IRF5 degraders and uses thereof

Abstract

The present disclosure provides compounds and compositions useful for the modulation of interferon regulatory factor 5 ("IRF5") protein via ubiquitination and / or degradation, as well as methods of using the same for treating diseases.

Description

Attorney Docket No.: KME-303WOIRF5 DEGRADERS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Application No.63 / 744,849, filed January 14, 2025; U. S. Provisional Application No. 63 / 802,471, filed May 8, 2025; U. S. Provisional Application No. 63 / 866,201, filed August 18, 2025; U. S. Provisional Application No. 63 / 897,396, filed October 10, 2025; and U. S. Provisional Application No.63 / 957,506, filed January 9, 2026, each of which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to compounds and methods useful for the modulation of interferon regulatory factor 5 (“IRF5”) via ubiquitination and / or degradation by compounds and compositions disclosed herein. The present disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compositions in the treatment of various diseases.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 druglike molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews, C., Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth, J. S. Jr., Chembiochem, 2005, 6(l):40-46).

[0005] Interferon regulatory factor 5 (“IRF5”) is a transcription factor belonging to the interferon regulatory factor family. The activation of IRF5 is dependent on both the initiating signal and the cell types involved. IRF5 produces Type I interferon (IFN) response, which is made up of Page 1 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO interferon beta 1 (IFNB1) gene and 13 closely related interferon alpha (IFNA) genes. The activity of IRF5 downstream of various pattern recognition receptors (PRRs) determines the extent of the Type I IFN production and the pattern of cytokines induces.

[0006] Type I IFN activity is important as a line of defense against pathogens. Chronic Type I IFN response can promote autoimmunity by increasing associated antigen (Ag) presentation, lymphocyte-mediated adaptive immune responses, and chemokine expression. IRF5 has been identified as an autoimmune susceptibility gene and correlates with higher levels of Type I IFN, tumor necrosis factor alpha (TNFa), interleukin 6 (IL6), plasmablasts, and anti nuclear antibodies (ANAs). Global immunosuppression to control disease activity remains the standard of care for autoimmune disorders, and there is still a high unmet need to develop drugs against targets involved in disease progression.SUMMARY

[0007] The present disclosure relates to novel bifunctional compounds, which function to recruit IRF5 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 IRF5 protein, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. Also provided are monovalent compounds, which find utility as inducers of targeted ubiquitination of IRF5 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 IRF5 protein. In addilion, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease or disorder, such as autoimmune disorders.

[0008] The present application further relates to targeted degradation of IRF5 protein through the use of bifunctional molecules, including bifunctional molecules that link a cereblon binding moiety to a ligand that binds IRF5 protein.

[0009] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are effective as degraders of IRF5 protein.

[0010] Disclosed herein, in some embodiments, are compounds of Formula Z':Page 2 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOor a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0011] Disclosed herein, in some embodiments, are compounds of Formula Z:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0012] Disclosed herein, in some embodiments, are compounds of Formula A:Page 3 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOor a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0014] Disclosed herein, in some embodiments, are compounds of Formula II:Page 4 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOor a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0016] Disclosed herein, in some embodiments, are compounds of Formula III:Page 5 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula III,or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0018] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with inflammatory Page 6 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO responses and / or immune pathways implicating IRF5 protein. Such diseases, disorders, or conditions include those described herein.

[0019] Compounds disclosed herein are also useful for the study of IRF5 protein in biological and pathological phenomena; the study of inflammatory responses and / or immune pathways occurring in bodily tissues; and the comparative evaluation of new IRF5 degraders, in vitro or in vivo.DETAILED DESCRIPTION

[0020] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula Z', Formula Z, Formula A, Formula I, Formula II, Formula B, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) and compositions comprising said compounds useful as degraders of IRF5 protein. Compounds and compositions disclosed herein are also useful for treating diseases or disorders.Definitions

[0021] As used herein, the following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.Chemical Definitions

[0022] Chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0023] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include Page 7 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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 each of one or more hydrogen atoms by deuterium or tritium, or the replacement of each of one or more carbon atoms by a13C- or14C-enriched carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0024] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “Ci-Ce alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0025] 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,”), 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”) refers to a monocyclic C3-C6 hydrocarbon that is substituted or unsubstituted and is completely saturated (i.e., cycloalkyl) or that contains one or more units of unsaturation (i.e., cycloalkenyl), 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 (e.g., spirocyclic carbocycle 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. A carbocyclic ring may include one or more bridged bicyclic and / or spirocyclic ring. A carbocyclic ring may include a bridged bicyclic carbocycle and a bridged bicyclic heterocycle.

[0026] 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 Page 8 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0027] As used herein, the term “bridged bicyclic carbocycle” refers to any bicyclic carbocyclic ring system, 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 carbocycle has 7-12 carbon ring members. Such bridged bicyclic carbocycles are well known in the art and include those groups set forth below where each group is atached to the rest of the molecule at any substitutable carbon atom. Unless otherwise specified, a bridged bicyclic carbocycle is optionally substituted with one or more substituents as set forthPage 9 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOfor aliphatic groups. Exemplary bridged bicyclic carbocycles include: and

[0028] As used herein, the term “bridged bicyclic heterocycle” refers to any bicyclic heterocyclic ring system, 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 heterocycle has 7-12 ring members and 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic heterocycles 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.

[0029] Additionally or allernali vely, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic heterocycles include:H

[0030] As used herein, the term “spirocyclic ring” refers to a spirocyclic ring system, where two rings are connected through exactly one shared atom. In an embodiment, the shared atom is a quaternary carbon atom. In an embodiment, the shared atom is a nitrogen atom. The rings may each independently be a carbocyclic or heterocyclic ring. Each ring can be a saturated or partially unsaturated ring. In an embodiment, one ring is carbocyclic and one ring is heterocyclic. In an embodiment, the two rings are carbocyclic rings. In an embodiment, the two rings are heterocyclic rings.

[0031] As used herein, the term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-C10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon Page 10 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO atoms (“C1-C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-Ce alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., for instance from 1 to 6 substituents, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkyl group is unsubstituted Ci-10 alkyl (e.g., -CH3). In some embodiments, the alkyl group is substituted Ci-10 alkyl. Common alkyl abbreviations include -Me (-CH3), -Et (-CH2CH3), -nPr (-CH2CH2CH3), -‘Pr (-CH(CH3)2), -nBu (-CH2CH2CH2CH3), -Bu (-CH2CH(CH3)2), -SBU (-CH(CH3)(CH2CH3)), and -‘Bu (-C(CH3))3).

[0032] As used herein, the term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-C20 alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-C9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-C7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2-4 alkenyl groups as Page 11 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO well as pentenyl (Cs), pentadienyl (Cs), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents (e.g., for instance from 1 to 6 substituents, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In some embodiments, the alkenyl group is substituted C2-C10 alkenyl.

[0033] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-C20 alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-C9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-C7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-C5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-C4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-C4 alkynyl groups as well as pentynyl (Cs), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents (e.g., for instance from 1 to 6 substituents, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkynyl group is unsubstituted C2-C10 alkynyl. In some embodiments, the alkynyl group is substituted C2-C10 alkynyl.

[0034] The term “haloalkyl” refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0035] As used herein, the term “hydroxyalkyl” refers to refers to alkyl, as defined above, substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and -C(CH3)2OH.Page 12 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0036] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent.

[0037] 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.

[0038] The term “halogen” means -F, -Cl, -Br, or -I.

[0039] The term “heteroatom” refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; and 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)).

[0040] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0041] 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.

[0042] 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 six to fourteen ring members, wherein at least one ring in the system is a 6-carbon atom aromatic ring. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, 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 cycloaliphatic (e.g., cycloalkyl or cycloalkenyl) rings, such as indanyl, 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.

[0043] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable monocyclic or 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, for example an oxygen atom, a sulfur atom or a nitrogen atom. 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 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as Page 13 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in A-substituted pyrrolidinyl). A heterocyclyl may include one or more bridged bicyclic and / or spirocyclic rings.

[0044] 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 14 ring atoms having 6, 10, or 14 % electrons shared in a cyclic array, preferably 5, 6, or 9 ring atoms having 6, 10, or 14 % electrons shared in a cyclic array; and wherein in addition to carbon atom(s), at least one ring atom is a heteroatom. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, and phenothiazinyl. 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).

[0045] Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, oxazepinyl, and morpholinyl. 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 or cycloaliphatic rings, such as indolinyl, chromanyl, or tetrahydroquinolinyl. 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, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0046] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, a 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 Page 14 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO substituents envisioned in the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0047] Suitable monovalent substituents on a substitutable carbon atom include halogen; -(Ctbjo-4R0; -(CH2)O-40R°; -0(CH2)O-4R°, -0-(CH2)O-4C(0)OR°; -(CH2)O4CH(ORO)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)o-4N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(R0)C(0)NR°2; -N(RO)C(S)NR°2; -(CH2)O-4N(R°)C(0)OR0; -N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)o-4C(0)OSiR03; -(CH2)o-40C(0)R°; - OC(0)(CH2)O-4S R°; -(CH2)O-4SC(0)R°; -(CH2)O-4C(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O-40C(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R0; -(CH2)O-4S(0)2OR0; -(CH2)O-40S(0)2R0; -S(O)2NR°2; -(CH2)O-4S(0)R°; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CH2)O-4P(0)2R0; -(CH2)O-4P(0)R02; -(CH2)O-40P(0)R02; -(CH2)O-40P(0)(OR0)2; SiR°3; -(Ci_4straight or branched alkylene)O-N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH2PI1, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having C 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 (M heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0048] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o 2R*, -(haloR*), -(CH2)O 2OH, -(CH2)o 2OR*, -(CH2)o2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)o-2C(O)R‘, -(CH2)O2C(O)OH, -(CH2)O2C(O)OR‘, -(CH2)O 2SR*, -(CH2)O 2SH, -(CH2)O -2NH2, -(CH2)O2NHR‘, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0- Page 15 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

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

[0050] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having ( heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Suitable substituents on a substitutable nitrogen include -R\ -NRf2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C N^NR^, or -NiR SiO R'; 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 ( - 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 ( - heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the aliphatic group of R' are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -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.

[0053] ‘ ‘Stereoisomers” refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are Page 16 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respecti vely). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0054] ‘ ‘Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound disclosed herein.Other Definitions

[0055] The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0056] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, the IRF5 is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0057] Disease, disorder, and condition are used interchangeably herein.

[0058] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.

[0059] As used herein, the term “IRF5 -mediated” disorder, disease, and / or condition means any disorder, disease, or condition in which IRF5 plays a role. In some embodiments, the present Page 17 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO disclosure relates to treating or lessening the severity of one or more diseases in which IRF5 plays a role.

[0060] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically cflccli vc amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0061] As used herein, the term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0062] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromatographic purification are contemplated herein (e.g., diammonium salts).

[0063] As used herein, the terms “provided compound” and “disclosed compound” refers to any genus, subgenus, and / or species set forth herein.

[0064] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. In some embodiments, a “reference” sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant comparison. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population,Page 18 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0065] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0066] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”).Compounds

[0067] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.Formula Z'

[0068] Disclosed herein, in some embodiments is a compound of Formula Z':Page 19 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Formula Z',or a pharmaceutically acceptable salt thereof, wherein:is an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula Z

[0069] Disclosed herein, in some embodiments is a compound of Formula Z:or a pharmaceutically acceptable salt thereof, wherein:Page 20 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO(RE)e is an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula A

[0070] Disclosed herein, in some embodiments is a compound of Formula A:or a pharmaceutically acceptable salt thereof, wherein:Page 21 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula I

[0071] Disclosed herein, in some embodiments is a compound of Formula I:Formula I,or a pharmaceutically acceptable salt thereof, wherein:Page 22 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO<REL is an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula II

[0072] Disclosed herein, in some embodiments is a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Page 23 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOis an IRF5 Binding Moiety;Z1is -C(O)-, Z2is O, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each of the remaining variables of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula B

[0073] Disclosed herein, in some embodiments is a compound of Formula B:Formula B,or a pharmaceutically acceptable salt thereof, wherein:Page 24 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOI IIv$ / ,,vA / 2 3(RE)e is an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula III

[0074] Disclosed herein, in some embodiments is a compound of Formula III:Formula III,or a pharmaceutically acceptable salt thereof, wherein:Page 25 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WONI / V2-N<REL is an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein each variable of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.Formula IV

[0075] Disclosed herein, in some embodiments is a compound of Formula IV:Formula IV,or a pharmaceutically acceptable salt thereof, wherein:Page 26 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOis an IRF5 Binding Moiety;L is a Linker; andLBM is a Ligase Binding Moiety,wherein:Z1is -C(O)-, Z2is O, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond; andeach of the remaining variables of the IRF5 Binding Moiety, Linker (L), and Ligase Binding Moiety (LBM) is as defined and described herein.IRF5 Binding Moiety

[0076] It should be understood that the IRF5 Binding Moieties described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular IRF5 Binding Moiety (e.g., in any one of Formula V', Formula V, Formula W-A, Formula X-I, Formula X-II, Formula W-B, Formula X-III, and Formula X-IV, and subformulas thereof), that IRF5 Binding Moiety can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this disclosure, embodiments have been described and depicted in a way that enables a clear and concise disclosure to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all IRF5 Binding Moieties described and depicted herein can be applicable to all aspects and embodiments of the disclosure(s)Page 27 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO described and depicted herein. As used herein, “in some embodiments” refers to any of the aspects and embodiments of the disclosure(s) described and depicted herein.Formula Z'

[0077] In some embodiments, the IRF5 binding moiety of the compound of Formula Z' is a compound of Formula V:Formula V,or a pharmaceutically acceptable salt thereof, wherein:U1is -O- or -S-;RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(C0-C6alkyl)-O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), and -(C1-C6alkyl)-RY;each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;Page 28 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*R11* represents a bond to or L as defined in Formula Z';each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;, W175 ■ 1,,1 r ' < 11 1 C - &&&is hydrogen, Ci-Ce alkyl, or *;p _ p o oeach of W1, W2, W3, and W4is, independently, CRW, N, or ’— | &&&as defined in Formula Z';each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;Page 29 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.. — &&&

[0078] In some embodiments, W5is ’

[0079] In some embodiments, each of W1, W2, W3, and W4is, independently, CRWor N.r [n0n08em0] In some embod,riment,s, v Wsrl i ■s C — &&&.TIn some em,bod,i.ments, Wvr2 i ■s C —s&&&.TIn some,,■. ■ C — | &&&, „r4. C — | &&&embodiments, W iss. In some embodiments, W is1

[0081] In some embodiments, W5is H or Ci-Ce alkyl.

[0082] In some embodiments, W5is H, -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0083] In some embodiments, W5is H, -Me, or -Et.

[0084] In some embodiments, W5is H or -Me.

[0085] In some embodiments, W5is H. In some embodiments, W5is -Me.Formula Z

[0086] In some embodiments, the IRF5 binding moiety of the compound of Formula Z is a compound of Formula V:Formula V,Page 30 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or1;w5- / 7^ / V\R11W\ \4i(E)s represents a bond to (R)e or L as defined in Formula Z;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;W5is hydrogen, Ci-C6alkyl, or&&&;each of W1, W2, W3, and W4is, independently, CRW, N, or’;Page 31 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WON-— RZ1ON^ V4,2^— [ &&&,,* represents a bond to as defined in Formula Z; each Rwis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, and C1-C6 haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.. c — &&&

[0087] In some embodiments, W5is *

[0088] In some embodiments, each of W1, W2, W3, and W4is, independently, CRWor N.C — f &&& C —! &&&

[0089] In some embodiments, W1is *. In some embodiments, W2is ’. In someembodiments, W3is «. In some embodiments, W4is'

[0090] In some embodiments, W5is H or Ci-Ce alkyl.Page 32 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0091] In some embodiments, W5is H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -lBu.

[0092] In some embodiments, W5is H, -Me, or -Et.

[0093] In some embodiments, W5is H or -Me.

[0094] In some embodiments, W5is H. In some embodiments, W5is -Me.Formula A

[0095] In some embodiments, the IRF5 binding moiety of the compound of Formula A is a compound of Formula W-A:Formula W-A,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;Page 33 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;C — j &&each of V1, V2, V3, and V4is, independently, CRV, N, orwherein* represents a bond to(R&)eor L as defined in Formula A; each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;C — 1 &&&each of W1, W2, and W3is, independently, CRW, N, or *- &&& wherein represents a bondto as defined in Formula A;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;Page 34 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.

[0096] In some embodiments, each of W1, W2, and W3is, independently, CRWor N.Formula I

[0097] In some embodiments, the IRF5 binding moiety of the compound of Formula I is a compound of Formula X-I:O(RE)eFormula X-I,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orPage 35 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, or -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4, when not attachedto or L as defined in Formula I, is, independently, CRVor or N;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3, when not attachedto, is, independently, CRWor N,wherein — 1 represents a bond to L as defined in Formula I;each Rwis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, or Ci-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;Page 36 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.

[0098] In some embodiments, each of W1, W2, and W3is, independently, CRWor N.Formula II

[0099] In some embodiments, the IRF5 binding moiety of the compound of Formula II is a compound of Formula X-II:Formula X-II,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;Page 37 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*IR"-Y) W1( )wherein* represents a bond to (Ror L as defined in Formula II; each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;c — &&&each of W1, W2, and W3is, independently, CRW, N, or *Formula II;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;Page 38 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.

[0100] In some embodiments, each of W1, W2, and W3is, independently, CRWor N.Formula B

[0101] In some embodiments, the IRF5 binding moiety of the compound of Formula B is a compound of Formula W-B:Page 39 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;C — J &&each of V1, V2, V3, and V4is, independently, CRV, N, or. | &&wherein represents a bondto or L as defined in Formula B; each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl;Page 40 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.Formula III

[0102] In some embodiments, the IRF5 binding moiety of the compound of Formula III is a compound of Formula X-III:Formula X-III,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;Page 41 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, or -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4, when not attachedto or L as defined in Formula III, is, independently, CRVor or N;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each Rwis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, or Ci-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;Page 42 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.Formula IV

[0103] In some embodiments, the IRF5 binding moiety of the compound of Formula IV is a compound of Formula X-IV:Formula X-IV,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY; orPage 43 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, Ci-Ce alkyl, Ci-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or<W1'N. / R22, W2R11W3wherein* represents a bond to (R)e or L as defined in Formula IV; each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 44 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl;ande is 0, 1, 2, 3, 4, 5, or 6.Variables

[0104] It should be understood that the variables described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular variable (e.g., in any one of Formula Z', Formula Z, Formula A, Formula I, Formula II, Formula B, Formula III, and Formula IV, and subformulas thereof; or in any one of Formula V', Formula V, Formula W-A, Formula X-I, Formula X-II, Formula W-B, Formula X-III, and Formula X-IV, and subformulas thereof), that variable can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. Where variables are presented as lists, each subgroup of the variable(s) is also disclosed, and any variable(s) can be removed from the group. In other words, within this disclosure, embodiments have been described and depicted in a way that enables a clear and concise disclosure to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all variables described and depicted herein can be applicable to all aspects and embodiments of the disclosure(s) described and depicted herein. As used herein, “in some embodiments” refers to any of the aspects and embodiments of the disclosure(s) described and depicted herein.

[0105] In some embodiments, U1is -O-.

[0106] In some embodiments, U1is -S-.

[0107] In some embodiments, RZ1is H.

[0108] In some embodiments, RZ1is selected from the group consisting of Ci-Ce alkyl, C1-C6haloalkyl, and -C(O)-(Ci-C6alkyl).

[0109] In some embodiments, RZ1is selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl.

[0110] In some embodiments, RZ1is Ci-Ce alkyl.

[0111] In some embodiments, RZ1is selected from the group consisting of H and Ci-Ce alkyl.

[0112] In some embodiments, RZ1is H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -lBu.

[0113] In some embodiments, RZ1is H, -Me, or -Et.

[0114] In some embodiments, RZ1is H or -Me.

[0115] In some embodiments, Z2is NRZ2.Page 45 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0116] In some embodiments, RZ2is H.

[0117] In some embodiments, RZ2is selected from the group consisting of Ci-Ce alkyl, C1-C6haloalkyl, and -C(O)-(Ci-C6alkyl).

[0118] In some embodiments, RZ2is selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl.

[0119] In some embodiments, RZ2is Ci-Ce alkyl.

[0120] In some embodiments, RZ2is selected from the group consisting of H and Ci-Ce alkyl.

[0121] In some embodiments, RZ2is H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -lBu.

[0122] In some embodiments, RZ2is H, -Me, or -Et.

[0123] In some embodiments, RZ2is H or -Me.

[0124] In some embodiments, Z2is CRZ3RZ4.

[0125] In some embodiments, RZ3is selected from the group consisting of H, halo, Ci-Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-RY.

[0126] In some embodiments, RZ3is selected from the group consisting of H, Ci-Ce alkyl, and -(Ci-C6alkyl)-RY.

[0127] In some embodiments, RZ3is selected from the group consisting of H and Ci-Ce alkyl.

[0128] In some embodiments, RZ3is H, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, or -lBu.

[0129] In some embodiments, RZ3is H, -Me, or -Et.

[0130] In some embodiments, RZ3is H or -Me.

[0131] In some embodiments, RZ4is selected from the group consisting of H, halo, Ci-Ce alkyl, Ci-C6haloalkyl, and -(Ci-C6alkyl)-RY.

[0132] In some embodiments, RZ4is selected from the group consisting of H, Ci-Ce alkyl, and -(Ci-C6alkyl)-RY.

[0133] In some embodiments, RZ4is selected from the group consisting of H and Ci-Ce alkyl.

[0134] In some embodiments, RZ4is H, -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, or -lBu.

[0135] In some embodiments, RZ4is H, -Me, or -Et.

[0136] In some embodiments, RZ4is H or -Me.

[0137] In some embodiments, RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene.

[0138] In some embodiments, RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-6 membered monocyclic carbocyclylene.

[0139] In some embodiments, RZ3and RZ4are taken together with the carbon atom to which each is attached form cyclopropylene or cyclobutylene.

[0140] In some embodiments, RZ3and RZ4are taken together with the carbon atom to which each is attached form cyclopropylene.Page 46 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0141] In some embodiments, RZ3and RZ4are taken together with the carbon atom to which each is attached form cyclobutylene.

[0142] In some embodiments, Z3is CRZ5.

[0143] In some embodiments, Z4is CRZ5.

[0144] In some embodiments, Z5is CRZ5.

[0145] In some embodiments, each RZ5is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and C1-C6haloalkyl.

[0146] In some embodiments, each RZ5is, independently, selected from the group consisting of hydrogen and C1-C6alkyl.

[0147] In some embodiments, each RZ5is, independently, H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or - Bu.

[0148] In some embodiments, each RZ5is, independently, H, -Me, or -Et.

[0149] In some embodiments, each RZ5is, independently, H or -Me.z\2rx1 / N'RZ1z3|Kz5X /

[0150] In some embodiments, the structureofzis selected from the groupPage 47 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOz\27xX / N^RZIZ3z5x /

[0152] In some embodiments, the structureof ' is selected from the groupconsisting of:ZX'Z\X / N'RZ1z3<XXZ5X /

[0153] In some embodiments, the structureofzis selected from the groupPage 48 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOz\27xX / N^RZIZ3z5X /

[0154] In some embodiments, the structureof ' is selected from the groupzx'z\X / N'RZ1Z3IXZ5y

[0155] In some embodiments, the structureofzis selected from the groupconsisting of:Page 49 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOz\27xX / N^RZIZ3z5X /

[0156] In some embodiments, the structureof ' is selected from the groupZ\27XX / N^RZ1z3|Kz5X /

[0157] In some embodiments, the structureofzis selected from the groupZX'Z\X / N'RZ1z3<xfZ X5X / ,

[0158] In some embodiments, the structureof < is selected from the groupPage 50 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0160] In some embodiments, the structure of is selected from the group consisting

[0161] In some embodiments, the structure of is selected from the group consistingPage 51 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0162] In some embodiments, the structure of is selected from the group consistingPage 52 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0164] In some embodiments, the structure of is selected from the group consisting

[0165] In some embodiments, the structure of is selected from the group consisting

[0166] In some embodiments, the structure of is selected from the group consistingPage 53 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0167] In some embodiments, the structure of is selected from the group consistingQ _ &&

[0168] In some embodiments, V1is >Q _ - &&

[0169] In some embodiments, V1is * wherein represents a bond toPage 54 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Q -

[0170] In some embodiments, V1is * whereinrepresents a bond to

[0171] In some embodiments, V1is CRV. In some embodiments, V1is N.Q _ &&

[0172] In some embodiments, V2is >Tn C - 1 &&. - 1 &&

[0173] In some embodiments, V iss, wherein * represents a bond toQ _

[0174] In some embodiments, V2is , wherein- I * && represents a bond to

[0175] In some embodiments, V2is CRV. In some embodiments, V2is N.C — && - &&

[0176] In some embodiments, V2is *, wherein * represents a bond to L.

[0177] In some embodiments, V3is CRV. In some embodiments, V3is N.C — && - &&

[0178] In some embodiments, V3is ®, wherein * represents a bond to L.

[0179] In some embodiments, V4is CRV. In some embodiments, V4is N.Page 55 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0180] In some embodiments, each Rvis, independently, selected from the group consisting of hydrogen and C1-C6alkyl.

[0181] In some embodiments, each Rvis, independently, H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or - Bu.

[0182] In some embodiments, each Rvis, independently, H, -Me, or -Et.

[0183] In some embodiments, each Rvis, independently, H or -Me.

[0184] In some embodiments, each Rvis H.

[0185] In some embodiments, W1is CRW.

[0186] In some embodiments, W2is CRW.

[0187] In some embodiments, each Rwis, independently, selected from the group consisting of hydrogen and C1-C6alkyl.

[0188] In some embodiments, each Rwis, independently, H, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, or - Bu.

[0189] In some embodiments, each Rwis, independently, H, -Me, or -Et.

[0190] In some embodiments, each Rwis, independently, H or -Me.

[0191] In some embodiments, each Rwis H.

[0192] In some embodiments, W3is N.

[0193] In some embodiments, each R11is, independently, selected from the group consisting of H and Ci-C6alkyl.

[0194] In some embodiments, each R11is, independently, H, -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, or - Bu.

[0195] In some embodiments, each R11is, independently, H, -Me, or -Et.

[0196] In some embodiments, each R11is, independently, H or -Me.

[0197] In some embodiments, each R22is, independently, selected from the group consisting of H and Ci-C6alkyl.

[0198] In some embodiments, each R22is, independently, H, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, or - Bu.

[0199] In some embodiments, each R22is, independently, H, -Me, or -Et.

[0200] In some embodiments, each R22is, independently, H or -Me.

[0201] In some embodiments, n is 1, 2, or 3.

[0202] In some embodiments, n is 1 or 2.

[0203] In some embodiments, n is 1.

[0204] In some embodiments, Ring E is phenyl.

[0205] In some embodiments, Ring E is 3-8 membered monocyclic carbocyclyl.

[0206] In some embodiments, Ring E is 3-6 membered monocyclic carbocyclyl.Page 56 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0207] In some embodiments, Ring E is 6 membered monocyclic carbocyclyl.

[0208] In some embodiments, Ring E is cyclohexanyl.

[0209] In some embodiments, Ring E is 5-14 membered bridged bicyclic carbocyclyl.

[0210] In some embodiments, Ring E is 5-10 membered bridged bicyclic carbocyclyl.

[0211] In some embodiments, Ring E is 8-14 membered bridged bicyclic carbocyclyl.

[0212] In some embodiments, Ring E is 5-14 membered spirocyclic carbocyclyl.

[0213] In some embodiments, Ring E is 5-10 membered spirocyclic carbocyclyl.

[0214] In some embodiments, Ring E is 8-14 membered spirocyclic carbocyclyl.

[0215] In some embodiments, each REis, independently, selected from the group consisting of halo, Ci-C6alkyl, and C1-C6haloalkyl.

[0216] In some embodiments, each REis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0217] In some embodiments, each REis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0218] In some embodiments, e is 0, 1, 2, 3, or 4.

[0219] In some embodiments, e is 2.

[0220] In some embodiments,(RE)e is selected from the group consistingofPage 57 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0222] In some embodiments,(RE)e is selected from the group consisting of F F 5embodiments,Page 58 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Linker (L)

[0225] It should be understood that the linkers (L’s) described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular linker (L), that linker (L) can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. Where linkers are presented as lists, each subgroup of the linkers is also disclosed, and any linker(s) can be removed from the group. In other words, within this disclosure, embodiments have been described and depicted in a way that enables a clear and concise disclosure to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all linkers (L’s) described and depicted herein can be applicable to all aspects and embodiments of the disclosure(s) described and depicted herein. As used herein, “in some embodiments” refers to any of the aspects and embodiments of the disclosure(s) described and depicted herein.

[0226] In some embodiments, L is selected from the group consisting of:Page 59 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclicPage 60 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0227] In some embodiments, L is selected from the group consisting of:Page 61 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO s Ar2^Lr31, I r2 Jc1— j > I r2 Jx1— I _ |_r1^L|_d I _ |_r1 — " L |_x1 I _ |_r1 - |_c1 i 5 5 5 > I d ^Lr3— I * ^Lr2-^Lx1— I? 1 d ^Lr2— 85 5 5 5 1 x1 ^Lx2—? s | ^Lr2— I > 1 r1 Jr2— j _ |_r 1L|_r2 I _ |_x1L|_x2 I _ |_x1 \ |_c1 I 5 5 5 > I X1 Lc3- j I I c1 JC28 8 I c1 8 |_LC1--L^LC2 IL11^L" U2l_r3~ |_Ln^L^Lr2^ ^Lc2-|, I d Lc28 i I C1 8 8 I C1 8 |_H^L'-Lr2 ^Lx1— | l_H^ 'L"'Lx1 Lr3— | [—Ln^L"Lx1 ^[_c2-| s 1 I |_dL r1|_c2 ^Lr3 ^~|_c3 — 88! 18 |_dLr1 |_c2 - 11? '--pl — 88 8 I |_d 1Lx ~1~~~ |_r1 ^Lc^2~Lr2— 88; I 11 _ I 1? 8 8 I x1 I it <. I x1. |_LC1-^L'-LC2LC1^L'-|_C2 ^[_C3-J |—Lc1^L'-|_r2^L^Lc2_|8 I c1 Ic2Lc3-! i rd I 12 I x1, ILr1-^L^|_r2 ^|_r3 I |_Lc1^L^Lc2^L^Lc3'' ^|_c4 -*, and!1, each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;Page 62 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3- 6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0228] In some embodiments, L is selected from the group consisting of:Page 63 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO s Ix1^Lr1—; i d ^-Lc2— I i | d S_|_C1^L\ |_C2 I L|_r1^L^|_r2! L|_r1^L''-[_r2S> ^lr2 / Lr3— Isp2 Jc1— I! I r2 Jx1— I> I cl Lr3— > _ ir2 [_x1— I s i d _^Lr2— I _ |_r1^L^U2* _ |_r1L|_d ’ _ |_r1L|_x1 ’> i x1 ^-Lx^ —? I J"1 ^Lr2— I > | r1 Jr2— I _ |_r1L|_r2 I _ |_X1-^L^ |_X2 I _ |_x1L|_c1 «> I d _ Lc2S > I c1, l?2 i i I c1 _ L°2I |_Lr1^L^Lr2' Lr3— | |_Lr1^L- |_r2-" ^ |_c2_| |— [_r1^L^Lr2^Lx1-|, I d Ir2>, | d _ Ir2< ■ r1 _ Ir2, |—Lr1^L"~Lx1 ^Lr3— | |_Lr1^L'-Lx1 ^ LC2-| pLd"L'-Lc2 ^~Lc3-|, | r1 s, i x1 [_c2s j _ I c1 ^-Lc2„_^LC3- 1 _ |_d —L'~~|_C2 ^-|_X1 — _ |_c1 —L'~~[_r1 ^'Lr2— — [_r1L[_r2^Lr3LLCI^L^L02^L03^Lc4-and I!, each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;Page 64 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0229] In some embodiments, L is selected from the group consisting of:Page 65 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;Page 66 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0230] In some embodiments, L is selected from the group consisting of:|— Lr1^Lr2H Lr1^LC1-1 |-Lc1^LrH |—Ln^L^Lr3- 1 |_Ln^L-Lr2 - 1Page 67 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > Lr1^-Lr3— > I pLc1-L-Lr2- n j_Lc1-L r1 ^L -Lx1— I r2- 1> i d -- Lc3— I pLd-L^Lr1 / Lc2-| » i xi ^-Lr2— J _ |_C1^L^-|_C2 I, ^| X1 / Lr1— |sI d Lc2— I I d ^Lx1— I _ |_dL|_c2 s S— [_rl L"'Lr2* _ |_r1L|_r2 *>. i r2 ^[_c1— I > _ | ir2^Lr3— I _r1 -L|_c1 I _ |_r1L|_x1 1 § L1*2^Lx^ — I PLM L^LC1> i c1 ^Lr2— I > I c1 ^Lr3— I > If2 ^Lx1— I L|_r1^L'-Lx1'^? _ |_r1L|_c1 * *> i ri -- Lr2—! > i xi _^Lx2— I > Lr1^Lr2— | pLr1-L^Lr2 / S_|_x1^L\ |_x2 I> I d _ I_x1 >, | d, Lc2s > I ci JC2S |_r1^L-Lr2^Lr3-| [_Lr1^L-Lr2^Lx1-| |_L^L- Lr2^Lc2-| > | c1 _. [_r2, s I l_r£ i |_Lr1^L^Lx1 ^Lr3— | |— |_r1^L" ~Lx1Lc2— |. | xi _ [_c2> > I r1, L1? § |_LC1^L^LC2 ^Lx1— j J_Lc1^L^Lr1 ^Lr2— |each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;Page 68 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0231] In some embodiments, L is selected from the group consisting of:, I X1 Jc3- 1 i Ir1^Lr3, i > I x1 ^LrJ „ i [— |_C1^L"-|_C2! |_LC1- 'L" -|_c2 ^Lr3— | |—LC1^L"-LC2 ^LC3_|, | n J <1! |_L^L^Lr2^Lc2-|each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,Page 69 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl;Page 70 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0232] In some embodiments, L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0233] In some embodiments, L is selected from the group consisting of:|— Lr1^LrM |-Lr1^LCH |-Lc1^LrH [—Lr1^Lr^Lr3- 1 |_Ln^L-Lr2 - 1> ^Lr1u2-| j— Lc1 L"> Lr1--L? _ |_dL^ |_C2r2— * ^L i |_Lc1-LrlLc2-LXM! |_d Lr\1|_r2 _^ / Lc2~ I |> Lr1^-Lr3— I > I _^Lx1— I _ |_c1L^|_r2 s pLd-L-Lxi-LrH _ LcKL^|_r2xs> Ir1^Lc3— I pLd-L<Lr1 / Lc2-| > i xi ^Lr2— I _ |_dL''' |_c2 s _ |_c1L[_r1 *> I d Lc2— I.C1 ^Lx1— I s ^| X1 / LrM |_|_c1L^ |_C2 1 pLr1-L ^Lr2 / pLr1-L ^Lr2 / > Lr2 / Lr3— I > Lr2^-Lc1—! ^lr2 / Lx1— i pLn^L-LC< ’ PLM L^LC1* > i d ^.[_r3— I > | r2 ^Lx1— Isi d _^Lr2— I L|_r1^L'-|_r2^ I, | x1 Lx2— I > | T1 Lr2- 1 s lr1^Lr2— I pLr1-L^Lr2 / |_X1^L"- |_X2 I, I d J <1 J Lc1^Lci.Lr3_| L ^Lr2^ [_L^L-Lr2^Lc2-j l~Lr1|-Lr1,. xi ic2i > i ci ^-Lc3 Lc3— | rt ^Lri I |—LC1-'LpLci^L^Ln^ '-Lr2— | |— Lr1^L~'Lr2Lr3^Lc2Lx1— |Page 71 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,1 6, and1 6,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl;Page 72 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.

[0234] In some embodiments, L is selected from the group consisting of:i d > > i d _ L*1 s s i °1Lr1^L-Lr2^ ^ [_rM ULn^L'-Lr2- - |_c2_^ L_ |_r1^L^-Lc? ^ |_x1Page 73 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOwherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rca, -ORcb, and -N(Rcc)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -C(O)Rra, -ORrb, and -N(Rrc)2, orPage 74 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO two RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl; andeach Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl.Lcl, Lc2, Lc3, and Lc4

[0235] In some embodiments, each of Lcl, Lc2and Lc3is, independently, selected from Ci-Cealkylene, C2-C6 alkenylene, C2-C6 alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0236] In some embodiments, each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene, and C2-C6 alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0237] In some embodiments, each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene, and C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0238] In some embodiments, each of Lcl, Lc2, Lc3, and Lc4is, independently, selected from Ci-Ce alkylene and C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.Page 75 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0239] In some embodiments, each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-C6 alkenylene, and C2-C6 alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0240] In some embodiments, each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene and C2-C6 alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0241] In some embodiments, each of Lcl, Lc2, and Lc3is Ci-Ce alkylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0242] In some embodiments, Lclis selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0243] In some embodiments, Lclis selected from Ci-Ce alkylene, C2-C6 alkenylene, and C2-C6 alkynylene,wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0244] In some embodiments, Lclis selected from Ci-Ce alkylene and C2-C6 alkynylene, wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0245] In some embodiments, Lclis selected fromwherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0246] In some embodiments, Lclis Ci-Ce alkylene, wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0247] In some embodiments, Lclis C2-C6 alkenylene, wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0248] In some embodiments, Lclis C2-C6 alkynylene, wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0249] In some embodiments, Lclis1 6, wherein Lclis unsubstituted or subsliluled with 1, 2, 3, 4, 5, or 6 Rc.Page 76 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0250] In some embodiments, Lclis1-6, wherein Lclis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0251] In some embodiments, Lc2is selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0252] In some embodiments, Lc2is selected from Ci-Ce alkylene, C2-C6 alkenylene, and C2-C6 alkynylene,wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0253] In some embodiments, Lc2is selected from Ci-Ce alkylene and C2-C6 alkynylene, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0254] In some embodiments, Lc2is selected fromwherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0255] In some embodiments, Lc2is Ci-Ce alkylene, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0256] In some embodiments, Lc2is C2-C6 alkenylene, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0257] In some embodiments, Lc2is C2-C6 alkynylene, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0258] In some embodiments, Lc2is1-6, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0259] In some embodiments, Lc2is1 6, wherein Lc2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0260] In some embodiments, Lc3is selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0261] In some embodiments, Lc3is selected from Ci-Ce alkylene, C2-C6 alkenylene, and C2-C6 alkynylene,Page 77 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0262] In some embodiments, Lc3is selected from Ci-Ce alkylene and C2-C6 alkynylene, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0263] In some embodiments, Lc3is selected fromwherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0264] In some embodiments, Lc3is Ci-Ce alkylene, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0265] In some embodiments, Lc3is C2-C6 alkenylene, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0266] In some embodiments, Lc3is C2-C6 alkynylene, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0267] In some embodiments, Lc3is1-6, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0268] In some embodiments, Lc3is1 6, wherein Lc3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0269] In some embodiments, Lc4is selected from Ci-Ce alkylene, C2-C6 alkenylene, C2-C6alkynylene,wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0270] In some embodiments, Lc4is selected from Ci-Ce alkylene, C2-C6 alkenylene, and C2-C6 alkynylene,wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0271] In some embodiments, Lc4is selected from Ci-Ce alkylene and C2-C6 alkynylene, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0272] In some embodiments, Lc4is selected fromwherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0273] In some embodiments, Lc4is Ci-Ce alkylene, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.Page 78 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0274] In some embodiments, Lc4is C2-C6 alkenylene, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0275] In some embodiments, Lc4is C2-C6 alkynylene, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0276] In some embodiments, Lc4is'1 6, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

[0277] In some embodiments, Lc4is1 6, wherein Lc4is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.Lrl, Lr2, and Lr3

[0278] In some embodiments, each of Lrl, Lr2, and Lr3is, independently, selected from 3-8 membered monocyclic carbocyclylene, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0279] In some embodiments, each of Lrl, Lr2, and Lr3is, independently, selected from 3-8 membered monocyclic carbocyclylene and 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0280] In some embodiments, Lrlis selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0281] In some embodiments, Lrlis selected from 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8Page 79 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0282] In some embodiments, Lrlis selected from 4-7 membered monocyclic carbocyclylene, 5-10 membered bridged bicyclic carbocyclylene, 7-12 membered spirocyclic carbocyclylene, 4-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0283] In some embodiments, Lrlis phenylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0284] In some embodiments, Lrlis 3-8 membered monocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0285] In some embodiments, Lrlis 4-7 membered monocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0286] In some embodiments, Lrlis 5 membered monocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0287] In some embodiments, Lrlis 6 membered monocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0288] In some embodiments, Lrlis 5-14 membered bridged bicyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0289] In some embodiments, Lrlis 5-10 membered bridged bicyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0290] In some embodiments, Lrlis 6-9 membered bridged bicyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0291] In some embodiments, Lrlis 7-8 membered bridged bicyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0292] In some embodiments, Lrlis 5-14 membered spirocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 80 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0293] In some embodiments, Lrlis 7-12 membered spirocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0294] In some embodiments, Lrlis 7-10 membered spirocyclic carbocyclylene, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0295] In some embodiments, Lrlis 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0296] In some embodiments, Lrlis 4-7 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0297] In some embodiments, Lrlis 5 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0298] In some embodiments, Lrlis 6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0299] In some embodiments, Lrlis 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0300] In some embodiments, Lrlis 4-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0301] In some embodiments, Lrlis 5-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0302] In some embodiments, Lrlis 4 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0303] In some embodiments, Lrlis 5 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0304] In some embodiments, Lrlis 6 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 81 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0305] In some embodiments, Lrlis 7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0306] In some embodiments, Lrlis 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0307] In some embodiments, Lrlis 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0308] In some embodiments, Lrlis 6-9 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0309] In some embodiments, Lrlis 7-8 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0310] In some embodiments, Lrlis 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0311] In some embodiments, Lrlis 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0312] In some embodiments, Lrlis 7-10 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lrlis unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0313] In some embodiments, Lr2is selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0314] In some embodiments, Lr2is selected from 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8Page 82 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0315] In some embodiments, Lr2is selected from 4-7 membered monocyclic carbocyclylene, 5-10 membered bridged bicyclic carbocyclylene, 7-12 membered spirocyclic carbocyclylene, 4-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0316] In some embodiments, Lr2is phenylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0317] In some embodiments, Lr2is 3-8 membered monocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0318] In some embodiments, Lr2is 4-7 membered monocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0319] In some embodiments, Lr2is 5 membered monocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0320] In some embodiments, Lr2is 6 membered monocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0321] In some embodiments, Lr2is 5-14 membered bridged bicyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0322] In some embodiments, Lr2is 5-10 membered bridged bicyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0323] In some embodiments, Lr2is 6-9 membered bridged bicyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0324] In some embodiments, Lr2is 7-8 membered bridged bicyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0325] In some embodiments, Lr2is 5-14 membered spirocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 83 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0326] In some embodiments, Lr2is 7-12 membered spirocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0327] In some embodiments, Lr2is 7-10 membered spirocyclic carbocyclylene, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0328] In some embodiments, Lr2is 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0329] In some embodiments, Lr2is 4-7 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0330] In some embodiments, Lr2is 5 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0331] In some embodiments, Lr2is 6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0332] In some embodiments, Lr2is 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0333] In some embodiments, Lr2is 4-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0334] In some embodiments, Lr2is 5-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0335] In some embodiments, Lr2is 4 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0336] In some embodiments, Lr2is 5 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0337] In some embodiments, Lr2is 6 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 84 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0338] In some embodiments, Lr2is 7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0339] In some embodiments, Lr2is 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0340] In some embodiments, Lr2is 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0341] In some embodiments, Lr2is 6-9 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0342] In some embodiments, Lr2is 7-8 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0343] In some embodiments, Lr2is 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0344] In some embodiments, Lr2is 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0345] In some embodiments, Lr2is 7-10 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr2is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0346] In some embodiments, Lr3is selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0347] In some embodiments, Lr3is selected from 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8Page 85 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0348] In some embodiments, Lr3is selected from 4-7 membered monocyclic carbocyclylene, 5-10 membered bridged bicyclic carbocyclylene, 7-12 membered spirocyclic carbocyclylene, 4-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0349] In some embodiments, Lr3is phenylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0350] In some embodiments, Lr3is 3-8 membered monocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0351] In some embodiments, Lr3is 4-7 membered monocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0352] In some embodiments, Lr3is 5 membered monocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0353] In some embodiments, Lr3is 6 membered monocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0354] In some embodiments, Lr3is 5-14 membered bridged bicyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0355] In some embodiments, Lr3is 5-10 membered bridged bicyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0356] In some embodiments, Lr3is 6-9 membered bridged bicyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0357] In some embodiments, Lr3is 7-8 membered bridged bicyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0358] In some embodiments, Lr3is 5-14 membered spirocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 86 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0359] In some embodiments, Lr3is 7-12 membered spirocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0360] In some embodiments, Lr3is 7-10 membered spirocyclic carbocyclylene, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0361] In some embodiments, Lr3is 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0362] In some embodiments, Lr3is 4-7 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0363] In some embodiments, Lr3is 5 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0364] In some embodiments, Lr3is 6 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0365] In some embodiments, Lr3is 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0366] In some embodiments, Lr3is 4-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0367] In some embodiments, Lr3is 5-7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0368] In some embodiments, Lr3is 4 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0369] In some embodiments, Lr3is 5 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0370] In some embodiments, Lr3is 6 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 87 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0371] In some embodiments, Lr3is 7 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0372] In some embodiments, Lr3is 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0373] In some embodiments, Lr3is 5-10 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0374] In some embodiments, Lr3is 6-9 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0375] In some embodiments, Lr3is 7-8 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0376] In some embodiments, Lr3is 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0377] In some embodiments, Lr3is 7-12 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0378] In some embodiments, Lr3is 7-10 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Lr3is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Lxland Lx2

[0379] In some embodiments, Lxlis -O-. In some embodiments, Lxlis -NRX-

[0380] In some embodiments, Lx2is -O-. In some embodiments, Lx2is -NRX- Rx

[0381] In some embodiments, each Rxis, independently, selected from the group consisting of H, Ci-C6alkyl, and C1-C6haloalkyl.

[0382] In some embodiments, each Rxis, independently, selected from the group consisting of H, Ci-C6alkyl, and -C(O)Rxa.

[0383] In some embodiments, each Rxis, independently, selected from the group consisting of H and Ci-C6alkyl.Page 88 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0384] In some embodiments, each Rxis, independently, selected from the group consisting of Ci-C6alkyl and C1-C6haloalkyl.

[0385] In some embodiments, each Rxis, independently, selected from the group consisting of Ci-C6alkyl and -C(O)Rxa.

[0386] In some embodiments, each Rxis, independently, selected from the group consisting of Ci-C6alkyl.

[0387] In some embodiments, each Rxis, independently, selected from the group consisting of Ci-C6haloalkyl.

[0388] In some embodiments, each Rxis, independently, selected from the group consisting of -C(O)Rxa.

[0389] In some embodiments, each Rxis, independently, H, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)‘Bu, -C(O)CF3, -C(O)CHF2, -C(O)CH2F, -C(O)CF2CH3, -C(O)CF(CH3)2, -C(O)CF2CF3, or -C(O)CH2CF3.

[0390] In some embodiments, each Rxis, independently, H, -Me, -Et, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, or -C(O)Et.

[0391] In some embodiments, each Rxis, independently, H, -Me, -Et, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0392] In some embodiments, each Rxis, independently, H, -Me, or -Et.

[0393] In some embodiments, each Rxis, independently, H or -Me.

[0394] In some embodiments, each Rxis H.

[0395] In some embodiments, each Rxis -Me.

[0396] In some embodiments, each Rxis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, -C(O)Et, -C(O)nPr, -C(O)‘Pr, -C(O)nBu, -C(O)iBu, -C(O)sBu, -C(O)‘Bu, -C(O)CF3, -C(O)CHF2, -C(O)CH2F, -C(O)CF2CH3, -C(O)CF(CH3)2, -C(O)CF2CF3, or -C(O)CH2CF3.

[0397] In some embodiments, each Rxis, independently, -Me, -Et, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, -CH2CF3, -C(O)Me, or -C(O)Et.Rc

[0398] In some embodiments, each Rcis, independently, selected from the group consisting of halo, Ci-C6alkyl, Ci-C6haloalkyl, -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclicPage 89 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0399] In some embodiments, each Rcis, independently, selected from halo, Ci-Ce alkyl, and C1-C6haloalkyl, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0400] In some embodiments, each Rcis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3, or two Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0401] In some embodiments, each Rcis, independently, -F, -Cl, -Me, -Et, -CF3, -CHF2, or -CH2F, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0402] In some embodiments, each Rcis, independently, -F, -Cl, -Me, or -CF3, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0403] In some embodiments, each Rcis, independently, -F, -Cl, or -Me, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0404] In some embodiments, each Rcis, independently, -F or -Me, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0405] In some embodiments, each Rcis, independently, selected from the group consisting of halo, Ci-C6alkyl, Ci-C6haloalkyl, -C(O)Rca, -ORcb, and -N(RCC)2.

[0406] In some embodiments, each Rcis, independently, selected from halo, C1-C6alkyl, and C1-C6haloalkyl.

[0407] In some embodiments, each Rcis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, - Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0408] In some embodiments, each Rcis, independently, -F, -Cl, -Me, -Et, -CF3, -CHF2, or -CH2F.

[0409] In some embodiments, each Rcis, independently, -F, -Cl, -Me, or -CF3.

[0410] In some embodiments, each Rcis, independently, -F, -Cl, or -Me.Page 90 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0411] In some embodiments, each Rcis, independently, -F or -Me.

[0412] In some embodiments, two Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0413] In some embodiments, two Rcgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.RR

[0414] In some embodiments, each RRis, independently, selected from the group consisting of halo, Ci-C6alkyl, Ci-C6haloalkyl, -C(O)Rca, -ORcb, and -N(RCC)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0415] In some embodiments, each RRis, independently, selected from halo, Ci-Ce alkyl, and C1-C6haloalkyl, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0416] In some embodiments, each RRis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3, or two RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0417] In some embodiments, each RRis, independently, -F, -Cl, -Me, -Et, -CF3, -CHF2, or -CH2F, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0418] In some embodiments, each RRis, independently, -F, -Cl, -Me, or -CF3, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0419] In some embodiments, each RRis, independently, -F, -Cl, or -Me, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0420] In some embodiments, each RRis, independently, -F or -Me, orPage 91 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO two RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.

[0421] In some embodiments, each RRis, independently, selected from the group consisting of halo, Ci-C6alkyl, Ci-C6haloalkyl, -C(O)Rca, -ORcb, and -N(RCC)2.

[0422] In some embodiments, each RRis, independently, selected from halo, C1-C6alkyl, and C1-C6haloalkyl.

[0423] In some embodiments, each RRis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0424] In some embodiments, each RRis, independently, -F, -Cl, -Me, -Et, -CF3, -CHF2, or -CH2F.

[0425] In some embodiments, each RRis, independently, -F, -Cl, -Me, or -CF3.

[0426] In some embodiments, each RRis, independently, -F, -Cl, or -Me.

[0427] In some embodiments, each RRis, independently, -F or -Me.

[0428] In some embodiments, two RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0429] In some embodiments, two RRgroups on the same atom, together with the atom to which both are attached, form oxo, cyclopropylene, cyclobutylene, or oxetanylene.Rxa

[0430] In some embodiments, each Rxais, independently, selected from the group consisting of Ci-C6alkyl.

[0431] In some embodiments, each Rxais, independently, selected from the group consisting of Ci-C6haloalkyl.

[0432] In some embodiments, each Rxais, independently, -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0433] In some embodiments, each Rxais, independently, -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, or -‘Bu.

[0434] In some embodiments, each Rxais, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Rca

[0435] In some embodiments, each Rcais, independently, selected from the group consisting of Ci-C6alkyl.

[0436] In some embodiments, each Rcais, independently, selected from the group consisting of Ci-C6haloalkyl.Page 92 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0437] In some embodiments, each Rcais, independently, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0438] In some embodiments, each Rcais, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, or - Bu.

[0439] In some embodiments, each Rcais, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0440] Rd,

[0441] In some embodiments, each Rcbis, independently, selected from the group consisting of Ci-C6alkyl.

[0442] In some embodiments, each Rcbis, independently, selected from the group consisting of Ci-C6haloalkyl.

[0443] In some embodiments, each Rcbis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0444] In some embodiments, each Rcbis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, or - Bu.

[0445] In some embodiments, each Rcbis, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Rcc

[0446] In some embodiments, each Rccis, independently, selected from the group consisting of Ci-C6alkyl.

[0447] In some embodiments, each Rccis, independently, selected from the group consisting of Ci-C6haloalkyl.

[0448] In some embodiments, each Rccis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0449] In some embodiments, each Rccis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, or -‘Bu.

[0450] In some embodiments, each Rccis, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Rra

[0451] In some embodiments, each Rrais, independently, selected from the group consisting of Ci-C6alkyl.Page 93 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0452] In some embodiments, each Rrais, independently, selected from the group consisting of Ci-C6haloalkyl.

[0453] In some embodiments, each Rrais, independently, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, -*Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0454] In some embodiments, each Rrais, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, or - Bu.

[0455] In some embodiments, each Rrais, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Rrb

[0456] In some embodiments, each Rrbis, independently, selected from the group consisting of Ci-C6alkyl.

[0457] In some embodiments, each Rrbis, independently, selected from the group consisting of Ci-C6haloalkyl.

[0458] In some embodiments, each Rrbis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0459] In some embodiments, each Rrbis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, or - Bu.

[0460] In some embodiments, each Rrbis, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Rrc

[0461] In some embodiments, each Rrcis, independently, selected from the group consisting of Ci-C6alkyl.

[0462] In some embodiments, each Rrcis, independently, selected from the group consisting of Ci-C6haloalkyl.

[0463] In some embodiments, each Rrcis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, - Bu, -sBu, -‘Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

[0464] In some embodiments, each Rrcis, independently, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, or -‘Bu.

[0465] In some embodiments, each Rrcis, independently, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.Exemplary Embodiments of L

[0466] In some embodiments, L is selected from the group consisting of:Page 94 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO iL,.-LrH U"-LCPiJ, and *

[0467] In some embodiments, L is selected from the group consisting of the structures of Table L2-a and Table L2-b:Table L2-a 04T ]FT J F O.NQ. F^^kZ^y ' kZ^y ^TXQXF 0pQN< X0 6 0.'^ZZXN^y ZZ^*N''y k / Ny k^Ny ^Y'Nyk^Ny kZ^^ ' 0 00y 0 >■ '\ / A'N'y^ V^Nyk'N'"y k'N'"yAy,F A LN. y / Fk'N''yk^Nx_^\k\ Z-^~^'N'00-Ny ^^^^kZ^yPage 95 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0468] In some embodiments, L is selected from the group consisting of the structures of Table L2-a.

[0469] In some embodiments, L is selected from the group consisting of the structures of Table L2-b.

[0470] In some embodiments, L is selected from the group consisting of:[—Lr1^LI\r3 - 1 |_Lr1^Lc^Lr2- 1 [.rl^^L01- 1 |_Lr1^LC\c2_||_Lr1^L<Lr2 - 1 |_Lr1^>-r^Lx1 1 |_Lc1^L^Lc2 - 1 |—Lc1 —Lr2 - 1i_Lc1-'L<Ln 1 [— Lx1^L^Lr21! <, and i <.

[0471] In some embodiments, L is selected from the group consisting of the structures of Table L3-a and Table L3-b:Page 96 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Table L3-a00 yO \ ^ bNO ' J yO'^NCXF1 qFYO'^AXp p / LL d 6 / \ LL d\'q q 0 b p1 p 0 0 My A / Ny p FA F ^NY / M 7 / p p b 0A / / zNY \ \F / q / zo- yN— | F Z^ N z\Z 0 N-^. F. F \Page 97 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO b r " yN-0 a nb>O> / k 0 Q 0X0N 0' / 000 / Ny 4 0 i. Al^yNA0 0 b> u. < y^N^'''''~ / ''''x'^^ yN^0 1^ p / y < 0 yx x0 QN~0A N X\ 7 / yN^J yNxkA bo^ o20N'^X> Q / k 0 Q'N''~y o’b / 0f\cf / z7 — k^N' k^N-xXX 0\N"0 x0\0^Nx / \ o / kxNx^\ / F Fk / N^xy b I ■’‘0'0 ^'00 / > X'N'0kxNx / \, 00'N'x~y ^ 0 00 ^00 0 0yN'xx^^A / X / N^Page 98 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 99 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 100 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 101 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 102 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOL3-a.

[0473] In some embodiments, L is selected from the group consisting of the structures of Table L3-b.

[0474] In some embodiments, L is selected from the group consisting of:Page 103 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Lr1---Lr2— > ^Lc2— I a ir1^Lr3— I Lr1^Lx1— j a ^_i |_c1L|_c2 I _ |_c1r1: i _ I_c1L''' |_r2 aL^|_C2 I |—LC1L^L' 5 > i r1 ^Lx1— I a A n ^Lc3— I a ir1^-Lr2— S_|_C1-^L'^|_C2 I _ |_dL|_r2! 5 > \ x1 ^Lr2— j a ix1^Lr1— j a A x1 / -Lc2— i |_Ld-L--Lrl- n _ |_dL|_c2 a [_cl L^Lr1.. r2 |_r3— I > i d Jc2— I a J c1 ^Lx1—! pLr1-L -Lr2- I |— Lrl L^Lr2* |_Lr1^L^L01*a Lr2^Lc1— I a Ir2^Lx1— I > ic1^-Lr3— i [— Lrl L~" Lr2* |_Lr1^L^L°1*> i d Lr2— I a 1 1-2 ^Lx1—i a Ix1^Lx2— I i _ |_r1L|_d a _ |_r1L~~~ |_x1 a [— Lrl L^Lr2*5 ir1--Lr2— J > I x1 ^ |_c3— a Ir1Lr2—! L_ |_X1-^L"- |_X2 a _LXI-L^LC< I L, and *

[0475] In some embodiments, L is selected from the group consisting of:a lr1_^Lr2— a I ^Lx^ — I a Lr^ ^Lc2— I a Lr^ ^L1"3— I _ I_c1 —L~~~~ |_c2 a _ |_c2 i _ |_d —L|_r2 a _ |_d —L|_r2 a 5 5 5 a _ir1^Lr2— i a -Lr1^Lx1— I a -i rl ^Lc3— I | _ |_dL^|_x1 a | _ [_c1^L[_r2 a a _ |_c1L|_c2 aa i _^Lc2— I a Lx1^Lr2—! a TX1 — j _ [_d —L'^|_r1"^ a _ |_d —L''' |_r1 a _ |_dL|_c2 aa _| c1 ^Lc2— I a I c1 Jx1— IsJ r2^Lr3— ia lr2 / Lc1—! a Ir2 / Lx1— Isi c1 Jr3— I L_ [_r1^L'^|_x1^ 1 L|_r1^'L\|_c1^ I l |_r1^L^Lr2*5 5 a Ir2^Lx1— I a Ic1^Lr2— a Ix1^Lx2— I _ [_r1^L'''-|_c1 a _ |_r1^L|_x1 a _ |_r1L|_r2 aa Lr1^Lr2— j a Lr1^Lr2—! _LX1^L\ |_X2 i _ |_x1^L^[_c1 i *, and ’ a _ ix1^-Lc3— I _ — "|_c2 I

[0476] In some embodiments, L is *

[0477] In some embodiments, L is selected from the group consisting of the structures of Table L4-a and Table L4-b:Table L4-aPage 104 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOy^jXX^XX^ L^Xy -^ y / N H H > / n„ <- I b oF FA.cra; ' '^U^y b b _ F00"' N'^XAFA C^Oy 1 A> b 0x0 / U zy X\c''XF 0\ XX^XX / 1 F / y b 0^0Q F F F8F XX^^ XX ' X\c''F,xF.y^N / ~y'0 F-^ / UU0 U"Ny0^N''~'VX0 Fv / 0 / N^J UNy ' O>yFy FyA^^yN'X0 ^^ANyXX^NyXyPage 105 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO F F / X^ ''^ X^y AJZ-A;AA^NX AA'A'A yA^tfA AX\X X / Ny Ac-'X-X X / Ny AX\X XNyA'Y'"''N'A yA^NA^ AX\X “ / X / Ny AXX X / Ny AxzXX X / NyyAzZ^N'X^XyAzA'X’''' AY^NA Ac-'XX X / NA^-XX X / Nyy AxzXX xX / Ny yA^N'X^ yy^'N'X 'XX\X X^Ny A^'XX X / Ny Ax'-'XX X / NyyX'^N'X A [ "X~N'AAX\X X / Ny Ax'~-XXC-'X / Nyy~y*^N'A / / — A"N" A z XX ''^NX ANZ yy AZ- X / Ny X-Ny / F \ ZX^N^X^F / NA ZAAFAy1Z^^XNA^FANAU-. / NX XX\ / -NX kXOZF\y^N^ ZA^A17ANXX,, / N^X X-X / N^xA^N'^Z \ FXNA^ 1 L-n y NxA '-X-A ^Ny AXXLNX ^ VA^NA yy^NA yAX AX' A XXX^-X / NX X-X / A~ / \ / NX XNy A_ / -'\A-X ^ 71 AN7V> — o o / Z^\AXN^\ X^NAA^^O^^X XJJF FXy / x'N'xy ZFA z^^xx^N'^yFyy^ A-^^N-^y^F Y"hA A^\ / N-X X-Ny XA / N-X xJXOPage 106 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO / F \ / F \X'A kA / N^k kxkxN~A kXO AA^NA / kxA Axx X" AF / AXNU ZxXX / NxX1rNX ^^'''-'^N'A r~A xx^-N-^xvFFyy AA kx\A~k k / k / N-xkkx\XN / k "^AxNyAxXx°y kAx^OyyxyOy yyx°y0A'M / xy XX / N-XA^N-^X 'N^1 1 iA.-OFXjNy AAJFX / Ny AUFX? Ny1 1 Xx.'N^. XX / X / Nx AXJrOy / . CO-Jk^J\^J ^Ny y^N'XXx / y y^N-x> KYX / Axxx-A AZX / N\J / k / N A’"^A^O^ xx "^A / OY^XFOA / NX^Y / A ZNK kxNxxkF^x-z X XX x y / F / A o...,. '" Ak^o^xA / N. / X / FFv'k / XX / N, XX xx y / Page 107 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOA. N. AX / NZ,,p_J 1V-NyFV vA,zFyk^Nx^x / F 7, 1v \ NHy^N'X^A\k^Nx^"yAA-X / N\A, F X / pp | / ^N'X^XA\ FA / X'N' / ^ / Ar°v"N / A VA^N^A Z^zAx / 0AAy VN^AXA 5 AA^N'A p / ~xy^N'x^ yy / x'N' / yyN-xA A-NA\ yN\A A / N-x^y yN\A k^Nx^xA\ / F / F \■AN'A FA^A / ANy PN'''\-A A / N\A\A A^NXA\A y-y^NxAE F / X, / v / ~~N y An'^yL^AX / NXAVFANYAxyA F A-NXA rXAr^O AN'x'ypy O^N"^y AxANx''y p^N'^y yp AAX / N\ / AA-X / N-XA 0 / ^N'xy A|\i^y ■A^yAAN / y |' / ~''tA AA'y |-^NA k_Ax / Nx_J Q. O* AAV / NXAF F F F F FA^A Afq'^<yNY y yyA AA^N^A yNxAoAA''Z / N'AF F j F FPage 108 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOTable L4-bPage 109 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0478] In some embodiments, L is selected from the group consisting of the structures of Table L4-a.

[0479] In some embodiments, L is selected from the group consisting of the structures of Table L4-b.

[0480] In some embodiments, L is selected from the group consisting of:|_Lc1^Lr^|_r2^L\Lc2_| |_Lr1^Lc^Lr2^Lc<Lr3_| |_Ln^Lc^Lr2^L<LC2_|Lr1^LC^Lr2'"L^ |_x1_| |_Lr1^-LCi~Lx1^L^Lr3_| [— [_r1^LC\x1'"1- [_c2~ |5 5 5, | r1 L1? i > I r1 s > i x1 _[_c2i | | [— |_d^L" \|_x1— | |_Lc1--L^Lr1 ^[_r2— |, I r1, lr3 i s i x1, lr-l s i ri i xi.Lc1" ' ^Lr3— | |and|_Lc1^L--Lr2^L^Lc2_|Page 110 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0481] In some embodiments, L is selected from the group consisting of:, LC1 i > I d _ I_x1 > Lr2l_r3~ j |_L^L-Lr2^Lc2-|Jr2^Lr3|_LC1^L'-LC2 ^Lr3— |?I X1 _ IrJ * i rl I x1. pLc1^L^ |_c2 ^LC3_| |_Lc1 ^L^Lr2- ^LC2_|

[0482] In some embodiments, L is selected from the group consisting of:i c1^L r1J |_r2-rl \ [_c2 Jc2i > I d _ U$1 s Lr2^Lr3-| [_Ln^ L -Lr2- ^LC2_|, I C1, LC28 / Lr2|LLL2L |Lxi ^Lr1"2— ^ -r^x~ Lx1^Lr3- |_c2

[0483] In some embodiments, L is selected from the group consisting of:i |_Lr1- ILc^1Lr2^ ^Lc^2Lr3_| i4|_Ln- |L c^iLr2^ ^lc2_| J, I C1 ^LC2i |_L^L-Lr2' 'Lx1— |, | r1 Ir3s > I r1 Jr3! L_Lc1^L^ |_r2 ^LC2H — |_C1'^L'--|_C2 ^Lr3H

[0484] In some embodiments, L is *!, 1 *,, I x1 _ Lrl I i r1 | x1. pLd-'L'--Lc2 ^LC3-|orj_Ld --L^Lr2^L'^Lc2_|s | r1 < | x1 > ILC1^'L'-LC2 ^ Lr3H k- LC1^L~^LC2LCM

[0485] In some embodiments, L is *s s, or > | r1 ^ L^l 8Lc1 ^L"- |_r2 ^LC2~ |

[0486] In some embodiments, L is selected from the group consisting of the structures of Table L5-a, Table L5-b, and Table L5-c:Table L5-aPage 111 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 112 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0487] In some embodiments, L is selected from the group consisting of the structures of Table L5-a.

[0488] In some embodiments, L is selected from the group consisting of the structures of Table L5-b.

[0489] In some embodiments, L is selected from the group consisting of the structures of Table L5-c.

[0490] In some embodiments,L is

[0491] In some embodiments,L is

[0492] In some embodiments,L is

[0493] In some embodiments,L isLigase Binding Moiety (LBM)

[0494] It should be understood that the Ligase Binding Moieties (LBM’s) described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular Ligase Page 113 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Binding Moiety (LBM), that Ligase Binding Moiety (LBM) can be used in various embodiments of compositions of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. Where Ligase Binding Moieties (LBM’s) are presented as lists, each subgroup of the Ligase Binding Moieties (LBM’s) is also disclosed, and any Ligase Binding Moiety (LBM) can be removed from the group. In other words, within this disclosure, embodiments have been described and depicted in a way that enables a clear and concise disclosure to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all Ligase Binding Moieties (LBM’s) described and depicted herein can be applicable to all aspects and embodiments of the disclosure(s) described and depicted herein. As used herein, “in some embodiments” refers to any of the aspects and embodiments of the disclosure(s) described and depicted herein.

[0495] As described herein, compounds disclosed herein comprise a ligase binding moiety (LBM). The LBM induces ubiquination of IRF5 by an E3 ubiquitin ligase. In some embodiments, the moiety binds to cereblon (CRBN). The moiety which binds to CRBN is referred to herein as a “cereblon binding moiety” or “CBM.” CRBN is a protein that acts as a substrate adapter for the Cullin-4 (CRL4) E3 ubiquitin ligase complex [CRL4CRBN], which comprises CRBN, damaged DNA binding protein 1 ( DDB 1 ), Cullin-4A scaffold protein, and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins and marks them for degradation via the proteasome.

[0496] In some embodiments, LBM is an E3 ligase ligand. In some embodiments, LBM comprises means for binding an E3 ubiquitin ligase. In some embodiments, LBM comprises means for binding a cereblon E3 ubiquitin ligase.Formula I-aa-1" and Formula I-aa-2"

[0497] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I-aa-2":Page 114 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 115 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-membered heterocyclene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0498] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1":Page 116 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0499] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2":o(R.lmHNz)j

[0500] In some embodiments, Ring A is selected from ' ‘Page 117 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0501] In some embodiments, In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i:I-aa-l"-i,wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-membered Page 118 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.Formula I-aa-1' and Formula I-aa-2'

[0502] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' or Formula I-aa-2':Page 119 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOwherein: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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered Page 120 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0503] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1':1— V2Page 121 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO I-aa-1'.

[0504] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2':

[0505] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1':I-aa-1',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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Page 122 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 0-3 heteroatoms, in addition to the carbon or nitrogen fromPage 123 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0506] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i:j — L1— X? ^=0X1— NHI-aa-l'-i,wherein:X1is a bivalent moiety selected from -CH2-or -C(0)-;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(0)-, -C(S)-, -CR2-, -CF2-, -NR-, - 0-, -S-, or -S(0)2;O (R1)mA / HNRing Ais;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from RA, halogen, -CN, -NO2, -OR, -SR, -NR2, - SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(0)NR2, -C(0)N(R)0R, - CR2N(R)C(0)R, -CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(0R), - CR2(NR2), -OC(O)R, -0C(0)NR2, -OP(O)R2, -OP(O)(OR)2, -0P(0)(0R)NR2, - OP(O)(NR2)2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, -N(R)S(O)2R, -N(R)P(0)R2, -N(R)P(0)(0R)2, -N(R)P(0)(0R)NR2, -N(R)P(O)(NR2)2, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6Page 124 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0507] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii:I — (CC) — L1— X2\=OX1- NHI-aa-l'-ii,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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Page 125 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO, (R1)mRing B is a fused ring selected from 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, andPage 126 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.Formula I-aa-1 and Formula I-aa-2

[0508] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of formula I-aa-1 or formula I-aa-2:K2>=OX1— NI-aa-2,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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Page 127 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO, (R1)mRing B is a fused ring selected from benzo and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and Page 128 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0509] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1:I — fTY- L1— X* ^=0X1— NHI-aa-1.

[0510] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2:| — ( A )— L1— K2)=OX1- N' - °\I-aa-2.

[0511] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of formula I-aa-1:I-aa-1,wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CH;Page 129 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo and 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 130 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.Exemplary Embodiments of LBM - Formula I-aa-1" and Formula I-aa-2" and Subformulas Thereof

[0512] In some embodiments, X1is -CH2-.

[0513] In some embodiments, X1is -C(O)-.

[0514] In some embodiments, X2is N.

[0515] In some embodiments, X2is CRx2.

[0516] In some embodiments, Rx2is H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -lBu.

[0517] In some embodiments, Rx2is H, -Me, or -Et.

[0518] In some embodiments, Rx2is H or -Me.

[0519] In some embodiments, Rx2is H.

[0520] In some embodiments, Rx2is -Me.

[0521] In some embodiments, L1is absent.

[0522] In some embodiments, L1is -C(O)NR- or -NRC(O)-. In some embodiments, L1is -O-, -S-, or -NR-.Page 131 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 132 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0525] In some embodiments, Ring A is selected from

[0526] In some embodiments, Ring A is

[0528] In some embodiments, Ring A is selected fromPage 133 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0529] In some embodiments, Ring B is benzo.

[0530] In some embodiments, Ring B is 5 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0531] In some embodiments, Ring B is 6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0532] In some embodiments, Ring B is 6 membered heterocyclyl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0533] In some embodiments, each R1is, independently, selected from the group consisting of Ci-Ce alkyl, halogen, and -OR, ortwo R1groups together with the atom to which each is attached form cyclopropylene or cyclobutylene.

[0534] In some embodiments, LBM is selected from the group consisting of:

[0535] In some embodiments, LBM is selected from the group consisting of:Page 134 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 135 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0538] In some embodiments, LBM is selected from the group consisting of:

[0539] In some embodiments, LBM is selected from the group consisting of:Page 136 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0541] In some embodiments, LBM is selected from the group consisting of:

[0542] In some embodiments, LBM is

[0543] In some embodiments, LBM is selected from the group consisting of:

[0544] In some embodiments, LBM is selected from the group consisting of:Page 137 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0548] In some embodiments, LBM is selected from the group consisting of:Page 138 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0550] In some embodiments, LBM is selected from the group consisting of:

[0551] In some embodiments, LBM is selected from the group consisting of:

[0553] In some embodiments, LBM is selected from the group consisting of:Page 139 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0554] In some embodiments, LBM is selected from the group consisting of:, and

[0556] In some embodiments, LBM is selected from the group consisting of:Page 140 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0558] In some embodiments,LBM is

[0559] In some embodiments,LBM is

[0560] In some embodiments,LBM isFormula I-aa-3"

[0561] In some embodiments, the present disclosure provides a compound of formula I-aa-3":I-aa-3"or a pharmaceutically acceptable salt thereof, wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;(R1C)mc 'A1A / A3-, f Ring is selected from the group consisting of'A(R1C)mcOre res nts h”1 'p e t e point of attachment toAin X NHPage 141 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -S(O)2R', -S(O)2NR'2, -S(O)R', -C(O)R', -C(O)OR', - C(0)NR'2, -C(O)N(R')OR', -CR'2N(R')C(O)R', -CR'2N(R')C(O)NR'2, -CFR'2, -CF2R', - CF3, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.Formula I-aa-3'

[0562] In some embodiments, LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3':I-aa-3',wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;Page 142 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach Ring B is a fused ring independently selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6-membered heterocyclene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -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, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; me is 0, 1, 2, 3 or 4.Exemplary Embodiments of LBM - Formula I-aa-3" and Subformulas Thereof

[0563] In some embodiments, X1is -CH2-.

[0564] In some embodiments, X1is -C(O)-.

[0565] In some embodiments, each R1Cis, independently, selected from the group consisting of Ci-Ce alkyl, halogen, and -OR', ortwo R1Cgroups together with the atom to which each is attached form cyclopropylene or cyclobutylene.

[0566] In some embodiments, each R' is, independently, selected from hydrogen, Ci-Ce alkyl, and C2-C6 alkenyl.Page 143 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0567] In some embodiments, each R' is, independently, selected from hydrogen and C1-C6alkyl.

[0568] In some embodiments, me is 0, 1, or 2. In some embodiments, me is 0. In some embodiments, me is 1. In some embodiments, me is 2

[0569] In some embodiments, Ring C is selected from

[0570] In some embodiments, Ring C is selected fromPage 144 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0572] In some embodiments, Ring C is selected from

[0573] In some embodiments, Ring C is selected from

[0574] In some embodiments, Ring C is

[0575] In some embodiments, Ring C is

[0576] In some embodiments, Ring C is selected fromPage 145 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0577] In some embodiments, RingC is

[0578] In some embodiments, RingC is

[0579] In some embodiments, Ring C is selected from

[0580] In some embodiments, RingC is

[0581] In some embodiments, RingC is

[0582] In some embodiments, Ring C is selected from

[0583] In some embodiments, RingC isPage 146 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0584] In some embodiments, RingC is

[0585] In some embodiments, Ring C is selected from

[0586] In some embodiments, RingC is

[0587] In some embodiments, Ring C is

[0589] In some embodiments, RingC is

[0590] In some embodiments, RingC isPage 147 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOExemplary CompoundsFormula Z'

[0593] In some embodiments, the compound is of Formula Z':Formula Z',or a pharmaceutically acceptable salt thereof, wherein:U1is -O- or -S-;Page 148 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(C0-C6alkyl)-O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), and -(C1-C6alkyl)-RY;each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;_each of V1, V2, V3, and V4is, independently, CRV, N, or ’;- 1 Otoe ' E* represents a bond to <Ror L as defined in Formula Z';each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;W,,,5 i ■s, hyd,rogen, r Ci- rCe a iliky il, o C i &&r * &;— I &&&each of W1, W2, W3, and W4is, independently, CRW, N, or*;— | &&&represents a bond to as defined in Formula Z';Page 149 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:Lr1''L'a~Lrt— } |_Lrl-L'Lx2— jj i _ |_d ILr1 |_r2 ^Lr3— I I >! _ [_c1 1Li*1 |_x1 ^.|_r2— I s j! _ [_c1 |L|_r2 ^Lx1— I I> | _ |_c1Lri |_c2 ^Lc3— I I 4 | _ |_c1 _L|_r1 ^Lc2— I s i! _ ^Lx1^Lr2— I 8s? _ |_dL x~1~~~ |_c2 ^Lr1— j > A s | _ |_r1^Ld ^Lc2— j I > | ic'1'C2^^Lx1— jPage 150 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > i J r2 ^L j _ |_r1.-IL r~2~~~ | ^Lr3— Ic1— j j __ir2 ^Lx1— j _c1 I _ |_r1 —L~--|_x1 I |— Lr1^Lc1I >.1 c1 ^-Lr3— j > I r2 ^ Lx11 > i_ci ^-Lr2— I [_L^L-Lr2* I _ |_r1L~~~ |_c1 * I I_r1 — I_x1 s> ^-Lx1--L*2— j > _ i rl ^-Lr2— I > _ I r1 Lr2- 1 [_L^L^Lr2* _Lx1 —1— - |_x2 i i |_x'lL~~~~ |_c1 ij _ |_ xl ^Lc3— i I r1 Jr-? S. I d _ |_c2 >_Lc1-^L^|_r2 ^Lc2-| |— Lr1^L^Lr2Lr3— |5, | d J < s > I C1, LC2! i Ic1^Lr£ s pLr1-L ^Lr2- \lc2_||_Lr1^L- Lr2~Lx1— | |—Lr1^L^|_x1 ^Lr3— |. | r1 _ 8 > I r1 |_r£ i [_Lr1^L^Lx1 ^LC2~ | |_LC1^L--LC2 "- |_C3— | |—LC1^'L"'LC2 ^Lx1— |, I r1 _ |r2> I L x^lLr1^ ^LLc^2Lc1Lr2 pLd^L'-Lc2 ^Lr3— |r1 A xl ^Lr2^Lc2|— LC1^L1 n ^L*?each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lcl, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;Page 151 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2" or Formula I-aa-3":I-aa-2",Page 152 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOX1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 153 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 0-3 heteroatoms, in addition to the carbon or nitrogen from Page 154 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl;m is 0, 1, 2, 3 or 4;2, -A1A / A3- _4' Ring C is selected from the group consisting of~A(R1C)mc, and* represents the point of attachment toAinO denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -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, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.

[0594] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:Page 155 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0595] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: [— Lr1^Lr2H |-Lr1^LCH l_c1^Lr1“ I Lr1^Lr\r3— | |— Lr1^LC\r2— |Page 156 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > i _ I_c1 _LLr1|_c2 _^Lr2— j I i dr1^Lx1— j > I _ |_c1,iLr1|_r2 _^Lc2— § I> or1^Lr3— I > I r1 ^-Lr2— I Lc1"" Lr2* I _ |_dL|_x1!! |—Lc1^ ^-LLr^1Lr2 ^Lx1— j i> i_r1 ^Lc3— I > [ X1 ^-Lc2— j > i_xi ^Lr2— I | _ |_c1L|_c2 s [— i _ |_c1L[_n * Lc1^Lr1I.. ci ^Lx1— ) > ^-\c1^-Lc2— j i _-Lx^ ^Lr1— j |_L^L-Lr2* |_L^L-Lr2. i r2 ^, Lr3j > Ir2_^Lc11 |_Lr1^L^Lc1 I _ l_rl-— '■ — -|jcK a |—Ln^L^Lc1 is j d — | >, Ir2^Lx1— I j ^Lc1^-Lr3— j | _ |_r1L|_c1 ’ I _ I_r1L|_x1 * |_L^L-Lr2* I I r1 |_r2 - >. I rl ^-Lr2— i ^-Lx2— [ I _ s I _ p1^L^|_c1 s [_L^L^Lr2* > | d _ [_c2 j! _ I x-1 ^Lc3— j pLr1-L-Lr2- ^Lr3_| [_ Lr1^ ^Lr2" LC2-| > i d _ i_c3 i, i ci _^l_r3 s pLn^L-Lx1^ ^Lr3-| |— |_r1 L■"•LX1 Lc2— | |_L^L-Lr2~Lx1— | > | r1 |_r2 s > | xi _ [_c2>, I r1. L1? I |_Ld — ^|_X1_ |LC11~ |_C2 Lc3— | |_ld^L^|_r1' ~Lr2— |

[0596] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:Lr1^L,^Lr3 - 1 P1^L%2-| [_L^LrH pLri^LCM |-Lci^LrHPage 157 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > A X1 | _ |_d — ^Lr1- ] i > Ac1| ~^|_r2 ^Lc2-! s A I | _ |_r1^L^|_r2 _^^-Lx1- j i> i r2 ^Lr3- 1 >.1r2 - 1 > I r2 - 1 | _ |_r1L|_cl » | _ |_r1L|_x1 I | _ j_r1L|_d s 5 5 5 s | _ |_r1L|_r2^Lr3— j * j | _ |_r1 iL|_c1 ^Lx1— I j I _ |_r1^ iLc ^l |_x1 ^Lr2— I s 5 5 5 j _ |_r1^ |Lx\1 |_r2 ^Lx2— I 1 j _ I ^Lr2— I j _ |_x1 iL|_c1 ^Lr2— I I 5 5 5 > I C1 I02i I C1 UXd s i I C1 J [— Lr1^L^ Lr2^Lr3-| [_Ln^L-Lr2- | [— |_r1^L- [_r2^, | d J1? S s | c1 _ Lt? S i | r1 _ [_r2, [— Lr1^L^ Lx1^Lr3~| Lr1^L"Lx1' | [ - |_C3_|5 5 5 > | r1, Lt? s i i x1 _ Lc2s PLc1^L~" [_c2 LLd^L'-Lr1 ^Lr2—fs, and Is.

[0597] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a i Ax1^-Lc3- 1 I _ pharmaceutically acceptable salt thereof, wherein L is* > I r1 I t? S i I x1 |rJ S, r1 I x1.^Lr3— | |or|—Lc1^L'-Lr2^L^Lc2_|

[0598] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I-aa-2".

[0599] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1". In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2".

[0600] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i; and Page 158 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2"; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0601] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' or Formula I-aa-2'.

[0602] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii.In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'.

[0603] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically Page 159 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0604] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2.

[0605] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0606] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3".

[0607] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'.

[0608] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0609] In some embodiments, the compound is of Formula Z', or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 160 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0610] In some embodiments, the compound is of Formula Z'-l:Formula Z'-l,or a pharmaceutically acceptable salt thereof.

[0611] In some embodiments, the compound is of Formula Z'-2:Formula Z'-2,or a pharmaceutically acceptable salt thereof.

[0612] In some embodiments, the compound is of Formula Z'-3:Page 161 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula Z'-3,or a pharmaceutically acceptable salt thereof.Formula Z

[0613] In some embodiments, the compound is of Formula Z:or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Page 162 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (C1-C6 alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or *w? / ?\R'11\'n(E)wherein I represents a bond to(RE)eor L;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;W,,,5 i ■s, hyd,rogen, r C' r ’ 11 i C I &&&i-Ce alkyl, or *;C — &&&each of W1, W2, W3, and W4is, independently, CRW, N, or sz2^Z3<ITz5oL-V'X<V1&&&.,Srepresents a bond toeach RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;Page 163 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_Lr1^>-r2— | |_Lr1^LCH [_Lc1^LrH |_Lr1^Lr^Lr3 1 |_r1^LC\r2 1> | _ |_d — JR1^Lr2— j S. | _ |_c1 — ^ILr~1~'|_C2 ^Lx1— I I >r1^Lc2— I Lc1 L^Lr2* > 1 r1 ^Lr3— j > 1 rd ^-Lr2— j >r1^Lx1— ] |— Lc1^Lr21 [— Lc1^Lr2 i> i rt ^L S _ |_c1L|_c2c3— I s > i _ |_c1 " ^LLx1|_r1 _^Lc2— I I > L I _ |_clLx1^-Lr2— ~~~~ |_r1 *i.1 xi ^|_r1— j > \ c1 ^-Lc2— [ > i d ^Lx1— jLn^L'-Lr2! |_L^L-Lr2* J.1 r2 ^Lr3- j I.1 r2 — j > I — I [— |_r1^Lc11 [_ri^L^Lx1* |_Lr1 —L^Ld 1Page 164 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;Page 165 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2" or Formula I-aa-3":Page 166 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOX1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 167 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 0-3 heteroatoms, in addition to the carbon or nitrogen from Page 168 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl;m is 0, 1, 2, 3 or 4;2, -A1A / A3- _4' Ring C is selected from the group consisting of~A(R1C)mc, and* represents the point of attachment toAinO denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -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, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.

[0614] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:Page 169 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO p-'-'M p-H p^’M p<-L%3_| pL<pLn^Lr\xi — |Ir1> > | x1 [—LC1^L\C2_ | |_Ld ^Lr2— | Lc1^L^U I - j j_Lx1^L\r2 - 1>! _ [_c1 iL_r1 |_c2 _^Lr2— I > I |_c 1 -LLr1|_c2 ^Lx1— I I > I_r1 _^Lc2—|-Lc1^L^Lr2> ^Lr1_-'Lr3— ] j _ Lr1^Lr2— j s ^Lr1^Lx1— | [_ri^L^Lr2* j p^L''~~p i |_L^L^Lr2> | _ |_C'1^ jLo ^-Lc3— I '^ |_C2 I > | _ |_d ^LLx1|_r1 ^Lc2— j I i ^Lx1^Lr2— Ij ^lx1^Lr1— I j ^1c1_--Lc2— j | _ |_C1L~~~~ Lc2? ^Ic1^Lx1—[_L^L-Lr2* [_L^L-Lr2* >.[ T2 _^[_r31 j I f2,^|_c1- 1 s ^Lr2^Lx1— } |— Lr1 L^Lc1I _ |_r1^’ — -|_x1 I |_L^L^LC1* > i d ^Lr3— I?. I r2 [_x^ — | > i d ^Lr2— [_L^L-Lr2* |— Lr1 L^Lc1I _ |_r1^L^|_x1 I> Jx1^-Lx2— j > _ |_r1 ^Lr2— j > I_r1 ^Lr2- § [_r1^L^Lr2* _ — "|_x2 S _ p1^L^|_c1 I! > I r1 i ^Lx1_^Lc3— j Ic1s _^Lr3i _ [_c1 —L'~'~|_C2 I Lr1^L^[_r2" Lr3-jLC1^L"-Lr2 ^-[_C2-|5, | ci i <! s I C1 J02! > I ci s |_L^L-Lr2^LC2-| -Lr1^L^Lr2^ ^ Lx1-| pLr1^L^Lx1 ^~Lr3— |, I d [_r-£ i » i r1. L^2, > i _ ^1^"' - LX1 ^Lc2— i |_LC1^L'-|_C2 ^LC3-|r1^ Lr2i pLd"L^Lc2 "-Lx1_|> I xi _ i_c3 § Ir1 ^-" L^ i i j _ |_c1 — ILx'~1~'|_C2 _Prl |_c3 — I |_Lc1^L^Lr1^Lr2-| -Lc1^ ^Lc2^Lr3H

[0615] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:Page 170 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0616] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: [— Lr1^Lr2H |-Lr1^LCH |-Lc1^LrH Lr1^Lr\r3— | |— [_r1^LC\r2— |Page 171 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > | _ |_c1 _iL_r1|_°2 _^Lr2— j? |_Lci-Lr\c2-LXM i j _ I_c1 ^LLr1|_r2 _^Lc2— I I > i_rl _^Lr3— j! ^-Lr1^L Lc1 x1— j "" Lr2* [_L^Lr\x^Lr2H [—Ld^L^ '[_r2 i> i_r1 i _ [_c1L~'' [_c2 ^Lc3— I i > ^Lx1^-Lc2— j > i xi ^Lr2— j |_L^L^Lr1* i _ |_dL|_r1 * j | _ |_d ILx! |_c2 ^Lr11 I ic1_^Lc2—!,. cl ^Lx1— j |_L^L-Lr2* |_L^L-Lr2> ir2^Lr3— j > I ^Lc1— s J f2 ^Lx1— j |_L^L^LC1* _ [_rl—1— -|_x1 I [—Ln^L^Lc1 1 ic1^-Lr3— J > Ir2^Lx1— I > I cl I _ I_r1 |_x ^, Lr2— I |_L^L-Lr2* | _ |_r1L|_c1 s 1 I> Jx1--L*2— j > _ I_r1 ^-Lr2— [ > _ |_r1 ^Lr2—! [_ri^L^Lr2* i _ |_x1 "L|_c1 s8 I [_c1L x'1'' [_c2 ^Lc3— I Ir1^ iL d^Lr2_ i_c3 i i |_Lrt IL c-1Lx1^L^Lr3_| iIl“l^ L1? s > I r1 ^-L1? s c1 —L|_c2 I _ |_cl — j

[0617] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: [— Lr1^LfM j-Lr1^L^ |-Lc1^LrHLr1^L,^Lr3 - 1 P1-L<L*-|Page 172 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO X1 ^Lr1- ] > ^Lc2-! s _^-Lx1- j | _ |_d — I | ~^|_r2 I | _ |_r1^L^|_r2^ I> i r2 ^Lr3- 1 >.1r2 - 1 > I r2 - 1 | _ |_r1L[_c1 I | _ |_r1L|_x1 I | _ j_r1L|_d I 5 5 5 s ^Lr3— j j i ^ Lx1— j i cl ^Lr2— I | _ |_r1L|_r2* | _ |_r1L|_c1 I I _ |_r1^L^|_x1 s 5 5 5 j | x1 ^Lx2— I j I ^Lr2— j i ^Lr2— I _ |_r1^L\|_r2^ 1 _ I _ |_x1L|_c1 I 5 5 5 > I C1 I02i I C1 UXd s i I C1 ^LC? J [— Lr1^L^ Lr2^Lr3-| [_Ln^L-Lr2- | [— |_r1^L-Lr2^ ^ |_x1~|, | d Lr-? S s | c1 _ Lt? S i | r1 _ [_r2, [— Lr1^L^ Lx1^Lr3~| Lr1^L"Lx1' | [ - |_C3_|5 5 5 > | r1, Lt? s i i x1 _ Lc2s I—, ULc1^L'^ Lr1Lr2—Is, and Is.

[0618] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a i ^-Lc3- 1 I _ I pharmaceutically acceptable salt thereof, wherein L is* > I r1 Lt? s i i x1 LrJ s, ri i xl.LC1'''L'-'LC2 ^ Lr3— | LC1"L^LC2LC3- 1 |—Lc1^L'-Lr2^L^Lc2_|

[0619] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I-aa-2".

[0620] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1". In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2".

[0621] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i; and Page 173 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2"; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0622] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' or Formula I-aa-2'.

[0623] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii.In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'.

[0624] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically Page 174 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0625] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2.

[0626] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0627] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3".

[0628] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'.

[0629] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0630] In some embodiments, the compound is of Formula Z, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.Page 175 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0631] In some embodiments, the compound is of Formula Z-l:Formula Z-l,or a pharmaceutically acceptable salt thereof.

[0632] In some embodiments, the compound is of Formula Z-2:Formula Z-2,or a pharmaceutically acceptable salt thereof.

[0633] In some embodiments, the compound is of Formula Z-3:Page 176 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula Z-3,or a pharmaceutically acceptable salt thereof.Formula A

[0634] In some embodiments, the compound is of Formula A:or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,Page 177 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;_ I 00each of V1, V2, V3, and V4is, independently, CRV, N, or*;' represents a bond toeach RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected fromPage 178 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:l_Lcl-L'’H I— Lrt-1-" Lr3- 1 [— Lr1^L^Lr2— | > I C1 > > I. | ^ — I |— Lr1^Lc2— | |— Lr1'Lr2- 1 pLr1^Lr^Lx1 - 11S S Ir1;Lc1^L\c2— | [— Lc1^L\r2— | Lc1^ ^Lr1- 1 [_x1 L^ Lr2— |> _ i r1 ^.[_r2— j » ^lr1 / Lx1— j > ir1^Lc2— §I I _ |_dL|_r2 s> ir1 / -Lr3— I > i rl ^Lr2— jsI r1 ^Lx1— I pLd^L'"Lr2 I _ l_cl— '1— -|_x-K I PLc1 L^Lr2 *> ^ Lr1^Lc3— I > ^Lx1^Lc2— j > L xl ^Lr2— I I _ |_c1L|_r1 s | _ |_c1L|_r1 i?_Lx1 / Lr1— j > I_c1 \_c2— | I _ |_dL\ |_c2 s! ^Ic1^-Lx1— I |_r1^L-Lr2* |_L^L-Lr2** r2 ^Lr3- j * j r2 — [ > _ i r2 — j I _ |_r1^L^|_CT I | ^ |—Lr1^L^Lc1 I» j cl ^Lr3— j > I r2 ^- Lx11 > _ i_cl ^Lr2— § [_L^L-Lr2* | _ |_r1L|_c1^;> ix1^Lx2— j >,i_ri ^Lr2— j > _ I r1 _^ Lr2— § |_r1^L^Lr2* _ — - |_x2 S _ |_X1^L\|_C1 i> i_ xl _^Lc3— I, | d dc2s > | r1 ^Lr-? S! [_c1 — I |_L^L- Lr2' Lr3-j pLc1^L^|_r2 |. I d, I ci [— Lr1^ ^ Lr2Lc2|— Lr1^ ^ Lr2^Lx- i_| |— ^Lr3-|> I d _ L1? s > > I r1, L'-B |_Lr1^L'-Lx1 ^[_c2~ | > Lr1L1?:3-| |—Ld^L^Lc2- ^Lx1-|Page 179 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic Page 180 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2" or Formula I-aa-3":I-aa-3",X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 181 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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), - Page 182 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl;m is 0, 1, 2, 3 or 4; / (R1C)mcA3^ / Ring C is selected from the group consisting of'APage 183 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO* represents the point of attachment toAinX NH •O denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -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, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.

[0635] In some embodiments, each of W1, W2, and W3is, independently, CRWor N.

[0636] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: |_Lr1-LrH |-Lr^LCH |- Lc^LrH j-L^^U3— | |_Ln- L<Lr2_|> ^Lr1^Lc3— \Page 184 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > i C1 _^Lr3- jsI r2 ^ Lx1- 1 i I C1 _^Lr2-! j _ |_r1-^L'~—|_r2 I | _ |_r1L|_c1 s j _ |_r1L|_x1 I> _ i xl _^-Lx2— j > \r1^-Lr2— [ > I ■"! ^-Lr2— I I _ I_r1L|_r2 J | _ |_x1L[_x2 S j _ |_x1L|_c1 t> i «1 ^Lc3— j, i ci Jc2i jr1„ t [ I pLr1^L-.Lr2^ '- [_r3— | |— [_cl L^Lr2^[_c2-|, I xi JC2s, I r1 [_r£ s ■ xl ^-Lr-t |_Lc1^L^|_r1 ^~Lr2— | J ^ Lr3— j c1^L'~'-|_c2 |_c3, | r1 JXJ isILr1^ iL c-1Lr2- ^-LLc^2Lr3 ^-Lc3- I *5 1, and

[0637] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: |_L^LrM |-Lr1^LCH |- ~ I |-Lr1^L\r3— | |-Lr1^LCkr2— ||_Lr1^L\c1 - 1 pLr1^LC\c2_| |_Lr1^L<Lr2 - 1 |_Lr1^L^Lx1 - ||— [_c1^L\c2— | |_Lc1^Lr\r2 - 1Lc1^L^Lr1 - 1 L_Lx1^L^Lr2 - 1> > > > * ^1r1^Lr2— j > I rl ^Lx1— I > I i"1,[_c2— | _ |_c1L|_c2 I | _ |^d^*-\ |_c2 I | _ |_c1 L. |_r2 t > > 5 > ^Lr1^Lr3— I s Ir1^Lr2— I * | o _^Lx1— I j |_dL|_r2 I | |_dL|_x1 I j |_d^L~~~ |_r2 I??? j ^L1"1^-Lc3— > I xi ^-Lc2— [ i ix1^Lr2— { j _ I | _ |_c1Lj_r1 s | _ |_c1 L~~~~ |_r1 I 3, 3 lx1_^Lr1— js| cl ^Lc2— |s| cl ^-Lx1— — |_c1 — I _ |_r1 —L|_r2 t _ |_r1 ~ [_r2 t > > 5 > _ I r2 ^Lr3- 1; Ir2 - 1; Ir2 ^Lx^ - | |_r1 -L|_c1 < | |_r1 -L|_x1 < | |_r1 -L[_c1 >3 3, 3 ^lc1 / -Lr3— | 3 I r2 ^ Lx1— I 3 I C1 Jr21 j _ |_r1^'^L^|_r2"^ I j _ |_r1L|_c1 i | _ |_r1^LIPage 185 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO I x1 r1 —1— -|_r2 i I _ I_x1 ^LLr'1~'|_X2 ^-Lr2—! S x1^ ^LLr^1Ld r2-| Ic1r^LC3 > I C1 s i I C1,n^L-L 2^ " JC2!|-Lr1^L~~" Lr2'LC2-| |— Lr1^L-Lr2^Lx1-| Ic1^Lr3 s r1 —L^|_x1 '[_r3_ I r1-^L c'1^-L ^Lx1ri ^LC2H s > _ [_C1-^ iLr'1-~|_C2 ^Lr2Lc3— |Ir1^L1? s _ Ix1^Lc2ic1,l C1^L'-LC2^LX1-| n^L-Lr2^c^2Lr3lLr'1-~|_C2 ^Lr\2|_C3 — 'and Hc1

[0638] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:Page 186 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO? I r1 ^ LC3! Lc1Lc2 | j—Lx1_| |_LC1 Lr1^l_r2-|

[0639] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: |_Lr1^Lr2— | |_Lr1^LCH |_Lc1^LrH |_Lr1^L^Lr3 - j l_Lr1^LC\r2 - 1> > > 5Lr1^Lr^Lc1 - 1 [_Lr1^LC^Lc2_|Lr1 —Lr2 - 1 |_|_r1^Lr\x1 - 1> > 5Ld^Lr\c2 - 1Lc1^Lr\r2 - 1 Lc1^LX\r1 - 1 |_Lx1^Lr^Lr2 - 1> > > > I n _^Lr2— j > | r1 _^Lx1— I > | r1 Jc2— I _ |_c1^L''-|_c2^ I I I _Lc1^L'^|_r2^ I! _ |_C1" ^ '-IL r1'Lr2 ^Lr3— j * > _ |_c1^ ILn~'~|_x1'^ Jr2— I i > _ |_c1^ ILr'1'- |_r2^ Jx1— I i< _ i_rl ^Lc3— IsA x! ^Lc2— j > | xl [_r2—! I — |_c1L~~'~ |_c2 I | |_c1LI_r1 8 | 8>x1^Lr1— j > | c1 Jc2— [ > | cl Jx1— I — [_c1L'"'|_c2 8 _ |_r1^L~~'|_r2 ( _ |_r1L[_r28> ~-\r2^-Lr3- 1 > I r2 Jc1- 1 > I r2 Jx1- 1 j — |_r1 -L|_d I j _ [_r1 -L[_x1 s | _ |_r1^'L'^|_c1 ii ^lc1^Lr3- j. A r2 ^Lx1- 1 > I C1 ^_Lr2- 1> ^Lx1_^Lx2— j > | r1 ^. Lr2— IsI r1 ^-Lr2— I j _ |_r1 -L|_r2 I j _ |_x1^*-\ |_x2 8 j _ |_x1-^L\[_c1 8

[0640] In some embodiments, the compound is of Formula A, or a subformula thereof, or a! _i x! | _ I ^Lc3— i 8 pharmaceutically acceptable salt thereof, wherein L isIPage 187 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0641] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I-aa-2".

[0642] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1". In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2".

[0643] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2"; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0644] In some embodiments, the compound is of Formula A, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' or Formula I-aa-2'.

[0645] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii.In some embodiments, the compound is of Formula A, or a subformula thereof, or a Page 188 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'.

[0646] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6RR.

[0647] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2.

[0648] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatomsPage 189 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0649] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3".

[0650] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'.

[0651] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3' '; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0652] In some embodiments, the compound is of Formula A, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-3'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0653] In some embodiments, the compound is of Formula A:Z\2^'Z\1 / N'RZ1(RE)eFormula A,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Page 190 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;p — i &&&each of W1, W2, and W3is, independently, CRW, N, or *each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;Page 191 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_L^Lr2H p L^LCH p i_ci^Lr1~ I^Lr2— j. ^Ir1^Lx1— I >r1^ Lc2— I | _ |_d —L~^|_c2 s | _ |_c1 — I Lc1 L^Lr2* > 1 r1 ^Lr3— j > 1 rd ^-Lr2— j >r1^Lx1— ] |— Lc1^Lr21 [— Lc1^Lr2* > S _ |_c1 iLrt |_c2 ^Lc3— I s > i _ |_c1 " ^LLx1|_r1 _^Lc2— I I > I _ |_cl LLx~~1~~ |_r1 ^-Lr2— *i.1 xi ^|_r1— j > \ c1 ^-Lc2— [ > i d ^Lx1— jLn^L'-Lr2! |_L^L-Lr2*.1 r2 ^Lr3- j I.1 r2 — j > [— |_r1^Lc11 [_ri^L^Lx1* |_Lr1 — IL^Ld — I 1Page 192 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 193 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1':I-aa-1'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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Page 194 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 0-3 heteroatoms, in addition to the carbon or nitrogen fromPage 195 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO which the two R groups are attached, independently selected from nitrogen, oxygen, and sulfur;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

[0654] In some embodiments, each of W1, W2, and W3is, independently, CRWor N.

[0655] In some embodiments, the compound is of Formula A-l:Formula A-l,or a pharmaceutically acceptable salt thereof.

[0656] In some embodiments, the compound is of Formula A-2:Page 196 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Formula A-2,or a pharmaceutically acceptable salt thereof.

[0657] In some embodiments, the compound is of Formula A-3:Formula A-3,or a pharmaceutically acceptable salt thereof.Formula I

[0658] In some embodiments, the compound is of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Page 197 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;Page 198 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:Lr3_| pLr1-L<Lr2_| u^'M j I c1 | > I pLr1^L-Lc1— | |_Lr1^L-Lc2— | |-Lr1^L'Lr2- 1 pLr1^Lr^Lx1 - 1pLd^L,^Lc2 - 1Ld^Lr^Lr2 - 1 -Lr1- 1 [—Lx1^Lr\r2 - 1» I fl ^Lr2— j * ^I | _ |_c1 —r1^Lx1— \ i > ^Lr1^-Lc2— j j— Lc1^Lr2’ > ir1^Lr3— j > i n -^Lr2— j |_L!r1^Lx1— ic1^L-^Lr2 i Lc1^Lr2! j _ lr1^-Lc3— I > _ | xi ^Lc2— j j.1 X1 1 i _ |_c1L|_r1 1s j xi ^Lr1— j ^-Lc2— j j _Lc1^Lx1— I j _ |_dL|_c2 I [_r1^L-Lr2* |_L^L-Lr2* > i r2 _^-Lr3- i __|r2 ^-LX^ 1 >r2^Lc1— j |—Lr1 L^Lc11 |—Ln^L^Lc1 Ii \ d ^Lr3— i » _.ir2^Lx1— I i _~LC1 ^-" Lr3—!! |_r1^^L^|_X1 I |_L^L-Lr2* Lr1 L^Lc1<; I r1 |_r2 - > _ i rl ^Lr2— I > Jx1^Lx2— j _Lx1 —1— - |_x2 S! |_x1^L^|_c'l I [_r1^L^Lr2*> | r1 ^Lr-? S j _ _ I x-1 ^_Lc3— j ic1s i _ [_c1 - 5 pLc1^L^|_r2 ^LC2-| -C1^L-Lr2'Lr3— | > I c1 _ |_c2 > | c1 s. | d <1ILr1^L^Lx1 ^~Lr3— |—Lr1^L^Lr2"'Lx1- [— Lr1^ ^Lr2Lc2Page 199 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO, pLc1^ |Lr'1-Lc2^ JL r'3^Lc3 -'' LLXJ^Lc4, - s 1each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, orPage 200 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO two RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2" or Formula I-aa-3":I-aa-3",X1is a bivalent moiety selected from -CH₂-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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(0)-, -C(S)-, -CR2-, -CF2-, -NR-, - 0-, -S-, or -S(0)2;Page 201 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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), - Page 202 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl;m is 0, 1, 2, 3 or 4; / (R1C)mcA3^ / Ring C is selected from the group consisting of'APage 203 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO' ”1 '* represents the point of attachment toAinX NH.O denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -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, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.

[0659] In some embodiments, the compound is of Formula I, or a subformula thereof, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:pLr1^LCH |_Lc1-LrM |_Lr1^Lr\r3 - 1 pr1Lr2 - |pLn^Lr\xi — ||_ pc1Lc^^Lr1_|Lx1^L\r2 - 14 | _ |_C1 1Lrl |_C2 ^Lr2— | 4 > | _ |_c1 ILr1 |_c2 ^Lx1— s j! _ [_c1 iLJi |_r2 ^Lc2— I 44.1 r1 ^-Lr3— j $,1 r1 ^Lr2— j j 1 r1 ^Lx1— j Lc1^Lr2* > 4 _ |_c1 JLr1|_c2 ^Lc3— I 4 » | _ |_c1.|Lx1|_r1 _^Lc2— I 4 4 | _ |_c1 _ iLx1|_r 1 ^Lr2— I 45 4 i _ |_dL|_c2 ^-Lr^ — j 4 > ic1_^Lc2— j s A |_r1^L-Lr2cl ^Lx1— j * |_Lr1^L-Lr2^4 i r2 ^|_r3- j |_Lr1^L- -Lc1! > | _ [_r1 — |_x1 ^Lc1— I I s S _ |_r1 - |L|_c1 ^Lx1— I sPage 204 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0660] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:|_L^Lr2H Lr1^LCl—I |-Lc1^LrH |_r1^Lr\r3— | |_r1^LC\r2— |> ^1r1^Lr2— I > i rl ^Lx1— I. i n Jc2— I LLC1-^L'^LC2^LI ILC1^L^ |_C2 I LLc1^L'-|_r2'^L!>r1^-Lr3— j > I r1 _^Lr2— | S | r1 Jx1— I i — [_d —L~~— j_r2 3 j I j Lc1^*-\[_r2 Iir1 / Lc3— I > i xi, Lc2— IsI X1 Jr2— I — [_c1L'''[_c2 I — |_c1^L|_r1! _ I> i x1 _^Lr1— js| cl ^Lc2— jsi cl,[_x1— I — [_c1 —L'''[_C2 I — [_r1^L~~~[_r2 I I " '[_r2 I> ^lr2_^Lr3- 1 > I r2 Jc1- 1sI r2 Jx1- 1 LLr1^L-^Lc1-^ i ILr1^L'^Lx1^LI LLr1^L\|_c1^LI3 — Ic1 / -Lr3— | 3 I r2 Jx1— I 3 I c1 Jr21 — [_r1L~~^]_r2 I | [_r1 - "L|_c1! | j_r1— ~^[_x1 IPage 205 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > ^lx1^Lx2— I I _ I r1 _^Lr2— I [_L^L^Lr2* Lx1^Land

[0661] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:|_LO1-L'H j_Lr1--L'\r3 - j [_Lr,-L=lLr2_| |_Lr1^L-Lc1_ | |_Lr1-L<Lc2_| |_Lr1^L<Lr2_| pLn^Lr^Lx1 - 15j _ I fl ^Lr2— I | j I r1 ^Lx1— I »ILc',^Li r^1Lr2_^Lc2— *! ir1^Lr3— j > I r1 Jr2— j > I rl Jx1— — |_c1 "L|_r2 I — [_c1—1— '-|jcK i _ i-d^1— -|_r2-^Li> ^Lr1^-Lc3—si xl ^-Lc2— j > i xl, ir2— I — |_d I _ |_d —L\ |_r1 - i _ |_d —L|_r1^Li> ix1--Lr1— | > i ci _Lc2— I a i ci Jx1—I ILr1^L^Lr2^Li L_Lr1^L'-[_r2^LI> Jr2^Lr3- j > I r2 [_c1- 1sI r2 Ix1- 1 L_ |_r1'^L'-|_c1^L- I ^_Lr1'^L\|_x1^LI L_Lr1^L^Lc1^LIic1^Lr3- 1, | r2, [_x1- 1 > I C1 lr2- 1 LLr1^L'-Lr2^LI ^_l_r1^L'-Lc1^L- I l_Lr1^L~-|_x1^LI> nx1^Lx2— js| r1 ^Lr2— I, | r1 Jr2— I — — ~~Lr2_ Lx1— — " Lx2’ _ Lx1— — ^[_dLIjL. L C1-'Lxd ^LCo^L 2c3— > x ci,[_ I |_Lr1^L^Lr2-'Lc'2s > -LI d,ixd t r3_j |_Lr1^L'-Lr2^L'^Lc2_|Page 206 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO?I r1 _ |J2 j j_Ld"L~-Lc2 \|_x1— | |— Lc1

[0662] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of:|_Le>-LrM |_Lr1^Lr^Lr3- 1[—Ld^Lr^Lc2 - 1Lc1^Lr\r2 - 1Lc1^LX\r1 - 1 L_Lx1^Lr\r2_> > 5 > Ir1_^Lr2— j > | ri _^Lx1— I > i ^-Lc2— | | |_c1 -L''' |_c2 I | 3 j |_c1 |_r2 i>r1^Lr3— I > I n ^Lr2— I s I r1, Lx1— j j |_c1L|_r2 I | |_c1 —L^~|_x1 | | |_ci^ L \ |_r2^ I> ^Lr1^Lc3— I < \x1^Lc2— jsI xl ^Lr2— j i _ |_c1L~~'~ |_c2 I I _ Lc1 LLr1| _ |_C1L^|_r1^ I>x1^Lr1— j > | C1 _^Lc2— j > | C1 ^Lx1— [ _ |_C1^L'~~-|_C2 I _ |_r1^L~~'|_r2 i _ |_r1 [_r2 s!r2 / Lr3- 1 > I 12 ^_|_c1- 1 > I 12 ^Lx1- 1 | _ |_r1L|_c1! j _ |_r1L|_x1! | _ |_r1 [_c1 I> j c! ^Lr3— I s ^1r2^ Lx1— I > | ci ^-Lr2— j | _ |_r1^L''■|_r2^ I | _ |_r1 -L|_c1! j _ |_r1-^Ls> I xl _^Lx2— > ir1^-Lr2—si 11 ^-Lr2— | _ |_r1 -L|_r2 i | _ |_x1L[_x2 S j _ |_x1L|_c1 i4 I C1, LC2„! > I C1, LXd! 4 I c1 Jc2|_Lr1—L-^|_r2 1 LLr1^L^Lr2 ^[_c2-j L|_r1^L^|_r2^ ^|_x1_; I cl L1^ £ * I c1 I $ I r1 I ^_Lr1^L--Lx1 ^Lr3- j j_Lr1^L^Lx1 ^- LC2-| |_LC1^L^LC2 \[_C3.

[0663] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable, I x! | C3 — I I r1 I 12, —LC1^L\ |_C2 I — |_c1- "L'~~ |_C2 \|_r3— salt thereof, wherein L is I, I1,Page 207 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO

[0664] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I-aa-2".

[0665] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1". In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2".

[0666] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1"; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l"-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2"; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6RR.

[0667] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1' or Formula I-aa-2'.

[0668] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-ii. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptablePage 208 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'.

[0669] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-l'-i; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1 ’ -ii; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubsliluled or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2'; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0670] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2.

[0671] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR. In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof, wherein the LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-2; and wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur that is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

[0672] In some embodiments, the compound is of Formula I:Page 209 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO(Rfc)eFormula I,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;C —each of V1, V2, V3, and V4is, independently, CRV, N, or *Page 210 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOR22R11wherein* represents a bond to or L;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;&&&each of W1, W2, and W3is, independently, CRW, N, or— I &&&wherein* represents a bond toeach RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 211 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:, I c1 |_L^Lr2H |-Lri^LClH |~Lci"'Lr1H |_Lr1-Lr^Lr3_| j— Lr1!r2r1- IL c1i Ix1|~Lr1^L" -Lc2_ |!x1|-Lc1^ x1^ \L r"1c1 — _ 1 rl ^-Lr2— j t ^Ir1^Lx1— I LC2-|\r1Lr3— | 1 n r c c1^ ' u 1 u2-| 1 1-^L^Lr2L'' ~ < c1-'L'-Lr2 Lx1— |_ I 0 ^- Lc3— L-- |_c2 I c1- _ LLx^1Lr1 c1- -LLx^1Lr1 |ix1I c1LC2_| d^L'-Lc2!c1LLn^ -Lr2x1— ||_L^L^Lr2r1Lr2^Lr3— I Ir2 — I ^L'~^ |_d t Lx1— | r1L|_x1 < [_r1^Lc11L c1LLr3— | s ^ L Lx1—,n^ ^ r2r2[—Ln^L^ |_c1 r1^L^ |_xTJx1Lx2— | > ^- lr1J,n^L^Lr2 |_LX^L^LX2 r1r2-| i d _ |_c2i r1 IC1■ d |c2 ^L"- |_r2^ Lr3— j,n^L-Lr2^ " LC2-|,n^L-Lr2" I_c1 Lri. > _ i r1 Lri.1n^ _ i r Lc ^ ^1 — ~ _x1LXl^ Lrit l ^ | Lr3— j LC2-| [_c1"- |_c2> I r1 _^Lr5; s s 1 x1 _ L ^LxlJ LLd^L'-Lr1 Lc2i *, and i each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;Page 212 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 213 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of formula I-aa-1':I-aa-1'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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Page 214 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each R1is, independently, selected from 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, and -N(R)S(O)2R, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, ...

Claims

Attorney Docket No.: KME-303WO CLAIMSWhat is claimed:

1. A compound of Formula Z':Formula Z',or a pharmaceutically acceptable salt thereof, wherein:U1is -O- or -S-;RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(C0-C6alkyl)-O-(C1-C6alkyl), -C(O)-(C1-C6alkyl), and -(C1-C6alkyl)-RY;each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;r — I &&each of V1, V2, V3, and V4is, independently, CRV, N, or*;Page 1479 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach Rvis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, and C1-C6 haloalkyl;C — j &&&W5is hydrogen, Ci-Ce alkyl, orC — J &&&each of W1, W2, W3, and W4is, independently, CRW, N, oreach Rwis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, and C1-C6 haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl;each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;Page 1480 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:pL'’-'L,H pLr,"L'H PL"-L,,H PL’"L?'L'3— | pLr,-L'Lr2— I!x1|_Lr1^L\c1_ | |_Ln^L-Lc2_| |_Ln^L-LXl— |! Ir1S i I r1 >x1|-Lc1^Lc2— | |~ |~LC1' pLx1-L-L,2_ |Lc1^L"> ir1--L > i d ^-Lc2— I jr2—! > | r1 ^Lx1—! _ |_c1L|_c2 i |_LC1-L-Lr2- n _ I_c1 —L[_c2 I; I 11 ^LX^ 1 > ^1 / 1 ^-Lr3— I |_LC1-L-Lr2- n pLc1-L-Lr2- H |_Lc1-L-Lx1-Lr2HsA r1 / Lc3— \ pLcl-L^Lr1 / Lc2-| > ix1--Lr2— I _ |_c1 -L|_c2 si A C1 ^Lc2— i.C1 ^Lx1— I |_Lcl-Lx^Lc2-Lr1— |L|_r1^L'-|_r2'^ I L|_r1^L^Lr2*>,i r2 ^Lc1— j pLri-Lr^LC<Lr3-| i ^Lr2^Lx1— I _ I_r1 —L~~-[_x1 1 |— Lr1 L^LC1* > I r2 [_x1— I >,—Lr2— I pL.,-^L.

2. L'M _ |_r1— -^LS _ |_r1 --L|_c1 s> i r1 ^Lr2— I > i n ^-Lr2— I |_x1^L'-|_x2 I _ |_X1 'L[_C1!> I r1 J S i ci JXJ i ic1^Lc2s |_Lc1-L^Lr2 / L^Lc2_| pLr1-L ^Lr2 / ^Lr3_| L -Lr2- -■ I d Jr2!. I cl J0? s > ^Lc1 / Lr2|_Lr1^L ^Lr2 / \LX1_| |_Lr1^L-Lx1 Lr1^ ^Lx1Lr3-|, ir1s i Ix1^L02; > ^1r1|_LC1^L\|_C2 ^|_X1-| |_[_C1^L^Lr1 ^Lr2-|Page 1481 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO. i r1 Jr3 s > i r1 s i cl i c2 | c3 — I |_Lc1^L^Lc2 ^Lr3-| [— Lc1^L^Lr2LC2-| Lr1^L^Lr2^ ^Lr3" *1Ln\|_C2^ Jr\2|_C3 ^, | — L and *c1each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclicPage 1482 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2" or Formula I-aa-3":I-aa-3",X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 1483 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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), - Page 1484 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl;m is 0, 1, 2, 3 or 4;Page 1485 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO (R1 C)mc2^A1A2 / A< / Ring is selected from the group consisting of'AA* represents the point of attachment toAinO denotes that the ring is aromatic;each dotted line independently represents a single or a double bond;each of A1, A2, A3, and A4is independently C, N, O, or Seach of A5, A6, A8, A9, A11, and A12is independently C, N, O, or S;each of A7and A10is independently absent, C, N, O, or S;each of A21, A22, A23, and A24is independently C or N;each R1Cis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -CN, -NO2, -OR', -SR', -NR'2, -S(O)2R', -S(O)2NR'2, -S(O)R', -C(O)R', -C(O)OR', - C(0)NR'2, -C(O)N(R')OR', -CR'2N(R')C(O)R', -CR'2N(R')C(O)NR'2, -CFR'2, -CF2R', - CF3, -CR2(OR'), -CR2(NR'2), -OC(O)R', -OC(O)NR'2, N(R')C(O)OR', -N(R')C(O)R', -N(R')C(O)NR'2, -N(R')S(O)2R', and -N(R)S(O)2R'; each R' is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;andme is 0, 1, 2, 3 or 4.

2. A compound of Formula Z:Page 1486 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula Z,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;r — I &&each of V1, V2, V3, and V4is, independently, CRV, N, or’;Page 1487 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO: A, I-W3' represents a bond to (Rb)e or L;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;C — j &&&W5is hydrogen, Ci-Ce alkyl, orC — J &&&each of W1, W2, W3, and W4is, independently, CRW, N, orz1N— RZ1O— &&&' represents a bond toeach RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl;Page 1488 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:p-L'H L^L'M |_Ln-L,<|_Lr1^L\c1— | |_Lr1^L-Lc2_| |_Ln-L- |_Lri^Lr\x1— ||_lc1^L\c2— | |-Lc1^L\r2_| |_Lx1-L^Lr2_|> I r1 ^Lr2— I > | r1 |_x1 — I > _ i i1 ^Lc2— I _ |_dL|_c2 s _ |_c1— ~'|_C2; _ |_c1L|_r2!> | r1 j_r3— I s Ir1 — I? |r1 ^Lx1— I? _ |_c1L^|_r2^ I I _ I s _ |_c1L^|_r2^ *pLci-Lr^Lc2 / Lc3-| pLd-L<Lr1 / Lc2- 1 p,_c1-L^Lr1 / Lr2- 1> I x1 _^Lr1— § i i c1 ^Lc2— I > i C1 [_x1— J?_|_C1^L\|_C2 I I— |_r1L"" Lr2* HLr1L'''l_r2 *>r2 / Lr3- i > I 12 Jc1- 1 > I 12 Jx1- 1 _ |_11L|_d i | |_r1— ~[_x1 _ [_r1 |_d " s, i d ^Lr3— I i 1 12 dxM! Ic1 / Lr2— I _ |_r1^L' ~~ |_r2 S _ |_r1^L'^[_c1 I _ [_r1L|_x1!> _ I x1 ^Lx2— > i 11 ^Lr2— > i ^Lr2— _ |_r1^L'^|_r2 I _ [_X1^L'^[_X2 I _ [_x1L[_d '> i c1 ^-Lc2s > i c1 JXJ s s ic1^Lc2pLH^L-Li2^ ^Lr3~j pLH^L-Li2^ \LC2_ | pLr1^L-Li2- ^|_xL> i c1 Jr-? s > Ic11 s 1 11 ^L1^ |_Lr1^L"'Lx1Lr3- 1Lr1^L^Lx1 ^LC2-| pLc1-'L'-[_c2 \|_c3_> _ |_C1^ iLi~i^|_C2 ^|_X1 — i 9 _ i xl ^LC3 I? 1 11|_c1^'L^|j'1^ ^Lr2— _ |_dL~~~~ |_c2 ^[_13_Page 1489 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > | r1 JXJ! i d Ic2 I c3 - i LLc1^L^|_r2 \|_c2J |Lr1^L-Lr2- |_r3^ 1s, t, andeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclicPage 1490 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2",:wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 1491 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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), - Page 1492 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

3. A compound of F ormula A:Page 1493 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula A,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;C — &&each of V1, V2, V3, and V4is, independently, CRV, N, orPage 1494 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOwherein* represents a bond toeach RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;Q - each of W1, W2, and W3is, independently, CRW, N, or *wherei ■nsrepresents a bond toeach RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 1495 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_L^Lr2H L1^LC1 -I (-L^H |-Lr1^L^Lr3— | )-Lr1^LC\r2— |> ^Lr2— I? I ^Lx1— I 4 | ^Lc2— I | _ |_dL|_c2 * I _ |_dLI_c2 ’ | _ |_c1L|_r2^ *> i rl --Lr3— | s _^-Lr2— > I rl ^Lx1— j? _ |_c1L|_r2 « j _ |_c1LLx1[ _ |_c1L|_r2’> ^-Lr1^Lc3— I > i x1 ^Lc2— j; \ x1 ^Lr2— | _ |_dL|_c2 I j _ |_c1 — i j _ [_c1L|_r1 Ij I xl ^Lr1—! 4 J ci ^Lc2— [ > I cl ^Lx1— § LLC1^L^|_C2^ I L|_r1^L^Lr2I {-Lr1L xLr2*s ^--Lr2 — I 4 I f2 — | 4 Ir2 — I > |_r1^L|_c1 * | |_r1^L^|_x1 I > |_r1^L^|_c1 I4 I ci ^Lr3— j 4 ^ LX^ — I 4 | ^Lr2— § |-Lr1L^Lr2 * L|_r1^L^|_c1 1 L|_r1^L^|_x1^ I> I x1 ^-Lx2— I s I r1 ^Lr2— I > i rl ^Lr2— I _Lr1- "L'~-Lr2'^ I I— |_X1^L~--LX2 I _LX1-^L\[_C1 Ieach of Lx1and Lx2is, independently, -O- or -NRX-;Page 1496 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-Ce alkenylene, C2-Cewherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 1497 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1:I-aa-1wherein: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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 memberedPage 1498 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

4. A compound of Formula I:Page 1499 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;r — I &&each of V1, V2, V3, and V4is, independently, CRV, N, or«;Page 1500 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOwherein* represents a bond toeach RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;Q - each of W1, W2, and W3is, independently, CRW, N, or *wherei ■n —i ’ &&& represents a bond toeach RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 1501 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_Ld-Lr2H pL''"L’H p'"L?'L'3— | |> I ^Lr2— I > | r1 ^Lx1— I 4 I ^Lc2— I LLC1^L^LC2^ i L_LC1-^L^LC2^Li LLc1^L^Lr2^ I> Ir1 ^Lr3—! 4 I ^Lr2— I j I ^Lx1— I _ |_c1L|_r2 * _ |_c1L|_x1 * _ |_c1L1 / 2, I r1 _^[_c3— I i Ix1^-Lc2— I * Ix1^Lr2— I _ |_c1L|_c2 i _ |_c1L|_r1 i _ |_c1 I> Ix1 / Lr1— I; i c1 ^Lc2— IsI c1 / Lx1— I _ |_dL|_c2 i _ |_r1 — i _ |_r1^L~"-|_r2^;Jr2 / Lr3— I > I r2 Jc1— I > I r2 Jx1— I — |_r1^L^|_c1 I | _ |_r1— i _ |_r1 — I> | c1 ^Lr3— I s I r2? _ IC1 ^Lr2— Is _ | x1 ^Lx2— I > _ Ir1 ^Lr2— I > | r1 ^Lr2— I _ |_r1L|_r2 I _ |_x1-^L''' |_x2 I _ |_x1^L\[_c1 Ieach of Lx1and Lx2is, independently, -O- or -NRX-;Page 1502 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-Ce alkenylene, C2-Cewherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 1503 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1:I-aa-1wherein: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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 memberedPage 1504 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

5. A compound of Formula II:Page 1505 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula II,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;r — s oeach of V1, V2, V3, and V4is, independently, CRV, N, or *;Page 1506 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOwherein* represents a bond toeach RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;Q - each of W1, W2, and W3is, independently, CRW, N, or *wherei ■n —8&&& represents a bond to each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 1507 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_Ld-Lr2H pL''"L’H p'"L?'L'3— | |> I ^Lr2— I > | r1 ^Lx1— I 4 I ^Lc2— I LLC1^L^LC2^ i L_LC1-^L^LC2^Li LLc1^L^Lr2^ I> Ir1 ^Lr3—! 4 I ^Lr2— I j I ^Lx1— I _ |_c1L|_r2 * _ |_c1L|_x1 * _ |_c1L1 / 2, I r1 _^[_c3— I i Ix1^-Lc2— I * Ix1^Lr2— I _ |_c1L|_c2 i _ |_c1L|_r1 i _ |_c1 I> Ix1 / Lr1— I; i c1 ^Lc2— IsI c1 / Lx1— I _ |_dL|_c2 i _ |_r1 — i _ |_r1^L~"-|_r2^;Jr2 / Lr3— I > I r2 Jc1— I > I r2 Jx1— I — |_r1^L^|_c1 I | _ |_r1— i _ |_r1 — I> | c1 ^Lr3— I s I r2? _ IC1 ^Lr2— Is _ | x1 ^Lx2— I > _ Ir1 ^Lr2— I > | r1 ^Lr2— I _ |_r1L|_r2 I _ |_x1-^L''' |_x2 I _ |_x1^L\[_c1 Ieach of Lx1and Lx2is, independently, -O- or -NRX-;Page 1508 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene, C2-Ce alkenylene, C2-Cewherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(0)Rra, -0Rrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 1509 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1:I-aa-1wherein: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)-, -CR2-, -CF2-, -NR-, - O-, -S-, or -S(O)2;Ring B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 memberedPage 1510 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

6. A compound of F ormula B:Page 1511 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOor a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, NRZ2, or CRZ3RZ4, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*;Page 1512 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOeach RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:p 1 )-Lri-L%3— | |~Lri"LCJ'Lx2— | 5 5 5 5 5 |_Lr1^L^Lc1_ | |_Ln^L<Lc2_| |_Lri^L<Lr2_| |_Lr1^Lr^LXl_|Page 1513 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO L ir1pLc1\X4 t ^L c2— | Lc1L%2— | |-Lc1X1^L- |_r2— |> 1 rl ^Lr2— I j _ |_c1L^-~|_C2 is_ |_C1 — _lLr~1~~|_C2 ^Lx1— I 3 pLCl^Lr2^2-|> i r1 ^Lr3— I > Ir1^Lr2— I _ |_C1L[_x1 I pLd-L<Lr2 / Lx1-|I r1 ^Lc3— I > i x1 ^Lc2— I I _ |_c1L'^|_C2 I |_Lci-Lx^Lr1 / Lr2-|> I x1 ^Lr1— I > |_Lr1- IL c^1 |_|_c1L~^|_c2LILr2^ / Lc2— “I i, pLr1- 1L c^1Lr2 / Lx1—?> 1 r2 / Lr3— ILLL> Ir2^-Lc1— > Lr^ — I p n^ -C< I— Lrl L'~'Lx1’ |_Lr1^L^Lc1> \ c1 ^Lr3— I; I l"2 ^L _ |_r1L X^ l |_c1 I >. Lc1-'Lr2— I L|_r1L^Lx1 ’> \ x1 ^Lx2— I > 1 r1 Lr2— I ir1^Lr2—? _Lr1^L'-~|_r2^ I j |J<1 — |_x2 I | _ |_x1 ILrl [_r1and > ^Lr1--L1^ [— Lc1^Lc2each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered Page 1514 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 1515 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2":wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 1516 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orPage 1517 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

7. A compound of Formula III:Formula III,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z2is NRZ2or CRZ3RZ4;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY; orPage 1518 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each of V1, V2, V3, and V4is, independently, CRV, N, or*;each RVis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;Page 1519 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:|_Ln--LrtLr3_|(-Lrl"Lr3'Lxl— | p---L<Lri_| pLxl-L'^Lr2_|>r1^Lr2— I > I r1 Jx1— i s ir1^Lc2— I j_Lc1 L^LC2LI LLC1-^L'-LC2''L1 ULc1^'L"'Lr2 *> Ir1^Lr3— IsI r1 Jr2— I i I r1 Jx1— I LLc1-^L^|_r2^ 1 |_c1^L\|_x1^ i L_Lc1^L'-|_r2^ Is dr1^Lc3—si xl ^-Lc2— I > ix1^Lr2— I — |_c1L|_c2 s _ |_c1L|_r1 I> I x1 / Lr1— I > I c1 -Lc2— I s I C1 Jx1— I — |_c1 L\.|_C2 i _ |_r1-^*- '''[J2* _ |_r1^L ~"’[_r2ss i^Lr3— j > I 12 ^Lc1— I > I 12 |_x1— I> I C1 Lr3— I I 1 12 JX1— I! I cl < Lr2— I — |_11L^Lr2' _ |_r1LLc1_!si *i _^Lx2— S > 1 11, Lr2— |, i n ir2— I — |_r1" ^Lr2' — — -|_x2 I _Li, I d, LC£ „ s > i c1 i i I d ^Lc2pLr1^L^Lr2 ^|_r3_ | |—LH^L^Lr2 ^|_c2-| |_HL|_12^L|_x1_1 Ic1^LrS J! I c1 A 12,. I r1 Jr2Lr1^L^Lx1Lr3-| pLr1^L^Lx1 ^Lc2~j |_Lc1-'L'-Lc2 \LC3_> 5 > 1 11. i s i xi ^Lc2t s 1 11 ^Lr3 LLC1^L^LC2 ^LXM L|_c1-^L'-Lr1 ^Lr2H LLC1-^L'-[_C2 ^ [_R3-Page 1520 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO > | r1 JXJ! i d Ic2 I c3 - i LLc1^L^|_r2 \|_c2J |Lr1^L-Lr2- |_r3^ 1s, t, andeach of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclicPage 1521 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2",:wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 1522 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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), - Page 1523 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

8. A compound of Formula IV:Page 1524 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula IV,or a pharmaceutically acceptable salt thereof, wherein:RZ1is selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)-(C1-C6alkyl);Z1is -C(O)-, Z2is O, and = represents a single bond,or Z1is N or CRZ3, Z2is N or CRZ3, and = represents a double bond;each of Z3, Z4, and Z5is, independently, CRZ5or N;RZ2is selected from the group consisting of H, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-Ce alkyl)-O- (Ci-C6alkyl), and -C(O)-(Ci-C6alkyl);each of RZ3and RZ4is, independently, selected from the group consisting of H, halo, C1-C6alkyl, C1-C6haloalkyl, and -(C1-C6alkyl)-RY; orRZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene;each RZ5is, independently, selected from the group consisting of hydrogen, halo, cyano, C1-C6alkyl, C1-C6haloalkyl, and -ORza;each Rzais, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;- each of V1, V2, V3, and V4is, independently, CRV, N, or *;Page 1525 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO- &&represents a bond toeach Rvis, independently, selected from the group consisting of hydrogen, halo, Ci-Ce alkyl, and C1-C6 haloalkyl;each of W1, W2, and W3is, independently, CRWor N;each RWis, independently, selected from the group consisting of hydrogen, halo, C1-C6alkyl, and C1-C6haloalkyl;each of R11and R22is, independently, H, halo, C1-C6alkyl, C1-C6haloalkyl, and 3-6 membered monocyclic carbocyclyl;n is 1, 2, 3, or 4;Ring E is selected from the group consisting of phenyl, 5-membered heteroaryl comprising a sulfur atom, 3-8 membered monocyclic carbocyclyl, 5-14 membered bridged bicyclic carbocyclyl, and 5-14 membered spirocyclic carbocyclyl; each REis, independently, selected from the group consisting of -CN, -NO2, halo, C1-C6alkyl, C1-C6haloalkyl, -C(O)Rea, -OReb, and -N(Rec)2;RYis selected from the group consisting of 3-8 membered monocyclic carbocyclyl and 3-8 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RYis unsubstituted or substituted with one or more instances of -C(O)Rya;each Reais, independently, selected from the group consisting of C1-C6alkyl, and C1-C6haloalkyl; each Rebis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Ryais, independently, selected from the group consisting of C1-C6alkyl and C1-C6haloalkyl; e is 0, 1, 2, 3, 4, 5, or 6;L is selected from the group consisting of:p 1 )-Lri-L%3— | |~Lri"LCJ'Lx2— |Page 1526 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO L ir1pLc1\X4 t ^L c2— | Lc1L%2— | |-Lc1X1^L- |_r2— |> 1 rl ^Lr2— I j _ |_c1L^-~|_C2 is_ |_C1 — _lLr~1~~|_C2 ^Lx1— I 3 pLCl^Lr2^2-|> i r1 ^Lr3— I > Ir1^Lr2— I _ |_C1L[_x1 I pLd-L<Lr2 / Lx1-|I r1 ^Lc3— I > i x1 ^Lc2— I I _ |_c1L'^|_C2 I |_Lci-Lx^Lr1 / Lr2-|> I x1 ^Lr1— I > |_Lr1- IL c^1 |_|_c1L~^|_c2LILr2^ / Lc2— “I i, pLr1- 1L c^1Lr2 / Lx1—?> 1 r2 / Lr3— ILLL> Ir2^-Lc1— > Lr^ — I p n^ -C< I— Lrl L'~'Lx1’ |_Lr1^L^Lc1> \ c1 ^Lr3— I; I l"2 ^L _ |_r1L X^ l |_c1 I >. Lc1-'Lr2— I L|_r1L^Lx1 ’> \ x1 ^Lx2— I > 1 r1 Lr2— I ir1^Lr2—? _Lr1^L'-~|_r2^ I j |J<1 — |_x2 I | _ |_x1 ILrl [_r1and > ^Lr1--L1^ [— Lc1^Lc2each of Lx1and Lx2is, independently, -O- or -NRX-;each of Lc1, Lc2, Lc3, and Lc4is, independently, selected from C1-C6alkylene, C2-C6alkenylene,C2-C6 alkynylene,wherein each of Lc1, Lc2, Lc3, and Lc4is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc;each of Lr1, Lr2, and Lr3is, independently, selected from phenylene, 3-8 membered monocyclic carbocyclylene, 5-14 membered bridged bicyclic carbocyclylene, 5-14 membered Page 1527 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO spirocyclic carbocyclylene, 3-8 membered monocyclic heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-14 membered bridged bicyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR;each Rxis, independently, selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, and -C(O)Rxa;each Rcis, independently, selected from the group consisting of halo, Ci-Ce alkyl, C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rca, -ORcb, and -N(RCC)2, ortwo Rcgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RRis, independently, selected from the group consisting of halo, Ci-Ce alkyl, and C1-C6haloalkyl, -(Co-C6alkyl)-O-(Ci-C6alkyl), -C(O)Rra, -ORrb, and -N(Rrc)2, ortwo RRgroups on the same atom, together with the atom to which both are attached, form oxo, 3-6 membered monocyclic carbocyclyl, or 3-6 membered monocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each Rxais, independently, selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl; each Rcais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rcbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Recis, independently, selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl;each Rrais, independently, selected from the group consisting of Ci-Ce alkyl, and C1-C6haloalkyl; each Rrbis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;each Rrcis, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci- Ce haloalkyl;Page 1528 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO LBM, an E3 ubiquitin ligase binding moiety, is a compound of Formula I-aa-1" or Formula I- aa-2":wherein:X1is a bivalent moiety selected from -CH2-or -C(O)-;X2is N or CRx2;Rx2is H or Ci-C6alkyl;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-, -NR-, - O-, -S-, or -S(O)2;Page 1529 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WORing B is a fused ring selected from benzo, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 6 membered heterocyclylene having 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, or two R1groups together with the atom to which each is attached form 3-6 membered carbocyclylene;each RAis, independently, selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-10 membered saturated or partially unsaturated carbocyclyl, 3-10 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R is, independently, selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, 3-7 membered saturated or partially unsaturated carbocyclyl, 3-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orPage 1530 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl 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;R2is hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -OC1-6 haloalkyl; andm is 0, 1, 2, 3 or 4.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein RZ1is H.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein RZ1is selected from the group consisting of Ci-Ce alkyl, C1-C6haloalkyl, and -C(O)-(Ci-C6alkyl).

11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein RZ1is selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl.

12. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein RZ1is Ci-Ce alkyl.

13. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein RZ1is selected from the group consisting of H and Ci-Ce alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein RZ1is H, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, or -‘Bu.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein RZ1is H, -Me, or -Et.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RZ1is H or -Me.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z2is NRZ2.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein RZ2is H.

19. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein RZ2is selected from the group consisting of Ci-Ce alkyl, C1-C6haloalkyl, and -C(O)-(Ci-Ce alkyl).

20. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein RZ2is selected from the group consisting of Ci-Ce alkyl and C1-C6haloalkyl.Page 1531 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 21. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein RZ2is Ci-C6alkyl.

22. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein RZ2is selected from the group consisting of H and Ci-Ce alkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein RZ2is H, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, or -‘Bu.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein RZ2is H, -Me, or -Et.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein RZ2is H or -Me.

26. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z2is CRZ3RZ4.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ3is selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY.

28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ3is selected from the group consisting of H, Ci-Ce alkyl, and -(Ci-Ce alkyl)-RY.

29. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ3is selected from the group consisting of H and Ci-Ce alkyl.

30. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ3is H, -Me, -Et, -nPr, - Pr, -nBu, - Bu, -sBu, or -‘Bu.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein RZ3is H, -Me, or -Et.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein RZ3is H or -Me.

33. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ4is selected from the group consisting of H, halo, Ci-Ce alkyl, C1-C6haloalkyl, and -(Ci-Ce alkyl)-RY.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein RZ4is selected from the group consisting of H, Ci-Ce alkyl, and -(Ci-Ce alkyl)-RY.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein RZ4is selected from the group consisting of H and Ci-Ce alkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein RZ4is H, -Me, -Et, -nPr, -‘Pr, -nBu, -‘Bu, -sBu, or -‘Bu.Page 1532 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein RZ4is H, -Me, or -Et.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein RZ4is H or -Me.

39. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-8 membered monocyclic carbocyclylene.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein RZ3and RZ4are taken together with the carbon atom to which each is attached form 3-6 membered monocyclic carbocyclylene.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein RZ3and RZ4are taken together with the carbon atom to which each is attached form cyclopropylene or cyclobutylene.

42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein Z3is CRZ5.

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein Z4is CRZ5.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein Z5is CRZ5.

45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein each RZ5is, independently, selected from the group consisting of hydrogen, Ci-Ce alkyl, and C1-C6haloalkyl.

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein each RZ5is, independently, selected from the group consisting of hydrogen and C1-C6alkyl.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein each RZ5is, independently, H, -Me, -Et, -nPr, - Pr, -nBu, -Bu, -sBu, or -Bu.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein each RZ5is, independently, H, -Me, or -Et.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein each RZ5is, independently, H or -Me.

50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein V2is CRV.

51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, wherein V4is CRV.Page 1533 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula I-A:O(RE)eFormula I-A,or a pharmaceutically acceptable salt thereof.

53. The compound of any one of claims 1 to 51, wherein the compound is of Formula I- J:Formula I- J,or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1 to 51, wherein the compound is of Formula I-K:Page 1534 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I-K,or a pharmaceutically acceptable salt thereof.

55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein each Rvis, independently, selected from the group consisting of hydrogen and Ci-C6alkyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein each Rvis, independently, H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -Bu.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein each Rvis, independently, H, -Me, or -Et.

58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein each Rvis, independently, H or -Me.

59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein each Rvis H.

60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein W1is CRW.

61. The compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, wherein W2is CRW.

62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein each Rwis, independently, selected from the group consisting of hydrogen and Ci-C6alkyl.

63. The compound of claim 62, or a pharmaceutically acceptable salt thereof, wherein each Rwis, independently, H, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, or - Bu.Page 1535 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein each Rwis, independently, H, -Me, or -Et.

65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein each Rwis, independently, H or -Me.

66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein each Rwis H.

67. The compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein W3is N.

68. The compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein each R11is, independently, selected from the group consisting of H and Ci-Ce alkyl.

69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein each R11is, independently, H, -Me, -Et, -nPr, -Pr, -nBu, -Bu, -sBu, or -Bu.

70. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein each R11is, independently, H, -Me, or -Et.

71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein each R11is, independently, H or -Me.

72. The compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, wherein each R22is, independently, selected from the group consisting of H and Ci-Ce alkyl.

73. The compound of claim 72, or a pharmaceutically acceptable salt thereof, wherein each R22is, independently, H, -Me, -Et, -nPr, -Pr, -nBu, - Bu, -sBu, or - Bu.

74. The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein each R22is, independently, H, -Me, or -Et.

75. The compound of claim 74, or a pharmaceutically acceptable salt thereof, wherein each R22is, independently, H or -Me.

76. The compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

77. The compound of claim 76, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

78. The compound of claim 77, or a pharmaceutically acceptable salt thereof, wherein n is 1.

79. The compound of any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein Ring E is phenyl.

80. The compound of any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, wherein Ring E is 3-8 membered monocyclic carbocyclyl.Page 1536 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 81. The compound of claim 80, or a pharmaceutically acceptable salt thereof, wherein Ring E is 3-6 membered monocyclic carbocyclyl.

82. The compound of claim 81, or a pharmaceutically acceptable salt thereof, wherein Ring E is 6 membered monocyclic carbocyclyl.

83. The compound of claim 82, or a pharmaceutically acceptable salt thereof, wherein Ring E is cyclohexanyl.

84. The compound of any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each REis, independently, selected from the group consisting of halo, C1-C6alkyl, and C1-C6haloalkyl.

85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein each REis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -sBu, -'Bu, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein each REis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -‘Pr, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

87. The compound of any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, wherein e is 0, 1, 2, 3, or 4.

88. The compound of claim 87, or a pharmaceutically acceptable salt thereof, wherein e is 2.

89. The compound of claim 4, wherein the compound is of Formula I-B to Formula I-I:Formula I-B, Formula I-C,Page 1537 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOPage 1538 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO Formula I-I,90. The compound of claim 4, wherein the compound is of Formula I-B-1 to Formula I-B-6:Page 1539 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I- B-5 Formula I- B-6, or a pharmaceutically acceptable salt thereof.

91. The compound of claim 4, wherein the compound is of Formula I-C-l to Formula I-C-Page 1540 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I-C-l,Page 1541 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I- C-5or a pharmaceutically acceptable salt thereof.

92. The compound of claim 4, wherein the compound is of Formula I-D-l to Formula I-D- 5:Formula I-D-2,Page 1542 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I- D-5,94or a pharmaceutically acceptable salt thereof.

93. The compound of claim 4, wherein the compound is of Formula I-H-l to Formula I-H- 4:Page 1543 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I-H-3, Formula I-H-4, or a pharmaceutically acceptable salt thereof.

94. The compound of claim 4, wherein the compound is of Formula I-G-l to Formula I-G- 4:Page 1544 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I-G-2,Formula I-G-3, Formula I-G-4,Page 1545 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WOFormula I-G-6,Formula I-G-7,or a pharmaceutically acceptable salt thereof.

95. The compound of any one of claims 1 to 94, or a pharmaceutically acceptable salt Lr1^"Lr2H Lr1^LCH thereof, wherein L is selected from the group consisting of:1 Jj-Lc1^LfH |-Lr1^L^Lr3— | |~l_r1^LdPage 1546 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO |_Lc1-L^Lr2_| |_Lc1-L-Lc2-Lr2H pLc1-L-Lr2-LC2H -L* ~ |5 5 5 5 > Ir1^Lr2— § j | c1 ^Lc2— I > I r2 _^[_r3— > i c1 Lr3— _ |_c1L|_x1 I _ |_r1L|_r2 i _ |_r1L|_c1 I _ |_r1^L~~'|_r2i 5 ’ 5 5 5 > i r1 ^-Lr2—? > _ IX"1 _^Lx2— _ |_x1 —L~~~~ |_x2 i _ |_r1L|_r2 I*, and* wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 nitrogen atoms.

96. The compound of any one of claims 1 to 94, or a pharmaceutically acceptable salt> I |_c1^ lLr'1'-|_c2 -" Lr2— I i thereof, wherein L is selected from the group consisting of:*>,| r1 _^Lc2— I i i r1 ^Lr3— I i I ^Lr2— I « i c1 ^Lc2— I _ |_c1L~'-~|_r2'^ I _ |_c1L^~pr2'^ i _ |_c1L|_x1 I _ |_r1^L'''|_r2^ 85 5 5 ’ 5 > Ir2^-Lr3— I i Ic”l ^Lr3— I a Ir1 _Mr2— I _ |_r1 -L|_c1 a _ |_r1-^L"'[_r2I _ |_x1Lpx2 I ’ J J, and > |_Lr1- IL x^1Lr2^ / -Lx2— I5wherein L comprises at least one 6-membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

97. The compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, wherein each of Lcl, Lc2, and Lc3is, independently, selected from Ci-Ce alkylene and C2- Ce alkynylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

98. The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein each of Lcl, Lc2, and Lc3is Ci-Ce alkylene,wherein each of Lcl, Lc2, and Lc3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 Rc.

99. The compound of any one of claims 1 to 96, or a pharmaceutically acceptable salt thereof, wherein each Rcis, independently, selected from halo, C1-C6alkyl, and C1-C6haloalkyl.

100. The compound of claim 90, or a pharmaceutically acceptable salt thereof, wherein each Rcis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -SBU, -‘BU, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

101. The compound of any one of claims 1 to 100, or a pharmaceutically acceptable salt thereof, wherein each of Erl, Er2, and Er3is, independently, selected from 3-8 membered Page 1547 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO monocyclic carbocyclylene, 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-14 membered spirocyclic heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

102. The compound of claim 92, or a pharmaceutically acceptable salt thereof, wherein each of Lrl, Lr2, and Lr3is, independently, selected from 3-8 membered monocyclic carbocyclylene and 3-8 membered monocyclic heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein each of Lr1, Lr2, and Lr3is, independently, unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 RR.

103. The compound of any one of claims 1 to 102, or a pharmaceutically acceptable salt thereof, wherein each RRis, independently, selected from halo, C1-C6alkyl, and C1-C6haloalkyl.

104. The compound of claim 94, or a pharmaceutically acceptable salt thereof, wherein each RRis, independently, -F, -Cl, -Br, -Me, -Et, -nPr, -‘Pr, -nBu, -'Bu, -SBU, -‘BU, -CF3, -CHF2, -CH2F, -CF2CH3, -CF(CH3)2, -CF2CF3, or -CH2CF3.

105. The compound of any one of claims 1 to 104, or a pharmaceutically acceptable salt thereof, wherein E1is absent.

106. The compound of any one of claims 1 to 105, or a pharmaceutically acceptable salt107. The compound of any one of claims 1 to 106, or a pharmaceutically acceptable salt thereof, wherein Ring B is benzo.

108. The compound of any one of claims 1 to 107, or a pharmaceutically acceptable salt thereof, wherein each R1is, independently, selected from the group consisting of Ci-Ce alkyl, halogen, and -OR, ortwo R1groups together with the atom to which each is attached form cyclopropylene or cyclobutylene.Page 1548 of 1550IPTS / 200285306.1Attorney Docket No.: KME-303WO 109. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

110. The compound of any one of claims 1 to 109, wherein one or more hydrogen atoms of the compound is replaced by deuterium.

111. A pharmaceutical composition comprising a compound of any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

112. A method of degrading IRF5 in a subject or biological sample, the method comprising administering to said subject or contacting said biological sample with a compound of any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 111.

113. A method of treating an IRF5-mediated disorder, disease, or condition in a subject in need thereof, the method comprising administering to said subject a compound of any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 111.

114. The method of claim 113, wherein the IRF5-mediated disorder, disease, or condition is an autoimmune disease.

115. The method of claim 114, wherein the IRF5-mediated disorder, disease, or condition is selected from ankylosing spondylitis, arthritis, asthma, autoimmune hepatitis, chronic obstructive pulmonary disease, Crohn’s disease, dermatomyositis, vasculitis, inflammatory bowel disease, juvenile idiopathic arthritis, lupus nephritis, myositis, polymyositis, psoriasis, rheumatoid arthritis, psoriatic arthritis, sclerosing cholangitis, Sjogren syndrome, cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE), systemic lupus erythematosus (SLE), systemic scleroderma, Type 1 diabetes mellitus, ulcerative colitis, macrophage activation syndrome (MAS), multiple sclerosis (MS), primary biliary cirrhosis (PBC), myocardial inflammation, and atherosclerosis.Page 1549 of 1550IPTS / 200285306.1

Images