ring S is, wherein indicates bond to Lsand Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, p, q, Xa, Xb, Xc, Xd, Ring SI, and Ring S2 are as defined and described herein;5 L is a bivalent moiety that connectsto DIM; and DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 3-A

[0064] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant 10 thereof, comprising administering a compound of formula 3-A:3-A25IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, p, q, Xa, Xb, Xc, Xd, Ring SI, and Ring S2 are as defined and described herein;L is a bivalent moiety that connects5 DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 3-1" and 3-H"

[0065] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1" or formula 3-II":3 1"26IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-II"or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, Xc, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;L is a bivalent moiety that connectsor27IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOXS4_XS3DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 3-1' and 3-II'5

[0066] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1' or formula 3-II':3-r28IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-II'or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, Xc, YS1, YS2, YS3, YS4, and Ring SI are as defined and 5 described herein;L is a bivalent moiety that connectsor29IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WODIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).Formula 3-1 and 3-II5

[0067] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1 or formula 3-II:3-130IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-IIor a pharmaceutically acceptable salt thereof, wherein:RS1, RS2, RS3, RS4, LS1, LS2, Xs1, Xs2, Xs3, Xs4, YS1, YS2, and Ring SI are as defined and 5 described herein;L is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety31IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO(LBM).Formula 3-III' and 3-IV

[0068] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-III' or formula 3-IV:RS13-III'RS13-IVor a pharmaceutically acceptable salt thereof, wherein10 RS1, Ls, Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;32IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3-III and 3-IV

[0069] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-III or formula 3-IV:33IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-IIIRS13 IV5 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;34IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3-V and 3-VI'

[0070] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-V or formula 3-VI':35IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3- VI'5 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;36IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3- V and 3- VI

[0071] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-V or formula 3 -VI:37IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-VI5 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, Xd, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;38IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3-VII' and 3-VIII'

[0072] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3- VII' or formula 3-VIII':39IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-VIII'5 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;40IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 Formula 3- VII and 3- VIII

[0073] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3- VII or formula 3-VIII:41IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-VIII5 or a pharmaceutically acceptable salt thereof, whereinRS1, Ls, Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, YS1, YS2, YS3, YS4, and Ring SI are as defined and described herein;42IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOL is a bivalent moiety that connectsDIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM).5 STAT6 Binding Moiety (SBM)Formula 1-1", l-I', l-I, l-II, l-III, and 1-IVFormula l-I"

[0074] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1" having a STAT6 Binding 10 Moiety (SBM) of:43IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, wherein:(^) withinthebicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and C3-C7 carbocyclylenyl;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orRS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group44IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOselected from Ci-Ce alkyl, -C(O)-Ci-Ce 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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted Ci-Ce alkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and 45IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aV^x'|^D2bRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; andp is 0 or 1.

[0075] In some embodiments, q is 0. In some embodiments, q is 1.

[0076] In some embodiments, p is 0. In some embodiments, p is 1.

[0077] In some embodiments q is 0 and p is 1. In some embodiments, q is 1 and p is 0. In some embodiments, q is 0 and p is 0. In some embodiments, q is 1 and p is 1.

[0078] In some embodiments, Ring S2 is an optionally substituted phenylenyl or 6-membered heteroarylenyl with 1-4 nitrogen atoms.

[0079] In some embodiments, Ring S2 is an optionally substituted phenylenyl.

[0080] In some embodiments, Ring S2 is an optionally substituted 5- to 6-membered heteroarylenyl with 1-4 nitrogen atoms. In some embodiments, Ring S2 is an optionally substituted 6-membered heteroarylenyl with 1-4 nitrogen atoms.

[0081] In some embodiments, Ring S2 is an optionally substituted C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted monocyclic C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted bridged C5-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted C3-C7 cycloalkylenyl. In someIPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOembodiments, Ring S2 is an optionally substituted monocyclic C3-C7 cycloalkylenyl. In some embodiments, Ring S2 is an optionally substituted bridged C3-C7 cycloalkylenyl.1x. xzxz’1

[0082] In some embodiments, Ring S2 is - 1—, whereini** indicates bond to RS1;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0083] In some embodiments, Ring S2 is selected from those depicted in Table 1.

[0084] In some embodiments, Lsis -G-LS1-LS2-GS-. In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0085] In some embodiments, Lsis -GS-LS2-LS1-G- In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0086] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-.

[0087] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0088] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0089] In some embodiments, Lsis selected from those depicted in Table 1.Formula 1-1'

[0090] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1' having a STAT6 Binding Moiety47IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO(SBM) of:0 or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, and Xcrepresentsthat said bicyclic ring is aromatic;RS1is 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)-10 NRN1RN2, -C(NRN7)-NRN1RN2, -C(NORD1)-NRN1RN2, -C(RC4RC5)-NRN1RN2, - CRC4RC5RC6, -S(O)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;15 each RS2, RS3, and RS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl, Ci-Cghaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or20 when YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are atached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;48IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, and Xs4are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted Ci-Ce alkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring with 1-4 heteroatoms 49IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from nitrogen, oxygen, and sulfur;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0091] In some embodiments, Lsis -G-LS1-LS2-GS-. In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0092] In some embodiments, Lsis -GS-LS2-LS1-G- In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0093] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-.

[0094] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0095] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.50IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0096] In some embodiments, Lsis selected from those depicted in Table 1.Formula 1-1

[0097] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-1 having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, wherein:RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl;RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;or RS1and RS2, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2;RS3is hydrogen, Ci-Ce alkyl group, or Ci-Ce haloalkyl,LS1is -C(O)- or -CH2-;LS2is -NH- or -O-,Xs1is N or CRS5,51IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORS5is hydrogen or halogen,Xs2, Xs3, and Xs4are each, independently, N or CRS6,RS6is hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-Cs alkoxy, C3-C6 cycloalkyl, or phenyl,wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano;YS1and YS2are each, independently, N or CRS7;RS7is hydrogen, Ci-Ce alkyl, or Ci-Ce alkyl haloalkyl,Ring S 1 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring SI is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, andwherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, - NRN1RN2C(O)RC1, imidazolyl, and thiazolyl;each RN1, RN2, RN3, RN4, RC1, RC2, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)- Ci-Ce alkyl; andRN5is H, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.Formula l-II

[0098] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula l-II having a STAT6 Binding Moiety (SBM) of:IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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(0)-NRN1RN2, -NRN3C(0)RC1, -C(S)- NRN1RN2, -C(NRN7)-NRN1RN2, -C(NORD1)-NRN1RN2, -C(RC4RC5)-NRN1RN2, - CRC4RC5RC6, -S(O)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is -G-LS1-L82-GS- or -G8-L82-L81-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;53IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG- -(CRC7RCG)I-2- or absent;Gsis -NRNL- -(CRC7RC8)I-2- or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted Ci-Ce alkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- C1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 54IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOgroup selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0099] In some embodiments, Lsis -G-LS1-LS2-GS-. In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0100] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0101] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0102] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0103] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0104] In some embodiments, Lsis selected from those depicted in Table 1.55IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOFormula l-III

[0105] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula l-III having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbonIPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOatoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2- or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL- -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3and Xs4are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted Ci-Ce alkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;57IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-C6 alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0106] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0107] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.58IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0108] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0109] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0110] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0111] In some embodiments, Lsis selected from those depicted in Table 1.Formula 1-IV

[0112] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 1-IV having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, and Xbrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl 59IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, and Xbare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted Ci-Ce alkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- 60IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOC1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form' R, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.61IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0113] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0114] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0115] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0116] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0117] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0118] In some embodiments, Lsis selected from those depicted in Table 1.RSI, RS2, and RS3

[0119] In some embodiments, RS1is 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)Rcl.

[0120] In some embodiments, RS1is an optionally substituted 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0122] In some embodiments, RS1is 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)Rcl, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0123] In some embodiments, RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0124] In some embodiments, RS1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0125] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.62IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0126] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0127] In some embodiments, RS1is an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0129] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.

[0130] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.

[0131] In some embodiments, RS1is pyridonyl, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.63IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0134] In some embodiments, RS1is -C(O)-NRN1RN2or -NRN3C(O)RC1. In some embodiments, RS1is -C(O)-NRN1RN2. In some embodiments, RS1is -NRN3C(O)RC1.

[0135] In some embodiments, RS1is -C(RC4RC5)NRN1RN2.5

[0136] 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.

[0137] 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 10 sulfur.

[0138] In some embodiments,RS1is RN1or RN1

[0139] In some embodiments, RS1is CRC4RC5RC6.

[0140] 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 15 selected from C3-C4 cycloalkylene.

[0141] In some embodiments, RC6is cyano or C1-C3 haloalkyl.RD2a

[0142] In some embodiments, RC4and RC5together form', wherein RD2aand RD2bare each independently hydrogen and Ci-Ce alkyl.

[0143] In some embodiments, RC6is halogen.64IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0144] In some embodiments, RS1is, NC,Or.

[0145] In some embodiments, RS2is hydrogen or optionally substituted Ci-Ce alkyl.

[0146] In some embodiments, RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0147] In some embodiments, RS2is hydrogen.

[0148] In some embodiments, RS3is hydrogen or optionally substituted Ci-Ce alkyl.

[0149] In some embodiments, RS3is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0150] In some embodiments, RS3is hydrogen.

[0151] In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0152] In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2.

[0153] In some embodiments, RS1is selected from those depicted in Table 1. In some embodiments, RS2is selected from those depicted in Table 1. In some embodiments, RS3is selected from those depicted in Table 1.G, Gs, LS1, and LS2

[0154] In some embodiments, G is -NRNG-. In some embodiments, G is -(CRC7RCG)I-2-. In some embodiments, G is -CH2-.

[0155] In some embodiments, Gsis -NRNL-. In some embodiments, Gsis -(CRC7RC8)I-2-. In some embodiments, Gsis -CH2-.65IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0156] In some embodiments, each RC7is independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RC7is hydrogen.

[0157] In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, or 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RC8is hydrogen.

[0158] In some embodiments, each RCGis independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RCGis hydrogen.

[0159] In some embodiments, each RNGis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNGis hydrogen.

[0160] In some embodiments, each RNLis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNLis hydrogen.

[0161] In some embodiments, RN6and RNGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0162] In some embodiments, RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0163] In some embodiments, LS1is -C(O)- or -CH2-. In some embodiments, LS1is -C(O)-. In some embodiments, LS1is -CH2-. In some embodiments, LS1is -S(O)i-2-.

[0164] In some embodiments, LS2is -NH- or -O-. In some embodiments, LS2is -NRN6-. In some embodiments, LS2is -NH-. In some embodiments, LS2is -O-. In some embodiments, LS2is -CRC4RC5-.

[0165] In some embodiments, LS1is -C(O)- and LS2is -NH-.

[0166] In some embodiments, G is selected from those depicted in Table 1. In some embodiments, Gsis selected from those depicted in Table 1. In some embodiments, LS1is selected from those depicted in Table 1. In some embodiments, LS2is selected from those depicted in Table 1.Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, Xd, RS4, RS5, and RS6

[0167] In some embodiments, XS1is N. In some embodiments, XS1is CRS5. In some embodiments, XS1is NRS4. In some embodiments, XS1is O. In some embodiments, XS1is S.

[0168] In some embodiments, RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-466IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOheteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS5is hydrogen or halogen.

[0169] In some embodiments, Xs2is N. In some embodiments, Xs2is CRS6. In some embodiments, Xs2is NRS4. In some embodiments, Xs2is O. In some embodiments, Xs2is S.

[0170] In some embodiments, Xs3is N. In some embodiments, Xs3is CRS6. In some embodiments, Xs3is NRS4. In some embodiments, Xs3is O. In some embodiments, Xs3is S.

[0171] In some embodiments, Xs4is N. In some embodiments, Xs4is CRS6. In some embodiments, Xs4is NRS4. In some embodiments, Xs4is O. In some embodiments, Xs4is S.

[0172] In some embodiments, Xs5is N. In some embodiments, Xs5is CRS6. In some embodiments, Xs5is NRS4. In some embodiments, Xs5is O. In some embodiments, Xs5is S.

[0173] In some embodiments, Xs6is N. In some embodiments, Xs6is CRS6. In some embodiments, Xs6is NRS4. In some embodiments, Xs6is O. In some embodiments, Xs6is S.

[0174] In some embodiments, each RS4is, independently, Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl, wherein RS4is optionally substituted with cyano.

[0175] In some embodiments, each RS4is, independently, Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl. In some embodiments, each RS4is, independently, hydrogen or Ci-Ce alkyl.

[0176] In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano. In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, C3-Ce cycloalkyl, or phenyl, wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano.

[0177] In some embodiments, Xs1, Xs2, and Xs4are each, independently, N or CH.

[0178] In some embodiments, XS1is CH, Xs2is CH, and Xs4is CH.

[0179] In some embodiments, XS1is N, Xs2is CH, and Xs4is CH.

[0180] In some embodiments, XS1is N, Xs2is CH, and Xs4is N.

[0181] In some embodiments, Xs2is CH.

[0182] In some embodiments, Xs5is N. In some embodiments, Xs5is C.67IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0183] In some embodiments, Xais N. In some embodiments, Xais C.

[0184] In some embodiments, Xbis N. In some embodiments, Xbis C.

[0185] In some embodiments, Xcis N. In some embodiments, Xcis C.

[0186] In some embodiments, Xdis N. In some embodiments, Xdis C.

[0187] In some embodiments, XS1is selected from those depicted in Table 1. In some embodiments, Xs2is selected from those depicted in Table 1. In some embodiments, Xs3is selected from those depicted in Table 1. In some embodiments, Xs4is selected from those depicted in Table 1. In some embodiments, Xs5is selected from those depicted in Table 1. In some embodiments, Xs6is selected from those depicted in Table 1. In some embodiments, Xais selected from those depicted in Table 1. In some embodiments, Xbis selected from those depicted in Table 1. In some embodiments, Xcis selected from those depicted in Table 1. In some embodiments, Xdis selected from those depicted in Table 1. In some embodiments, RS4is selected from those depicted in Table 1. In some embodiments, RS5is selected from those depicted in Table 1. In some embodiments, RS6is selected from those depicted in Table 1. YS1, YS2, and RS7

[0188] In some embodiments, YS1is N. In some embodiments, YS1is CRS7.

[0189] In some embodiments, YS2is N. In some embodiments, YS2is CRS7.

[0190] In some embodiments, each RS7is, independently, hydrogen, Ci-Ce alkyl, or Ci- Ce haloalkyl.

[0191] In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0192] In some embodiments, YS1and YS2are each, independently, N or CH.

[0193] In some embodiments, YS1is CH and YS2is CH.

[0194] In some embodiments, YS1is N and YS2is CH.

[0195] In some embodiments, YS1is CH and YS2is N.

[0196] In some embodiments, YS1is selected from those depicted in Table 1. In some embodiments, YS2is selected from those depicted in Table 1. In some embodiments, RS7is 68IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOselected from those depicted in Table 1.Ring SI

[0197] In some embodiments, Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl, whereineach RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6- membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC3, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0198] In some embodiments, Ring SI is phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0199] In some embodiments, Ring SI is an optionally substituted phenyl. In some embodiments, Ring SI is phenyl, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.69IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0200] In some embodiments, Ring SI is an optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring S 1 is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, _NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0201] In some embodiments, Ring SI is an optionally substituted naphthyl. In some embodiments, Ring SI is naphthyl, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0202] In some embodiments, Ring SI is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is 8- to 10-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN9RNi0f_C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0203] In some embodiments, each RN1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0204] In some embodiments, each RN2is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN2is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0205] 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 70IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsubstituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0206] In some embodiments, each RN3is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-C6alkyl.

[0207] In some embodiments, each RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN4is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0208] In some embodiments, each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, and and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, hydrogen, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.

[0209] In some embodiments, each RN6is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN6is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0210] In some embodiments, each RN7is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN7is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0211] In some embodiments, each RD1is, independently, hydrogen, or an optionally 71IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsubstituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RD1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0212] In some embodiments, each RC1is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC1is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0213] In some embodiments, each RC2is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC2is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0214] In some embodiments, each RC3is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.-4—, —I™., ~4™, or -4™, wherein RS8is hydrogen, -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; and RS9is hydrogen, halogen, or Ci-Ce alkyl.72IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0216] In some embodiments, Ring SI is, or, wherein: RS8is hydrogen, -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; and RS9is hydrogen, halogen, or Ci-C6alkyl.R'

[0217] In some embodiments, Ring SI is, wherein: RS8is hydrogen, cyano, Ci-Ce alkyl, -C(O)-NRN4RN5, imidazolyl, or thiazolyl; and RN5is hydrogen, halogen, or Ci-Ce alkyl, wherein RN5is optionally substituted 1 substituent selected from cyano and -NCH3.

[0218] In some embodiments, Ring S1 is ~d~- or — 1—

[0219] In some embodiments, Ring SI is selected from those depicted in Table 1.Formula 2-1", 2-1', 2-1, 2-II, 2-III, and 2-IVFormula 2-1"

[0220] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1” having a STAT6 Binding Moiety (SBM) of:IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOS1or a pharmaceutically acceptable salt thereof, wherein:within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and C3-C7 carbocyclylenyl;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orRS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl, -C(O)-Ci-Cg alkyl, C3-C5 carbocyclyl, and 3- to 5- 74IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RCGindependently is hydrogen, halogen, cyano, or optionally substituted Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- 75IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; andp is 0 or 1.

[0221] In some embodiments, q is 0. In some embodiments, q is 1.

[0222] In some embodiments, p is 0. In some embodiments, p is 1.

[0223] In some embodiments q is 0 and p is 1. In some embodiments, q is 1 and p is 0. In some embodiments, q is 0 and p is 0. In some embodiments, q is 1 and p is 1.

[0224] In some embodiments, Ring S2 is an optionally substituted phenylenyl or 6-membered heteroarylenyl with 1-4 nitrogen atoms.

[0225] In some embodiments, Ring S2 is an optionally substituted phenylenyl.

[0226] In some embodiments, Ring S2 is an optionally substituted 5- to 6-membered heteroarylenyl with 1-4 nitrogen atoms. In some embodiments, Ring S2 is an optionally substituted 6-membered heteroarylenyl with 1-4 nitrogen atoms.

[0227] In some embodiments, Ring S2 is an optionally substituted C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted monocyclic C3-C7 carbocyclene. In76IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsome embodiments, Ring S2 is an optionally substituted bridged C5-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted C3-C7 cycloalkylenyl. In some embodiments, Ring S2 is an optionally substituted monocyclic C3-C7 cycloalkylenyl. In some embodiments, Ring S2 is an optionally substituted bridged C3-C7 cycloalkylenyl.yS 1 yS3y ISI2 y IS4

[0228] In some embodiments, Ring S2 is -4—, wherein* indicates bond to RS1;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0229] In some embodiments, Ring S2 is selected from those depicted in Table 2.

[0230] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis - G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0231] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0232] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0233] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0234] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.77IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0235] In some embodiments, Lsis selected from those depicted in Table 2.Formula 2-1'

[0236] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1' having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, and Xcrepresents thatsaid bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from78IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOnitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;79IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing SI is an optionally substituted ring selected from phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0237] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0238] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.80IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0239] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0240] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0241] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0242] In some embodiments, Lsis selected from those depicted in Table 2.Formula 2-1

[0243] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-1 having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, wherein:RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl;RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;or RS1and RS2, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2;RS3is hydrogen, Ci-Ce alkyl group, or Ci-Ce haloalkyl;RS4is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-Ce alkyl-C3-Ce cycloalkyl, wherein RS4is optionally substituted 81IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith cyano;LS1is -C(O)- or -CH2-;LS2is -NH- or -O-,Xs1is N or CRS5,RS5is hydrogen or halogen,Xs2, Xs3, and Xs4are each, independently, N or CRS6,RS6is hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C alkoxy, C3-C6 cycloalkyl, or phenyl,wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano;YS1and YS2are each, independently, N or CRS7;RS7is hydrogen, Ci-Ce alkyl, or Ci-Ce alkyl haloalkyl,Ring SI is phenylene or 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring SI is optionally fused with a ring to form 8- to 10-membered arylene or 8- to 10- membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, andwherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl;each RN1, RN2, RN3, RN4, RC1, RC2, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)- Ci-Ce alkyl; andRN5is H, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.Formula 2-II

[0244] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-II having a STAT6 Binding Moiety (SBM) of:82IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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(0)-NRN1RN2, -NRN3C(0)RC1, -C(S)- NRN1RN2, -C(NRN7)-NRN1RN2, -C(NORD1)-NRN1RN2, -C(RC4RC5)-NRN1RN2, - CRC4RC5RC6, -S(O)I-2-NRN1RN2, or-NRN3S(O)i-2RC2;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is -G-L81-L82-GS- or -G8-L82-L81-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;L82is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;83IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOGsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce 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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring 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 84IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOgroup selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0245] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0246] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0247] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0248] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0249] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0250] In some embodiments, Lsis selected from those depicted in Table 2.85IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOFormula 2-III

[0251] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-III having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic;R81is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is -G-L81-L82-GS- or -G8-L82-L81-G-;86IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLS1is -C(O)-, -CH2- or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG- -(CRC7RCG)I-2- or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C -Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- C1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and 87IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0252] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0253] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0254] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-88IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0255] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0256] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0257] In some embodiments, Lsis selected from those depicted in Table 2.Formula 2-IV5

[0258] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 2-IV having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, and Xbrepresentsthat said bicyclic ring is aromatic;RS1is 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 15 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms 25 independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon89IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOatoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2- or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL- -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, and Xbare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,90IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOoxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0259] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.91IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0260] In some embodiments, Lsis -GS-LS2-LS1-G- In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0261] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0262] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0263] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0264] In some embodiments, Lsis selected from those depicted in Table 2.RS1, RS2, and RS3

[0265] In some embodiments, RS1is 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)Rcl.

[0266] In some embodiments, RS1is an optionally substituted 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0267] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0268] In some embodiments, RS1is 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)Rcl, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0269] In some embodiments, RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0270] In some embodiments, RS1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0271] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.

[0272] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted 92IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0273] In some embodiments, RS1is an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0274] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0275] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.10

[0276] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.

[0277] In some embodiments, RS1is pyridonyl, wherein RS1is optionally substituted 15 with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0279] In some embodiments, RS1is:IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0280] In some embodiments, RS1is -C(O)-NRN1RN2or -NRN3C(O)RC1. In some embodiments, RS1is -C(O)-NRN1RN2. In some embodiments, RS1is -NRN3C(O)RC1.

[0281] In some embodiments, RS1is -C(RC4RC5)NRN1RN2.

[0282] 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.

[0283] 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.

[0284] In some embodiments, RS1is -C(O)-NRN1RN2or -NRN3C(O)RC1. In some embodiments, RS1is -C(O)-NRN1RN2. In some embodiments, RS1is -NRN3C(O)RC1.

[0285] In some embodiments, RS1is -C(RC4RC5)NRN1RN2.

[0286] 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.

[0287] 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.

[0288] In some embodiments, RS2is hydrogen.

[0289] In some embodiments, RS3is hydrogen or optionally substituted Ci-Ce alkyl.

[0290] In some embodiments, RS3is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0291] In some embodiments, RS3is hydrogen.

[0292] In some embodiments, RS1and an optional substituent on Ring S2, together with94IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOthe atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0293] In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2.

[0294] In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0295] In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2.

[0296] In some embodiments, RS1is selected from those depicted in Table 2. In some 95IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOembodiments, RS2is selected from those depicted in Table 2. In some embodiments, RS3is selected from those depicted in Table 2.G, Gs, LS1, and LS2

[0297] In some embodiments, G is -NRNG- In some embodiments, G is -(CRC7RCG)I-2-. In some embodiments, G is -CH2-.

[0298] In some embodiments, Gsis -NRNL- In some embodiments, Gsis -(CRC7RC8)I-2-. In some embodiments, Gsis -CH2-.

[0299] In some embodiments, each RC7is independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RC7is hydrogen.

[0300] In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, or 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RC8is hydrogen.

[0301] In some embodiments, each RCGis independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RCGis hydrogen.

[0302] In some embodiments, each RNGis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNGis hydrogen.

[0303] In some embodiments, each RNLis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNLis hydrogen.

[0304] In some embodiments, RN6and RNGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0305] In some embodiments, RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0306] In some embodiments, LS1is -C(O)- or -CH2-. In some embodiments, LS1is -C(O)-. In some embodiments, LS1is -CH2-. In some embodiments, LS1is -S(O)i-2-.

[0307] In some embodiments, LS2is -NH- or -O-. In some embodiments, LS2is -NRN6-. In some embodiments, LS2is -NH-. In some embodiments, LS2is -O-. In some embodiments, LS2is -CRC4RC5-.

[0308] In some embodiments, LS1is -C(O)- and LS2is -NH-.

[0309] In some embodiments, G is selected from those depicted in Table 2. In some embodiments, Gsis selected from those depicted in Table 2. In some embodiments, LS1is selected from those depicted in Table 2. In some embodiments, LS2is selected from those depicted in Table 2.96IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOXs1, Xs2, Xs3, Xs4, Xs5, Xs6, X“, Xb, Xc, Xd, RS4, RS5, and RS6

[0310] In some embodiments, XS1is N. In some embodiments, XS1is CRS5. In some embodiments, XS1is NRS4. In some embodiments, XS1is O. In some embodiments, XS1is S.

[0311] In some embodiments, RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS5is hydrogen or halogen.

[0312] In some embodiments, Xs2is N. In some embodiments, Xs2is CRS6. In some embodiments, Xs2is NRS4. In some embodiments, Xs2is O. In some embodiments, Xs2is S.

[0313] In some embodiments, Xs3is N. In some embodiments, Xs3is CRS6. In some embodiments, Xs3is NRS4. In some embodiments, Xs3is O. In some embodiments, Xs3is S.

[0314] In some embodiments, Xs4is N. In some embodiments, Xs4is CRS6. In some embodiments, Xs4is NRS4. In some embodiments, Xs4is O. In some embodiments, Xs4is S.

[0315] In some embodiments, Xs5is N. In some embodiments, Xs5is CRS6. In some embodiments, Xs5is NRS4. In some embodiments, Xs5is O. In some embodiments, Xs5is S.

[0316] In some embodiments, Xs6is N. In some embodiments, Xs6is CRS6. In some embodiments, Xs6is NRS4. In some embodiments, Xs6is O. In some embodiments, Xs6is S.

[0317] In some embodiments, each RS4is, independently, Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl, wherein RS4is optionally substituted with cyano.

[0318] In some embodiments, each RS4is, independently, Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl.

[0319] In some embodiments, each RS4is, independently, hydrogen or Ci-Ce alkyl.

[0320] In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano. In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, C3-Ce cycloalkyl, or phenyl, wherein RS6is optionally substituted with 1-3 substituents, each 97IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from -OH and cyano.

[0321] In some embodiments, Xs1, Xs2, and Xs4are each, independently, N or CH.

[0322] In some embodiments, XS1is CH, Xs2is CH, and Xs4is CH.

[0323] In some embodiments, XS1is N, Xs2is CH, and Xs4is CH.

[0324] In some embodiments, XS1is N, Xs2is CH, and Xs4is N.

[0325] In some embodiments, Xs2is CH.

[0326] In some embodiments, Xs5is N. In some embodiments, Xs5is C.

[0327] In some embodiments, Xais N. In some embodiments, Xais C.

[0328] In some embodiments, Xbis N. In some embodiments, Xbis C.

[0329] In some embodiments, Xcis N. In some embodiments, Xcis C.

[0330] In some embodiments, Xdis N. In some embodiments, Xdis C.

[0331] In some embodiments, XS1is selected from those depicted in Table 2. In some embodiments, Xs2is selected from those depicted in Table 2. In some embodiments, Xs3is selected from those depicted in Table 2. In some embodiments, Xs4is selected from those depicted in Table 2. In some embodiments, Xs5is selected from those depicted in Table 2. In some embodiments, Xs6is selected from those depicted in Table 2. In some embodiments, Xais selected from those depicted in Table 2. In some embodiments, Xbis selected from those depicted in Table 2. In some embodiments, Xcis selected from those depicted in Table 2. In some embodiments, Xdis selected from those depicted in Table 2. In some embodiments, RS4is selected from those depicted in Table 2. In some embodiments, RS5is selected from those depicted in Table 2. In some embodiments, RS6is selected from those depicted in Table 2. ys / , yS2, and RS7

[0332] In some embodiments, YS1and YS2are each, independently, N or CH.

[0333] In some embodiments, YS1is CH and YS2is CH.

[0334] In some embodiments, YS1is N and YS2is CH.

[0335] In some embodiments, YS1is CH and YS2is N.

[0336] In some embodiments, YS1is N. In some embodiments, YS1is CRS7.

[0337] In some embodiments, YS2is N. In some embodiments, YS2is CRS7.

[0338] In some embodiments, each RS7is, independently, hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0339] In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they 98IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOare attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0340] In some embodiments, Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl, whereineach RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6- membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC3, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0341] In some embodiments, YS1is selected from those depicted in Table 2. In some embodiments, YS2is selected from those depicted in Table 2. In some embodiments, RS7is selected from those depicted in Table 2.Ring SI

[0342] In some embodiments, Ring SI is phenylene, 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthylene, and 8- to 10-membered bicyclic heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)- 99IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WONRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0343] In some embodiments, Ring SI is an optionally substituted phenylene. In some embodiments, Ring SI is phenylene, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0344] In some embodiments, Ring SI is an optionally substituted 5- to 6-membered monocyclic heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is 5- to 6-membered heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN9RN10, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0345] In some embodiments, Ring SI is an optionally substituted naphthylene. In some embodiments, Ring SI is naphthylene, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0346] In some embodiments, Ring SI is an optionally substituted 8- to 10-membered bicyclic heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is 8- to 10-membered bicyclic heteroarylene with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN9RN10, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0347] In some embodiments, each RN1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.100IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0348] In some embodiments, each RN2is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN2is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0349] 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.

[0350] In some embodiments, each RN3is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-C6alkyl.

[0351] In some embodiments, each RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN4is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0352] In some embodiments, each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, and and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, hydrogen, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.

[0353] In some embodiments, each RN6is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN6is, independently, hydrogen, Ci-Ce alkyl, or-C(O)- 101IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOCi-C6alkyl.

[0354] In some embodiments, each RN7is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN7is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0355] In some embodiments, each RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RD1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0356] In some embodiments, each RC1is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC1is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0357] In some embodiments, each RC2is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC2is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0358] In some embodiments, each RC3is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0359] In some embodiments, Ring SI is102IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO, or, wherein * denotes a bond to G or G and ** denotes a bond to L; and RS9is hydrogen, halogen, or Ci-Ce alkyl.

[0360] In some embodiments, Ring S 1 is, wherein * denotes a bond to G or Gsand ** denotes a bond to L; and RS9is hydrogen, halogen, or Ci-Ce alkyl.

[0361] In some embodiments, Ring SI isdenotes a bond to G or Gsand ** denotes a bond to L.

[0362] In some embodiments, Ring SI is, or, wherein * denotes a bond to LS2and ** denotes a bond to L; and RS9is hydrogen, halogen, or Ci-Ce alkyl.10

[0363] In some embodiments, Ring S 1 is, wherein * denotes a bond to LS2and ** denotes a bond to L; and RS9is hydrogen, halogen, or Ci-Ce alkyl.

[0364] In some embodiments, Ring SI is, wherein *103IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOdenotes a bond to LS2and ** denotes a bond to L.

[0365] In some embodiments, RS4is Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-Cs alkoxy, -C2-C6 alkyl-C’i-C’3 haloalkoxy, or -Ci-Cg alkyl-Ci-O, cycloalkyl.

[0366] In some embodiments, Ring SI is selected from those depicted in Table 2.5 Formula 3-A ', 3-A, 3-1", 3-1', 3-1, 3-II", 3-IF, 3-II, 3-III', 3-III, 3-IV, 3-IV, 3-V, 3-V, 3-VF, 3-VI, 3-VIF, 3-V II, 3-VIII’, and 3-VIIIFormula 3-A '

[0367] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-A’ having a STAT6 10 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, wherein:Ring S isXs3, wherein indicates bond to Ls;within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C3-C7 carbocyclylenyl, and 5- to 6-membered monocyclic 20 heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;104IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered 105IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmonocyclic 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;RN6is hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 RC4and RC5is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; andp is 0 or 1.

[0368] In some embodiments, Ring S2 is optionally substituted 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring S2 is optionally substituted C3-C7 carbocyclylenyl. In some embodiments, Ring S2 is optionally substituted and 5- to 6-membered monocyclic heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring S2 is optionally substituted ring phenylenyl.

[0369] In some embodiments, Ring S2 is substituted with RS1, wherein RS1is 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, - 106IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOC(NORD1)-NRN1RN2, -C(RC4RC5)-NRN1RN2, -CRC4RC5RC6, -S(O)I.2-NRN1RN2, -NRN3S(O)I-2RC2, or -NRN3C(O)NRN1RN2; orRS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN1, RN2, RN3, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andRC6is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy.

[0370] In some embodiments, Ring S2 is selected from those depicted in Table 3.

[0371] In some embodiments, q is 0. In some embodiments, q is 1.

[0372] In some embodiments, p is 0. In some embodiments, p is 1.

[0373] In some embodiments q is 0 and p is 1. In some embodiments, q is 1 and p is 0. In some embodiments, q is 0 and p is 0. In some embodiments, q is 1 and p is 1.

[0374] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0375] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0376] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0377] In some embodiments, Ring Lsis selected from those depicted in Table 3.Formula 3-A107IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0378] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-A having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, wherein:within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and C3-C7 carbocyclylenyl;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orRS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;108IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOeach RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce 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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- 109IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; andp is 0 or 1.

[0379] In some embodiments, Ring S2 is an optionally substituted phenylenyl, 5- to 6-membered heteroarylenyl with 1-4 nitrogen atoms, or C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted phenylenyl or 5- to 6-membered heteroarylenyl with 1-4 nitrogen atoms. In some embodiments, Ring S2 is an optionally substituted phenylenyl or 6-membered heteroarylenyl with 1-4 nitrogen atoms.

[0380] In some embodiments, Ring S2 is an optionally substituted phenylenyl.

[0381] In some embodiments, Ring S2 is an optionally substituted 5- to 6-membered heteroarylenyl with 1-4 nitrogen atoms. In some embodiments, Ring S2 is an optionally substituted 6-membered heteroarylenyl with 1-4 nitrogen atoms.110IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0382] In some embodiments, Ring S2 is an optionally substituted C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted monocyclic C3-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted bridged C5-C7 carbocyclene. In some embodiments, Ring S2 is an optionally substituted C3-C7 cycloalkylenyl. In some embodiments, Ring S2 is an optionally substituted monocyclic C3-C7 cycloalkylenyl. In some embodiments, Ring S2 is an optionally substituted bridged C3-C7 cycloalkylenyl.yS 1Z**^^^* yS3II IyS2 yS4

[0383] In some embodiments, Ring S2 is, whereinI * indicates bond to RS1;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3; andeach RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.IllIPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0384] In some embodiments, Ring S2 is, whereinI * indicates bond to RS1;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;5 YS4is N or CRS3; andeach RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms 10 independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.15

[0385] In some embodiments, the compound has a STAT6 Binding Moiety (SBM) of:Xs3l ■ 1Y5^^. YsRS1or a pharmaceutically acceptable salt thereof.112IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0386] In some embodiments, Ring S2 is selected from those depicted in Table 3.

[0387] In some embodiments, q is 0. In some embodiments, q is 1.

[0388] In some embodiments, p is 0. In some embodiments, p is 1.

[0389] In some embodiments q is 0 and p is 1. In some embodiments, q is 1 and p is 0. In some embodiments, q is 0 and p is 0. In some embodiments, q is 1 and p is 1.

[0390] In some embodiments, Lsis -G-LS1-LS2-GS-. In some embodiments, Lsis - G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0391] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis - GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0392] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0393] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0394] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0395] In some embodiments, Lsis selected from those depicted in Table 3.Formula 3-1” and 3-II”

[0396] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1" or formula 3-II" having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;RS1is an optionally substituted monocyclic ring selected from 5- to 6- membered heteroaryl 113IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 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)I.2-NRN1RN2, -NRN3S(O)I.2RC2, or -NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;114IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, and Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional 115IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOheteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form*, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0397] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0398] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0399] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0400] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0401] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0402] In some embodiments, Lsis selected from those depicted in Table 3.Formula 3-1' and 3-II'

[0403] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1' or formula 3-II* having a STAT6 Binding Moiety (SBM) of:116IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, and Xcrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;LSis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;117IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLS1is -C(O)-, -CH2- or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG- -(CRC7RCG)I-2- or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, XS3, XS4, and Xs5, are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C -Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- C1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,118IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOnaphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aW^RD2bRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0404] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0405] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0406] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0407] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.119IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0408] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0409] In some embodiments, Lsis selected from those depicted in Table 3.Formula 3-1 and 3-II

[0410] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-1 or 3-II having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, wherein:RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl;RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;or RS1and RS2, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2;RS3is hydrogen, Ci-Ce alkyl group, or Ci-Ce haloalkyl;RS4is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-Ce alkyl-C3-Ce cycloalkyl, wherein RS4is optionally substituted with cyano;120IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLS1is -C(O)- or -CH2-;LS2is -NH- or -O-,Xs1is N or CRS5,RS5is hydrogen or halogen,Xs2, Xs3, and Xs4are each, independently, N or CRS6,RS6is hydrogen, halogen, cyano, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl group, Ci-Ce haloalkyl, -C2-Ce alkyl-Ci-Cs alkoxy, C3-C6 cycloalkyl, or phenyl,wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano;YS1and YS2are each, independently, N or CRS7;RS7is hydrogen, Ci-Ce alkyl, or Ci-Ce alkyl haloalkyl,Ring S 1 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring SI is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10- membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, andwherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)- Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl;each RN1, RN2, RN3, RN4, RC1, RC2, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)- Ci-Ce alkyl; andRN5is H, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.Formula 3-III' and 3-IV

[0411] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-III* or formula 3-IV having a STAT6 Binding Moiety (SBM) of:121IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;R81is 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)I-2-NRN1RN2, -NRN3S(O)I-2RC2, or-NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted ring selected from122IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2- or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,123IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOoxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orR02aV^ 'pD2oRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.124IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0412] In some embodiments, Lsis -G-LS1-LS2-GS-. In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0413] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0414] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0415] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0416] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0417] In some embodiments, Lsis selected from those depicted in Table 3 Formula 3-III and 3-IV

[0418] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-III or formula 3-1 V having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; or125IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;126IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOXs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-Ce 127IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOcarbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to formRD2b, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0419] In some embodiments, XS1is N. In some embodiments, XS1is CRS6. In some embodiments, XS1is NRS4. In some embodiments, XS1is O. In some embodiments, XS1is S. In some embodiments, Xs3is N. In some embodiments, Xs3is CRS6. In some embodiments, Xs3is NRS4. In some embodiments, Xs3is O. In some embodiments, Xs3is S. In some embodiments, Xs4is N. In some embodiments, Xs4is CRS6. In some embodiments, Xs4is NRS4. In some embodiments, Xs4is O. In some embodiments, Xs4is S. In some embodiments, Xs5is N. In some embodiments, Xs5is CRS6. In some embodiments, Xs5is NRS4. In some embodiments, Xs5is O. In some embodiments, Xs5is S. In some embodiments, Xs5is S. In some embodiments, Xs6is N. In some embodiments, Xs6is CRS6. In some embodiments, Xs6is NRS4. In some embodiments, Xs6is O. In some embodiments, Xs6is S.

[0420] In some embodiments, Xais C. In some embodiments, Xbis C. In some embodiments, Xcis C. In some embodiments, Xdis C. In some embodiments, Xais N. In some embodiments, Xbis N. In some embodiments, Xdis N.

[0421] In some embodiments, the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa,Ls. In some embodiments, the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, andXdrepresentsindicates bond to Ls. In some embodiments, the bicyclic ring containing XsXs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents128IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WON — RS4, wherein indicates bond to Ls. In some embodiments, thebicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents, wherein indicates bond to Ls. In some embodiments, the bicyclic ring containingXs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresentsindicates bond to Ls. In some embodiments, the bicyclic ring containing Xs1, Xs3, Xs4, Xs5,Xs6, Xa, Xb, Xc, and Xdrepresents, wherein ’ indicates bond to Ls.

[0422] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis - G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0423] In some embodiments, Lsis -GS-LS2-LS1-G- In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0424] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0425] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0426] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0427] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, Xs 1is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3.129IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOFormula 3-V' and 3-VI'

[0428] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-V’ or formula 3-VI’ having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, -NRN3S(O)I-2RC2, or-NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl130IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- 131IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOG> alkyl-C -Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- C1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently 132IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOselected from nitrogen, oxygen, and sulfur, orRD2aX^xRD2bRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0429] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0430] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0431] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0432] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0433] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0434] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, Xs 1is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3.Formula 3- V and 3-VI

[0435] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-V or formula 3-VI having a STAT6 Binding Moiety (SBM) of:133IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOor a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic;R81is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;134IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, and Xs5, are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl 135IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orR02aV^ 'pD2oRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0436] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0437] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0438] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-136IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0439] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0440] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0441] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, Xs1is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3.Formula 3-VII' and 3-VIII'

[0442] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a mutant thereof, comprising administering a compound of formula 3-VII' or formula 3-VIII' having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;RS1is 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, - 137IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOCRC4RC5RC6, -S(O)I.2-NRN1RN2, -NRN3S(O)I.2RC2, or -NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl,138IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOC2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xaand Xbare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 139IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOgroup selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0443] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0444] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0445] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0446] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0447] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0448] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, XS1is selected from those depicted in Table 3. In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, Xs2is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3.Formula 3-VII and 3-VIII

[0449] Disclosed herein, in some embodiments, is a method of degrading STAT6, or a140IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmutant thereof, comprising administering a compound of formula 3- VII or formula 3- VIII having a STAT6 Binding Moiety (SBM) of:or a pharmaceutically acceptable salt thereof, whereinwithin the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, and Xbrepresentsthat said bicyclic ring is aromatic;RS1is 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 10 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;15 Y84is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms 20 independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are atached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and 141IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, and Xbare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;142IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

[0450] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0451] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -Gs— LS2— LS1— G—, wherein G and Gsare each absent.

[0452] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-143IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0453] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0454] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0455] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, XS1is selected from those depicted in Table 3. In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, Xs2is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3.RS1, RS2, and RS3

[0456] In some embodiments, RS1is 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)Rcl.

[0457] In some embodiments, RS1is an optionally substituted 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0458] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0459] In some embodiments, RS1is 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)Rcl, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0460] In some embodiments, RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0461] In some embodiments, RS1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted 144IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0462] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.

[0463] In some embodiments, RS1is 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.

[0464] In some embodiments, RS1is an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0465] In some embodiments, RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl.

[0466] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl and Ci-Ce haloalkyl.

[0467] In some embodiments, RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.

[0468] In some embodiments, RS1is pyridonyl, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-Ce haloalkyl.145IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0470] In some embodiments, RS1is:

[0471] In some embodiments, RS1is -C(O)-NRN1RN2or -NRN3C(O)RC1. In some embodiments, RS1is -C(O)-NRN1RN2. In some embodiments, RS1is -NRN3C(O)RC1.

[0472] In some embodiments, RS1is -C(RC4RC5)NRN1RN2.

[0473] 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.

[0474] 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.OR»2 V R“ $ / ,N 1 N 1

[0475] In some embodiments, RS1is RN1or RN1

[0476] In some embodiments, RS1is CRC4RC5RC6.

[0477] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C4 cycloalkylene.

[0478] In some embodiments, RC6is cyano or C1-C3 haloalkyl.RD2a

[0479] In some embodiments, RC4and RC5together form', wherein RD2aand RD2bare each independently hydrogen and Ci-Ce alkyl.

[0480] In some embodiments, RC6is halogen.146IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0481] In some embodiments, RS1is

[0482] In some embodiments, RS1is -NRN3C(O)NRN1RN2.

[0483] In some embodiments, RS1is optionally substituted5

[0484] In some embodiments, RS1is optionally substitutedO

[0485] In some embodiments, RS1is R° R°

[0486] In some such embodiments, R° is hydrogen or Ci-6 aliphatic.

[0487] In some embodiments, RS1is optionally substituted

[0489] 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 15 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0490] As defined above and described herein, Ring Xa1is an optionally substituted 3-147IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO7 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.

[0491] 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.Oi A VL-N -RTI mS14 2 s eS1

[0009] n o e mbodiments, R is 1-2. In some embodiments, R is O I XVWmoptionally substituted' 0-3, where Wmis as described above and defined herein. In O#|— ^ °- 1 N>wm3some embodiments, RS1is ' '0-3. In some embodiments, RS1is optionally substituted O Ott I — N I a I — N I * K> Wm* kj-Wm' '0-3. In some embodiments, RS1is ' '0-3. In some embodiments, RS1is O C> # L|— N W 1 # LHN O\ / . In some embodiments, RS1is \.

[0493] In some embodiments, RS1is an optionally substituted ring selected from:148IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0494] In some embodiments, RS1is selected from:R° wherein each R° is a defined above and described herein (e.g., hydrogen or Ci-6 aliphatic).

[0495] In some embodiments, RS1is:

[0496] In some embodiments, YS3is N. In some embodiments, YS3is CRS2.

[0497] In some embodiments, YS4is N. In some embodiments, YS4is CRS3.

[0498] In some embodiments, RS2is hydrogen or optionally substituted Ci-Ce alkyl.

[0499] In some embodiments, RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0500] In some embodiments, RS2is hydrogen, -F, -Cl, -CF3, -CHF2, -CH2F, -CF2CF3, -CH(CF3)2, -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS2is hydrogen, -F, -CF3, -CHF2, -CH2F, or -Me. In some embodiments, RS2is hydrogen.

[0501] In some embodiments, RS3is hydrogen or optionally substituted Ci-Ce alkyl.

[0502] In some embodiments, RS3is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0503] In some embodiments, RS3is hydrogen, -F, -Cl, -CF3, -CHF2, -CH2F, - CF2CF3, -CH(CF3)2, -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS3is hydrogen, -F, -CF3, -CHF2, -CH2F, or -Me. In some embodiments, RS3is hydrogen.

[0504] In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1- 149IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-C6alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0505] In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1and RS2, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(O)RC2.

[0506] In some embodiments, RS1is selected from those depicted in Table 3. In some embodiments, RS2is selected from those depicted in Table 3. In some embodiments, RS3is selected from those depicted in Table 3.G, Gs, LS1, and LS2

[0507] In some embodiments, Lsis -G-LS1-LS2-GS- In some embodiments, Lsis -G-LS1-LS2-GS-, wherein G and Gsare each absent.

[0508] In some embodiments, Lsis -GS-LS2-LS1-G-. In some embodiments, Lsis -GS-LS2-LS1-G-, wherein G and Gsare each absent.

[0509] In some embodiments, G is -NRNG-. In some embodiments, G is -CH2CH2-. In some embodiments, G is -(CRC7RCG)I-2- In some embodiments, G is -CH2-.

[0510] In some embodiments, Gsis -NRNL-. In some embodiments, G is -(CRC7RC8)I-2-. In some embodiments, Gsis -CH2CH2-. In some embodiments, Gsis -CH2-.O#| — X /

[0511] In some embodiments, Lsis an optionally substitutedv G-4or O O1-4. In some embodiments, L S is an optionally substituted# L^ ' ) ' 1-2Or O150IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOo

[0512] In some embodiments, Lsis optionally substitutedO O O#AA'R° ANAR0 #ANA'R}=V N=^7 }=N7

[0513] In some embodiments, LsisRO RO,RO, orRO

[0514] In some such embodiments, R° is hydrogen or Ci-6 aliphatic.

[0515] In some embodiments, Lsis an optionally substitute

[00516] , 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.

[0517] 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.

[0518] In some embodiments, Ring Xa1an optionally substituted 5 membered151IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmonocyclic 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.5

[0519] In some embodiments, LsisIn some embodiments, Lsis O#1— N^po-3optionally substituted\v'°-3, where Wmis as described above and defined herein. In# I-NH’O-Ssome embodiments, Lsis. In some embodiments, Lsis optionally substituted O O# I — N 1 #i—* (q-wm' '0-3. In some embodiments, L is 0-3. in some embodiments, L isIn some embodiments, Lsis10

[0520] In some embodiments, Lsis an optionally substituted ring selected from:152IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0522] wherein each R° is a defined above and described herein (e.g., hydrogen or Ci-6 aliphatic.

[0523] In some embodiments, Lsis:

[0524] In some embodiments, each RC7is independently hydrogen, halogen, cyano, Ci- Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RC7is hydrogen.

[0525] In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, or 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC8is independently hydrogen, halogen, cyano, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RC8is hydrogen.

[0526] In some embodiments, each RCGis independently hydrogen, halogen, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In some embodiments, each RCGis hydrogen.

[0527] In some embodiments, each RNGis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNGis hydrogen.

[0528] In some embodiments, each RNLis independently hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl. In some embodiments, each RNLis hydrogen.

[0529] In some embodiments, RN6and RNGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0530] In some embodiments, RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0531] In some embodiments, Lsis -LS1-LS2-. In some embodiments, Lsis -LS2-LS1-

[0532] In some embodiments, LS1is -C(O)- or -CH2-. In some embodiments, LS1is - C(O)-. In some embodiments, LS1is -CH2-. In some embodiments, LS1is -S(O)i-2-.

[0533] In some embodiments, LS2is -NH- or -O-. In some embodiments, LS2is -NRN6-. In some embodiments, LS2is -NH-. In some embodiments, LS2is -O-. In some embodiments, LS2is -CRC4RC5-.

[0534] In some embodiments, LS1is -C(O)- and LS2is -NH-.153IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0535] In some embodiments, Lsis selected from those depicted in Table 3. In some embodiments, G is selected from those depicted in Table 3. In some embodiments, Gsis selected from those depicted in Table 3. In some embodiments, LS1is selected from those depicted in Table 3. In some embodiments, LS2is selected from those depicted in Table 3.Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, Xd, RS4, RS5, and RS6

[0536] In some embodiments, XS1is N. In some embodiments, XS1is CRS5. In some embodiments, XS1is NRS4. In some embodiments, XS1is O. In some embodiments, XS1is S.

[0537] In some embodiments, RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS5is hydrogen or halogen.

[0538] In some embodiments, Xs2is N. In some embodiments, Xs2is CRS6. In some embodiments, Xs2is NRS4. In some embodiments, Xs2is O. In some embodiments, Xs2is S.

[0539] In some embodiments, Xs3is N. In some embodiments, Xs3is CRS6. In some embodiments, Xs3is NRS4. In some embodiments, Xs3is O. In some embodiments, Xs3is S.

[0540] In some embodiments, Xs4is N. In some embodiments, Xs4is CRS6. In some embodiments, Xs4is NRS4. In some embodiments, Xs4is O. In some embodiments, Xs4is S.

[0541] In some embodiments, Xs5is N. In some embodiments, Xs5is CRS6. In some embodiments, Xs5is NRS4. In some embodiments, Xs5is O. In some embodiments, Xs5is S.

[0542] In some embodiments, Xs6is N. In some embodiments, Xs6is CRS6. In some embodiments, Xs6is NRS4. In some embodiments, Xs6is O. In some embodiments, Xs6is S.

[0543] In some embodiments, each RS4is, independently, Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl, wherein RS4is optionally substituted with cyano. In some embodiments, each RS4is, independently, Ci-C6alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-Ce alkyl-C3-C6 cycloalkyl. In some embodiments, each RS4is, independently, hydrogen or Ci-Ce alkyl.

[0544] In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some 154IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOembodiments, RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano. In some embodiments, each RS6is, independently, hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C alkoxy, C3-C6 cycloalkyl, or phenyl, wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano.

[0545] In some embodiments, Xs1, Xs2, and Xs4are each, independently, N or CH.

[0546] In some embodiments, XS1is CH, Xs2is CH, and Xs4is CH.

[0547] In some embodiments, XS1is N, Xs2is CH, and Xs4is CH.

[0548] In some embodiments, XS1is N, Xs2is CH, and Xs4is N.

[0549] In some embodiments, YS1and YS2are each, independently, N or CH.

[0550] In some embodiments, Xs2is CH.

[0551] In some embodiments, Xs5is N. In some embodiments, Xs5is C.

[0552] In some embodiments, Xais N. In some embodiments, Xais C.

[0553] In some embodiments, Xbis N. In some embodiments, Xbis C.

[0554] In some embodiments, Xcis N. In some embodiments, Xcis C.

[0555] In some embodiments, Xdis N. In some embodiments, Xdis C.

[0556] In some embodiments, XS1is selected from those depicted in Table 3. In some embodiments, Xs2is selected from those depicted in Table 3. In some embodiments, Xs3is selected from those depicted in Table 3. In some embodiments, Xs4is selected from those depicted in Table 3. In some embodiments, Xs5is selected from those depicted in Table 3. In some embodiments, Xs6is selected from those depicted in Table 3. In some embodiments, Xais selected from those depicted in Table 3. In some embodiments, Xbis selected from those depicted in Table 3. In some embodiments, Xcis selected from those depicted in Table 3. In some embodiments, Xdis selected from those depicted in Table 3. In some embodiments, RS4is selected from those depicted in Table 3. In some embodiments, RS5is selected from those depicted in Table 3. In some embodiments, RS6is selected from those depicted in Table 3.ysr yS2 yS3? S4and RS7

[0557] In some embodiments, YS1is CH and YS2is CH.

[0558] In some embodiments, YS1is N and YS2is CH.

[0559] In some embodiments, YS1is CH and YS2is N.

[0560] In some embodiments, YS1is N. In some embodiments, YS1is CRS7.

[0561] In some embodiments, YS2is N. In some embodiments, YS2is CRS7.

[0562] In some embodiments, each RS7is, independently, hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl.155IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO

[0563] In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, when YS1is CRS7, RS1and RS7, together with the atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-C6haloalkyl, and -C(O)RC2.

[0564] In some embodiments, YS1is selected from those depicted in Table 3. In some embodiments, YS2is selected from those depicted in Table 3. In some embodiments, YS3is selected from those depicted in Table 3. In some embodiments, YS4is selected from those depicted in Table 3. In some embodiments, RS7is selected from those depicted in Table 3.Ring SI

[0565] In some embodiments, Ring SI is an optionally substituted 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is an optionally substituted 5- to 6-membered heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring SI is an optionally substituted 6-membered heteroaryl with 1-2 nitrogen atoms.

[0566] In some embodiments, Ring SI is an optionally substituted 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring SI is an optionally substituted 9-membered bicyclic heteroaryl with 1-2 nitrogen atoms.

[0567] In some embodiments, Ring SI is optionally substituted naphthyl.

[0568] In some embodiments, Ring SI is an optionally substituted phenyl.

[0569] In some embodiments, Ring SI is optionally substituted with 1-5 substituents each independently selected from halogen, -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC2, optionally substituted group selected from Ci-Ce alkyl, Ci-Ce alkoxy, -C(O)-Ci-Ce alkyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, -C(O)-NRN4RN5, -NRN3C(O)RC3, imidazolyl, thiazolyl, -C(O)NRS13RS1°, -NRS11C(O)RS12, -C(O)OH, wherein156IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORN4, RN5, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl;each of RS1°, Rsn, and RS13is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, 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; andRS12is an optionally substituted group selected from Ci-Ce alkyl, 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.

[0570] In some embodiments, Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl, whereineach RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6- membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC3, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0571] In some embodiments, Ring SI is phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, or 8- to 10-membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl- 157IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOC1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0572] In some embodiments, Ring SI is an optionally substituted phenyl. In some embodiments, Ring SI is phenyl, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0573] In some embodiments, Ring SI is an optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring S 1 is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0574] In some embodiments, Ring SI is an optionally substituted naphthyl. In some embodiments, Ring SI is naphthyl, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-C1-C3 alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

[0575] In some embodiments, Ring SI is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring SI is 8- to 10-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN9RN10, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

[0576] In some embodiments, each RN1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)- 158IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOCi-C6alkyl.

[0577] In some embodiments, each RN2is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN2is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0578] 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.

[0579] In some embodiments, each RN3is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-C6alkyl.

[0580] In some embodiments, each RN4is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN4is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0581] In some embodiments, each RN5is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, and and 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN5is, independently, hydrogen, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.

[0582] In some embodiments, each RN6is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen,159IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOand sulfur. In some embodiments, each RN6is, independently, hydrogen, Ci-Ce alkyl, or-C(O)- Ci-C6alkyl.

[0583] In some embodiments, each RN7is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RN7is, independently, hydrogen, Ci-Ce alkyl, or-C(O)- Ci-C6alkyl.

[0584] In some embodiments, each RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RD1is, independently, hydrogen, Ci-Ce alkyl, or-C(O)-Ci-C6alkyl.

[0585] In some embodiments, each RC1is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC1is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0586] In some embodiments, each RC2is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC2is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.

[0587] In some embodiments, each RC3is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.160IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORS8 / =N y=NM(RS8)ISYNY'—s,, or -~1~, wherein RS8is hydrogen, -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, 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; and RS9is hydrogen, halogen, or Ci-Ce alkyl; and s is 0, 1, 2, 3 or 4.

[0589] In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, 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; and RS9is hydrogen, halogen, or Ci-Ce alkyl.

[0591] , wherein RS8is hydrogen, -OH, halogen,161IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOcyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; and RS9is hydrogen, halogen, or Ci-Ce alkyl.-S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)- NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; and RS9is hydrogen, halogen, or Ci- 10 C6alkyl.> pS8RS9^^T

[0593] In some embodiments, Ring SI is~-L~, wherein: RS8is hydrogen, cyano, Ci-Ce alkyl, -C(O)-NRN4RN5, imidazolyl, or thiazolyl; and RN5is hydrogen, halogen, or Ci-Ce alkyl, wherein RN5is optionally substituted 1 substituent selected from cyano and -RS8is -C(O)NRS13RS1°, -NRS11C(O)RS12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and162IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RS1°, Rsn, and RS13is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, 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;RS12is an optionally substituted group selected from Ci-Ce alkyl, 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;s is 0, 1, 2, 3 or 4;each RS9is, independently, H, halogen, -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, - NRN3S(O)2RC2, optionally substituted group selected from Ci-Ce alkyl, Ci-Ce alkoxy, and -C(O)-Ci-C6alkyl, -C(O)-NRN4RN5, -NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)-Ci-Ce alkyl.In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0597] In some embodiments, RS8is -C(O)NRS13RS1° or -NRS11C(O)RS12. In some 163IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOembodiments, RS8is -C(O)NRS13RS1°. In some embodiments, RS8is -NRS11C(O)RS12.

[0598] In some embodiments, RS1° is hydrogen or an optionally substituted group selected from Ci-Ce alkyl, 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. In some embodiments, RS1° is hydrogen or an optionally substituted group selected from Ci-Ce alkyl and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS1° is hydrogen or an optionally substituted group selected from Ci-Ce alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with Ci-Ce alkyl or C3-C5 cycloalkyl. In some embodiments, RS1° is hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, Rsiois hydrogen, -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS1° is hydrogen. In some embodiments, Rsiois -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS1° is hydrogen or -Me.

[0599] In some embodiments, RS11is hydrogen or an optionally substituted group selected from Ci-Ce alkyl, 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. In some embodiments, Rsnis hydrogen, -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, Rsnis hydrogen. In some embodiments, Rsnis -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, Rsnis hydrogen or -Me.

[0600] In some embodiments, RS12is an optionally substituted group selected from Ci-Ce alkyl, 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. In some embodiments, RS12is hydrogen, -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, Rsnis hydrogen. In some embodiments, RS12is -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, Rsnis hydrogen or -Me.

[0601] In some embodiments, RS13is hydrogen or an optionally substituted group selected from Ci-Ce alkyl, 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. In some embodiments, RS13is hydrogen or optionally substituted Ci-Ce alkyl. In some embodiments, Rsnis hydrogen,164IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO-Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS13is hydrogen. In some embodiments, Rsi3is -Me, -Et, -nPr, -iPr, -nBu, -sBu, or -tBu. In some embodiments, RS13is hydrogen or -Me.

[0602] In some embodiments, RS8is 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, RS8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RS8is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0603] In some embodiments, RS8is optionally substitutedO O. In some embodiments, RS8is optionally substituted

[0604] In some embodiments, RS8is optionally substituted\= / , NR' N"KN 'N N }=N

[0605] In some embodiments, RS8is io'

[0606] In some such embodiments, R° is hydrogen or Ci-6 aliphatic.

[0607] In some embodiments, RS8is optionally substituted165IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOis 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.

[0609] 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.

[0610] 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\\, Rs ANT* 1N\ J)

[0611] In some embodiments, RS8is '1-2. In some embodiments, RS8is Ooptionally substitutedwhere W™ is as described above and defined herein. In O#|— N'^'P0- I KA-Wm 3some embodiments, RS8is' '0-3. In some embodiments, RS8is optionally substituted166IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOO O$ I — I — *1 i \A-WmI RAW"1' '0-3. in some embodiments, RS8is ' 'o-s. in some embodiments, R...

Claims

PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOCLAIMS1. A compound of formula 3-A’:3-A’,or a pharmaceutically acceptable salt thereof, wherein:L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by - Cy-, -CHF-, -CF2-, -O-, -NR-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR- -P(O)R-, -P(O)NR2-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-;each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6579IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:(R1)mI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, - NR’-, -O-, -S-, or -S(O)2;580IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing 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 C1-6 aliphatic, phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo 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;581IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOIXs5xdz^xS4V>^xS3x(XS6) ^(X52) | *Ring Sis 'q v pwherein’ indicates bond to Ls;within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C3-C7 carbocyclylenyl, and 5- to 6-membered monocyclic heterocyclylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl and Ci-Cg alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl, -C(O)-Ci-Cg 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 Ci-Ce alkyl and Ci-Cg alkoxy;RNGis hydrogen or optionally substituted Ci-Cg alkyl;R is hydrogen or optionally substituted Ci-Cg alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Cg alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen,582IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOoxygen, and sulfur;Xs2, Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-C6 cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- C1-C3 alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;RN6is hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 RC4and RC5is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-Ce carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aV?^RD2bRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; and583IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOp is 0 or 1.

2. A compound of formula 3-A:3-Aor a pharmaceutically acceptable salt thereof, wherein:L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by - Cy-, -CHF-, -CF2-, -O-, -NR-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR- -P(O)R-, -P(O)NR2-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - NRC(O)-, -C(O)NR-, -OC(O)NR-, or -NRC(O)O-;each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;584IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOeach R is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:(R1)mI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, - NR’-, -O-, -S-, or -S(O)2;585IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing 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 C1-6 aliphatic, phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R’ is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo 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 atached, independently selected from nitrogen, oxygen, and sulfur;586IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOm is 0, 1, 2, 3 or 4;within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xs6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring S2 is an optionally substituted bivalent ring selected from phenylenyl, 5- to 6-membered monocyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and C3-C7 carbocyclylenyl;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orRS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Cg alkyl, -C(O)-Ci-Cg 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 Ci-Cg alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;R is hydrogen or optionally substituted Ci-Cg alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl 587IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xs5, Xa, Xb, Xc, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, -C2-Ce alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-Cs carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted 588IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOgroup selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl;q is 0 or 1; andp is 0 or 1.

3. The compound of claim 1 or 2, wherein Ring S2 is an optionally substituted phenylenyl or 6-membered heteroarylenyl with 1-4 nitrogen atoms.

4. The compound of any one of claims 1-3, wherein Ring S2 is, whereinI * indicates bond to RS1;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and589IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOsulfur.

5. A compound of formula 3-1” or formula 3-II”:3-II”or a pharmaceutically acceptable salt thereof, whereinL is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -10 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-, -590IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WONRC(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 heteroaryl enyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:(R1)mI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the 591IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOchain 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, C1-6 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 C1-6 aliphatic, phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered 592IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOheterocyclic 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 Ci-6 5 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 atached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; / 15N within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, and Xcrepresentsthat said bicyclic ring is aromatic;RS1is 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 20 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)I-2-NRN1RN2, -NRN3S(O)1-2RC2, or-NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted 30 group selected from Ci-Cg alkyl, Ci-Cghaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Cg alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms 593IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOto which they are attached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2- or absent;Gsis -NRNL-, -(CRC7RC8)I-2- or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, and Xs4, and Xs5are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- 594IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOmembered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2a\^-pD2bRC4and RC5are optionally taken together to form ', wherein each RD2aand RD2bis,595IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently, hydrogen or optionally substituted Ci-Ce alkyl.

6. A compound of formula 3-1’ or formula 3-II’:3-IFor a pharmaceutically acceptable salt thereof, whereinL is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -10 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-, -596IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WONRC(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 heteroaryl enyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:(R1)mI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the 597IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOchain 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, C1-6 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 C1-6 aliphatic, phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered 598IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOheterocyclic 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 Ci-6 5 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 atached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4; / 15N within the bicyclic ring containing Xs1, Xs2, Xs3, Xs4, Xs5, Xa, Xb, and Xcrepresentsthat said bicyclic ring is aromatic;RS1is 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 20 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms 30 independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are atached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;599IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs2, Xs3, Xs4, and Xs5, are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xcare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl 600IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOwith 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

7. A compound of formula 3-III’ or formula 3-IV’:601IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3 IV’5 or a pharmaceutically acceptable salt thereof, whereinL is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by - Cy-, -CHF-, -CF2-, -O-, -NR-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR- -P(O)R-, -P(O)NR2-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, - 10 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 602IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOcarbocyclylenyl, 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 heteroaryl enyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:OX^NHI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, - NR’-, -O-, -S-, or -S(O)2;603IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing 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 C1-6 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 604IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from nitrogen, oxygen, and sulfur;each R’ is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo 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 atached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4;within the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, -NRN3S(O)1-2RC2, or-NRN3C(O)NRN1RN2; or RS1and an optional substituent on Ring S2, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;YS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andR87is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are atached, combine to form an optionally substituted ring selected from 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from 605IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOnitrogen, oxygen, and sulfur and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.Lsis -G-LS1-LS2-GS- or -GS-LS2-LS1-G-;LS1is -C(O)-, -CH2-, or -S(O)i-2-;LS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG-, -(CRC7RCG)I-2-, or absent;Gsis -NRNL-, -(CRC7RC8)I-2-, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C3-Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- Ci-C3alkoxy, C3-Ce cycloalkyl, phenyl, Ci-Ce alkoxy, C3-Ce carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms 606IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from nitrogen, oxygen, and sulfur;Ring S 1 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;each RN1, RN2, RN3, RN6, RN7, and RD1is hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted ring selected from 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aV^xRD2bRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.607IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO8. A compound of formula 3-III or formula 3-IV:5 3-IVor a pharmaceutically acceptable salt thereof, whereinL is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by - Cy-, -CHF-, -CF2-, -O-, -NR-, -SiR2-, -Si(OH)R-, -Si(OH)2-, -P(O)OR- -P(O)R-, 10 -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 608IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOcarbocyclylenyl, 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 heteroaryl enyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:I-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2- or -C(O)-;X2is N or CH;L1is a covalent bond or a C1-3 bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR’2-, -CF2-, - NR’-, -O-, -S-, or -S(O)2;609IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORing 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 C1-6 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 610IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from nitrogen, oxygen, and sulfur;each R’ is independently hydrogen, or an optionally substituted group selected from Ci-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, ortwo 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 atached, independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3 or 4;within the bicyclic ring containing Xs1, Xs3, Xs4, Xs5, Xs6, Xa, Xb, and Xdrepresentsthat said bicyclic ring is aromatic;RS1is 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)I-2-NRN1RN2, or-NRN3S(O)i-2RC2; orYS1and YS2are each, independently, N or CRS7;YS3is N or CRS2;YS4is N or CRS3;each RS2, RS3, andRS7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, Ci-Cehaloalkyl, phenyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Ci-Ce alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orwhen YS3is CRS2or YS1is CRS7, RS1and RS2, or RS1and RS7together with the carbon atoms to which they are atached, combine to form an optionally substituted 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L8is -G-LS1-L82-GS- or -G8-L82-L81-G-;LS1is -C(O)-, -CH2-, or-S(O)i-2-;611IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOLS2is -NH-, -O-, -NRN6-, or -CRC4RC5-;G is -NRNG- -(CRC7RCG)I-2- or absent;Gsis -NRNL- -(CRC7RC8)I-2- or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl and Ci-Ce alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-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 Ci-Ce alkyl and Ci-Ce alkoxy;RNGis hydrogen or optionally substituted Ci-Ce alkyl;RNLis hydrogen or optionally substituted Ci-Ce alkyl;Xs1is N, CRS5, NRS4, O, or S;RS5is hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Xs3, Xs4, Xs5, and Xs6are each, independently, N, CRS6, NRS4, O, or S;Xa, Xb, and Xdare each, independently, C or N;each RS4is, independently, hydrogen or optionally substituted group selected from Ci-Ce alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, and -Ci- Ce alkyl-C -Ce cycloalkyl;each RS6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, -C2-C6 alkyl- C1-C3 alkoxy, C3-C6 cycloalkyl, phenyl, Ci-Ce alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring SI is an optionally substituted ring selected from phenyl, 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8- to 10-membered bicyclic heteroaryl ring with 1-4 heteroatoms 612IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOindependently selected from nitrogen, oxygen, and sulfur;each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN6and 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 Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, C3-C5 carbocyclyl, 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl 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 Ci-Ce alkyl and Ci-Ce alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRD2aRC4and RC5are optionally taken together to form', wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted Ci-Ce alkyl.

9. The compound of any one of claims 1-8, wherein Lsis -LS1-LS2-.

10. A compound of Formula 3-1 or Formula 3-II:613IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WO3-13-II5 or a pharmaceutically acceptable salt thereof, wherein:L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 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-, -10 NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl,614IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOan 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 Ci-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;DIM is a degradation inducing moiety selected from an E3 ubiquitin ligase binding moiety (LBM);LBM is a compound of formula I-aa-1:(R1)mI-aa-1or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CEE-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)-, -CR2-, -CF2-, - 615IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WONR-, -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, -NR2, SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - CR2N(R)C(O)R, -CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), - CR2(NR2), -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, - OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R, - N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)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 C1-6 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,616IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOoxygen, 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 Ci-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;RS1is 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 RS1is optionally substituted with 1-3 substituents, each independently selected from oxo, Ci-Ce alkyl, and Ci-Ce haloalkyl;RS2is hydrogen, Ci-Ce alkyl, or Ci-Ce haloalkyl;or RS1and RS2, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, and -C(0)RC2;RS3is hydrogen, Ci-Ce alkyl group, or Ci-Ce haloalkyl;RS4is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, -C2-C6alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-Ce alkyl-C3-Ce cycloalkyl, wherein RS4is optionally substituted with cyano;LS1is -C(O)- or -CH2-;LS2is -NH- or -O-,Xs1is N or CRS5,RS5is hydrogen or halogen,617IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOXs2, Xs3, and Xs4are each, independently, N or CRS6,RS6is hydrogen, halogen, cyano, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl group, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C alkoxy, C3-C6 cycloalkyl, or phenyl,wherein RS6is optionally substituted with 1-3 substituents, each independently selected from -OH and cyano;YS1and YS2are each, independently, N or CRS7;RS7is hydrogen, Ci-Ce alkyl, or Ci-Ce alkyl haloalkyl,Ring S 1 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring SI is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10- membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, andwherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)- Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl;each RN1, RN2, RN3, RN4, RC1, RC2, and RC3is, independently, hydrogen, Ci-Ce alkyl, or -C(O)- Ci-Ce alkyl; andRN5is H, Ci-Ce alkyl, -C(O)-Ci-Ce alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein RN5is optionally substituted with 1-3 substituents, each independently selected from cyano and -NCH3.

11. The compound of any one of claims 1-10, wherein RS1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.

12. The compound of any one of claims 1-10, wherein RS1is 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RS1is optionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.

13. The compound of any one of claims 1-10, wherein RS1is pyridonyl, wherein RS1is 618IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOoptionally substituted with 1-3 substituents, each independently selected from Ci-Ce alkyl and Ci-C6haloalkyl.O 014. The compound of any one of claims 1-10, wherein RS1isN1;^ / NO,0,0' N -—J J O N -—J j15. The compound of any one of claims 4-14, wherein RS2is hydrogen.

16. The compound of any one of claims 4-15, wherein RS3is hydrogen.

17. The compound of any one of claims 1-16, wherein LS1is -C(O)- and LS2is -NH-.

18. The compound of any one of claims 1-4 and 6-14, wherein Xs1, Xs2, and Xs4are each, independently, N or CH.

19. The compound of any one of claims 1-6 and 9-18, wherein XS1is CH, Xs2is CH, and Xs4is CH.

20. The compound of any one of claims 1-6 and 9-18, wherein XS1is N, Xs2is CH, and Xs4is CH.

21. The compound of any one of claims 1-6 and 9-18, wherein XS1is N, Xs2is CH, and Xs4is N.

22. The compound of any one of claims 4-21, wherein YS1is N or CH.

23. The compound of any one of claims 4-22, wherein YS1is CH.

24. The compound of any one of claims 4-23, wherein YS2is N or CH.

25. The compound of any one of claims 4-24, wherein YS2is CH.

26. The compound of any one of claims 1-4 and 6-22, wherein Xs2is CH.

27. The compound of any one of claims 1-26, wherein Ring SI is phenyl, wherein Ring SI619IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOis optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN9RNi0f_C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, and thiazolyl.

28. The compound of any one of claims 1-26, wherein Ring SI is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring SI is optionally substituted with 1-3 substituents, each independently selected from -OH, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6alkoxy, -Ci-C6alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl- NRN9RN1°, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl and thiazolyl.

29. The compound of any one of claims 1-26, wherein Ring SI isNRS8is hydrogen, -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, CI-C6alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy, -Ci-Ce alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; andRS9is hydrogen, halogen, or Ci-Ce alkyl.

30. The compound of any one of claims 1-26, wherein Ring SI isN, wherein:RS8is hydrogen, -OH, halogen, cyano, -NRN1RN2, -S(O)2NRN1RN2, -NRN3S(O)2RC3, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy, -Ci-Ce alkyl-Ci-C3alkoxy, -C(O)-Ci-C6alkyl, -Ci-C6alkyl-NRN1RN2, -C(O)-NRN4RN5, -NRN1RN2C(O)RC1, imidazolyl, or thiazolyl; and620IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WORS9is hydrogen, halogen, or Ci-Ce alkyl.The compound of any one of claims 1-26, wherein Ring SI iswherein:RS8is hydrogen, cyano, Ci-Ce alkyl, -C(O)-NRN4RN5, imidazolyl, or thiazolyl; andRN5is hydrogen, halogen, or Ci-Ce alkyl,wherein RN5is optionally substituted 1 substituent selected from cyano and -NCH3.

32. The compound of any one of claims 1-26, wherein Ring S1 is33. The compound of any one of claims 1-32, wherein RS4is Ci-Ce alkyl, Ci-Ce haloalkyl, -C2-C6 alkyl-Ci-C3alkoxy, -C2-C6alkyl-Ci-C3haloalkoxy, or -Ci-C6alkyl-C3-C6cycloalkyl.

34. A compound selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

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

36. A compound selected from any one of the compounds of Table 3, or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

38. A method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject a compound of any one of claims 1-36 or a pharmaceutical composition of claim 37.

39. A method of degrading STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or contacting the biological sample with a compound of 621IPTS / 128935854.1PCT / US25 / 24608 14 April 2025 (14.04.2025)Attorney Docket No. KME-127WOany one of claims 1-36 or a pharmaceutical composition of claim 37.

40. A method of treating a STAT6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of claims 1-36 or a pharmaceutical composition of claim 37.5 41. The method of claim 40, wherein the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, 10 thrombin- induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.622IPTS / 128935854.1

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