STAT6 inhibitors and uses thereof

Abstract

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

Description

STAT6 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 670,869, filed July 12, 2024; U.S. Provisional Application No. 63 / 679,040, filed August 2, 2024; U.S. Provisional Application No. 63 / 681,711, filed August 9, 2024; U.S. Provisional Application No. 63 / 767,515, filed March 5, 2025; U.S. Provisional Application No. 63 / 767,443, filed March 5, 2025; U.S. Provisional Application No. 63 / 837,760, filed July 2, 2025; and U.S. Provisional Application No. 63 / 837,775, filed July 2, 2025, each of which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to compounds and methods useful for modulating (e.g., inhibiting) signal transducer and activator of transcription 6 (“STAT6”). The present disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed herein and methods of using said compositions in the treatment of various disorders. BACKGROUND

[0003] Signal transducer and activator of transcription 6 (STAT6 or Interleukin-4-Stat / IL4-STAT) is an undruggable transcription factor belonging to the structurally conserved Signal Transducer and Activator of Transcription (STAT) family of proteins (STAT1 through STAT6). Activation of STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

[0004] STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4 / IL- 13-mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells (Hebenstreit et al. "Signaling mechanisms, interaction partners, and target genes of STAT6." Cytokine & growth factor reviews 17.3 (2006): 173-188; Chapoval et al. "Regulation of the T helper cell type 2 (Th2) / T regulatory cell (Treg) balance by IL‐4 and STAT6." Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin-4 (IL4) and interleukin-13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema (GoenkaThere is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases and cancers (Glosson et al. "Wheezing and itching: The requirement for STAT proteins in allergic inflammation." Jak-Stat 1.1 (2012): 3-15; Loh et al. "Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication." Frontiers in oncology 9 (2019): 48).

[0005] Accordingly, there remains a need to develop STAT6 inhibitors useful as therapeutic agents. SUMMARY

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

[0007] Disclosed herein, in some embodiments, is a compound of Formula X-I’-A’:Formula X-I’-A’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0008] Disclosed herein, in some embodiments, is a compound of Formula X-I’:Formula X-I’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0026] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’’-A’’:Formula X-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0027] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’-A’:Formula X-I’-A’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0028] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’:Formula X-I’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0029] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I:Formula X-I, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0030] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0031] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0032] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0033] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0034] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II:Formula II, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0035] Disclosed herein, in some embodiments, is an inhibitor compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0036] Disclosed herein, in some embodiments, is an inhibitor compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0037] Disclosed herein, in some embodiments, is an inhibitor compound of Formula V:Formula V, or a pharmaceutically acceptable salt thereof wherein each of the variables is as defined herein

[0038] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0039] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0040] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0041] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0042] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-II:Formula M-II, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0043] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-III:Formula M-III, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0044] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-IV:Formula M-IV, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0045] Disclosed herein in some embodiments is an inhibitor compound of Formula M V:Formula M-V, or a pharmaceutically acceptable salt thereof, wherein each of the variables is as defined herein.

[0046] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0047] Compounds disclosed herein are also useful for the study of STAT6 protein in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new STAT6 inhibitors or other regulators of cell cycling, metastasis, angiogenesis, and immune cell evasion, in vitro or in vivo. DETAILED DESCRIPTION

[0048] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula X-I’’-A’’, Formula X-I’- A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), compositions comprising said compounds, and methods useful for treating diseases or disorders (e.g., cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder).Definitions

[0049] 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.

[0050] 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.

[0051] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is substituted or unsubstituted and is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0052] 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 skeletalatom 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:

[0053] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0054] The term “haloalkyl” refers to a C1-6straight or branched alkyl group that is substituted with one or more halogen atoms and “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0055] The term “unsaturated,” as used herein, means that a moiety has one or more units of t ti

[0056] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0057] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0058] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:.

[0059] The term “halogen” means –F, –Cl, –Br, or –I.

[0060] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl). Unless otherwise specified, an aryl is optionally substituted with one or more substituents.

[0061] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl pyridyl pyridazinyl pyrimidinyl pyrazinyl indolizinyl purinyl naphthyridinyl andpteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0062] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). Unless otherwise specified, a heterocyclyl is optionally substituted with one or more substituents.

[0063] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term“heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0064] 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.

[0065] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned in the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0066] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4S R°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; –(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; – (CH2)0–4P(O)2R°; –(CH2)0–4P(O)R°2; –(CH2)0–4OP(O)R°2; –(CH2)0–4OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0067] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0– 2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR●, –(CH2)0–2NRl2, –NO2, –SiRl3, –OSiRl3, -C(O)SRl,–(C1–4straight 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, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0068] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2– 3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 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.

[0069] 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0070] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group i l d R†NR†C(O)R†C(O)OR†C(O)C(O)R†wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] Suitable substituents on the aliphatic group of R†are independently halogen, –or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0073] 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 presentcompounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0074] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0075] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits STAT6 protein with measurable affinity.

[0076] As used herein, an “inhibitor compound” is a compound that binds a protein of interest. In some embodiments, an inhibitor compound binds a protein of interest and decreases its activity. In some embodiments, binding of an inhibitor compound to a protein of interest does not result in degradation of the protein of interest. In another embodiment, an inhibitor compound does not bind an E3 ligase in a manner that results in degradation of the protein of interest. In another embodiment, an inhibitor compound does not, in vivo or in vitro, bind an E3 ligase in a manner that results in degradation of the protein of interest. In some embodiments, an inhibitor compound binds STAT6. In some embodiments, an inhibitor compound binds STAT6 and decreases its activity. In some embodiments, binding of an inhibitor compound to STAT6 does not result in degradation of STAT6. In another embodiment, an inhibitor compound but does not bind an E3 ligase in a manner that results in degradation of the STAT6. In some embodiments, an inhibitor compound binds a protein of interest (e.g., STAT6) but does not bind an E3 ligase. In some embodiments, an E3 ligase is selected from a cereblon E3 ubiquitin ligase, a VHL E3 ubiquitin ligase, a DCAF E3 ubiquitin ligase, (e.g., a DCAF1 E3 ubiquitin ligase, a DCAF15 E3 ubiquitin ligase, or a DCAF16 E3 ubiquitin ligase), an IAP E3 ubiquitin ligase, an MDM2 E3 ligase, or a KLHDC2 E3 ubiquitin ligase. It will be understood that, throughout this disclosure, reference to a “compound” or a “provided compound” refers to an inhibitor compound as defined above. In some embodiments, an E3 ligase is a cereblon E3 ubiquitin ligase. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 mM, less than about 1 mM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0077] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in STAT6 protein activity between a sample comprising a compound of thepresent disclosure, or composition thereof, and STAT6 protein, and an equivalent sample comprising STAT6 protein, in the absence of said compound, or composition thereof.

[0078] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. In some embodiments, a “reference” sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant comparison. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control. Compounds

[0079] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0080] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are useful as inhibitors of STAT6 protein. In some embodiments, a compound disclosed herein modulates STAT6. In some embodiments, a compound disclosed herein inhibits STAT6. Formula X-I’’-A’’ and Related Formulas Formula X-I’’-A’’

[0081] Disclosed herein, in some embodiments, is a compound of Formula X-I’’-A’’:Formula X-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to formD2a D2b, wherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0082] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’’-A’’:Formula X-I’’-A’’, or a pharmaceutically acceptable salt thereof. Formula X-I’-A’

[0083] Disclosed herein, in some embodiments, is a compound of Formula X-I’-A’:Formula X-I’-A’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl witheach of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0084] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’-A’:Formula X-I’-A’, or a pharmaceutically acceptable salt thereof. Formula X-I’

[0085] Disclosed herein, in some embodiments, is a compound of Formula X-I’:or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independentlyRNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0086] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I’:Formula X-I’, or a pharmaceutically acceptable salt thereof. Formula X-I

[0087] Disclosed herein, in some embodiments, is a compound of Formula X-I:Formula X-I, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form wherein eD2a D2bach R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; RO2is hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6.

[0088] Disclosed herein, in some embodiments, is an inhibitor compound of Formula X-I:Formula X-I, or a pharmaceutically acceptable salt thereof. RE9

[0089] In some embodiments, RE9is hydrogen, –ORO2, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments, RO2is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RO2is hydrogen or C1-C6alkyl. In some embodiments, RO2is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, RO2is hydrogen, –Me, or –Et. In some embodiments, RO2is hydrogen or –Me. In some embodiments, RO2is hydrogen. In some embodiments, RO2is –Me.

[0092] In some embodiments, RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0093] In some embodiments, RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, RE9is selected from the groups depicted in the compounds in Table 1. Formula I’’-A’’

[0095] Disclosed herein, in some embodiments, is a compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; V isRing E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring;e1 is 0, 1, 2, 3, or 4.

[0096] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof. Formula I’-A’

[0097] Disclosed herein, in some embodiments, is a compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms;Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0098] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof. Formula I’

[0099] Disclosed herein, in some embodiments, is a compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, whereinLE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

[0100] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I’:or a pharmaceutically acceptable salt thereof. LE

[0101] In some embodiments, LEis –G–LE1–LE2–GS–. In some embodiments, LEis –GS–LE2–LE1– G–.

[0102] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent.

[0103] In some embodiments, G is –NRNG–.

[0104] In some embodiments, LE1is –C(O)–.

[0105] In some embodiments, LE2is –NRN6.

[0106] In some embodiments, RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0107] In some embodiments, LEis an optionally substituted. In some embodiments,LEis an optionally substituted.

[0108] In some embodiments, LEis optionally substituted, , or[

[0110] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0111] In some embodiments, LEis an optionally substitute

[0112] In some embodiments, L iswherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0113] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0114] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, LEis In some embodiments, LEis optionallysubstituted, where Wmis as described above and defined herein. In some embodiments, LEisIn some embodiments, LEis optionally substituted46. In some embodiments,. In some embodiments, LEis. , .

[0116] In some embodiments, LEis an optionally substituted ring selected from:, , wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0118] In some embodiments, LEis:wherein each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; e2 is 0, 1, 2, 3, 4, 5 or 6; and represents a bond to Ring E.

[0120] In some embodiments, LEis selected from the groups depicted in the compounds in Table 1. Formula I

[0121] Disclosed herein, in some embodiments, is a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12;RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6.

[0122] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof. Formula II

[0123] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula II:Formula II, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A

[0124] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A:Formula M-II-A, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-1

[0125] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-1:Formula M-II-A-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-2

[0126] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-2:Formula M-II-A-2,Formula M-II-A-3

[0127] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-3:Formula M-II-A-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-4

[0128] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-4:Formula M-II-A-4, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-5

[0129] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-5:Formula M-II-A-5, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-6

[0130] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-6:Formula M-II-A-6, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-7

[0131] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-7:Formula M-II-A-7, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-8

[0132] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-8:Formula M-II-A-8, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-9

[0133] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-9:Formula M-II-A-9, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-10

[0134] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-10:Formula M-II-A-10, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-11

[0135] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-11:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-12

[0136] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-12:Formula M-II-A-12, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-13

[0137] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-13:Formula M-II-A-13, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-14

[0138] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-14:Formula M-II-A-14,Formula M-II-A-15

[0139] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-15:Formula M-II-A-15, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-16

[0140] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-16:Formula M-II-A-16, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-17

[0141] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-17:Formula M-II-A-17, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-18

[0142] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-18:Formula M-II-A-18, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-19

[0143] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-19:Formula M-II-A-19, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-20

[0144] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-20:Formula M-II-A-20, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-21

[0145] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-21:Formula M-II-A-21, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-22

[0146] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-22:Formula M-II-A-22, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-23

[0147] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-23:Formula M-II-A-23, h i ll bl l h f h i h f h ibl dfi d h iFormula M-II-A-24

[0148] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-24:Formula M-II-A-24, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-25

[0149] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-25:Formula M-II-A-25, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-26

[0150] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-A-26:Formula M-II-A-26, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-27

[0151] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-27:Formula M-II-A-27, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-28

[0152] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-28:Formula M-II-A-28, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B

[0153] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B:Formula M-II-B, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-1

[0154] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-1:Formula M-II-B-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-2

[0155] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-2:Formula M-II-B-2, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-3

[0156] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-3:Formula M-II-B-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-4

[0157] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-4:Formula M-II-B-4, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-5

[0158] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-5:Formula M-II-B-5, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-6

[0159] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-6:Formula M-II-B-6, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-7

[0160] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-7:Formula M-II-B-7, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-8

[0161] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-8:Formula M-II-B-8, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula III

[0162] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula IV

[0163] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula IV:or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula V

[0164] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula V:Formula V, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. RE1

[0165] In some embodiments, RE1is optionally substituted monocyclic ring selected from 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)-NRN1RN2, or –NRN3C(O)RC1.

[0166] In some embodiments, RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6alkyl, C2-C6 alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6cycloalkoxy, C1-C6amine, and C1-C6haloalkyl.

[0167] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, or – NRN3C(O)RC1, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0168] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0169] In some embodiments, RE1is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0170] In some embodiments, RE1is 6-membered heteroaryl with 1-3 nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from C1-C6 alkyl, and C1-C6haloalkyl.

[0171] In some embodiments, RE1is 5-membered heterocyclyl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0172] In some embodiments, RE1is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0173] In some embodiments, RE1is 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0174] In some embodiments, RE1is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0175] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, – C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3NRN3C(O)NRN1RN2, wherein Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl; d is 0, 1, 2, 3, 4, 5, or 6; and each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6 alkyl, –C(O)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5-membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form etheneoxo ( ), 3- to 5-membered monocycliccarbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0176] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and – NRN3C(O)NRN1RN2.

[0177] In some embodiments,.

[0178] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl.

[0179] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0180] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0181] In some embodiments, Ring F2 is selected from the group consisting of 4- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0182] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0183] In some embodiments, Ring F2 is selected from the group consisting of 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0184] In some embodiments, d is 0. In some embodiments, d is 1, 2, 3, 4, 5, or 6. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5. In some embodiments, d is 6.

[0185] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attachedto form ethene ( ), oxo ( ), 3- to 5-membered monocyclic carbocyclylene, or 3- to5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0186] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0187] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3-or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0188] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attachedto form ethene ( ), oxo ( ), 3- to 5-membered monocyclic carbocyclylene, or 3- to5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0189] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected

[0190] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, and –(3- to 5-membered carbocyclyl).

[0191] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0192] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, and –(3- to 5-membered carbocyclyl).

[0193] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0194] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0195] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0196] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0197] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0198] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0199] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0200] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0201] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0202] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0203] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0204] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0205] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0206] In some embodiments, two RDgroups are taken together with the carbon atom or carbonatoms to which each is attached to form ethene 3- to 5-membered monocycliccarbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0207] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0208] In some embodiments, two RDgroups are taken together with the carbon atom or carbonatoms to which each is attached to form ethene (), oxo ( ), cyclopropylene, orcyclobutylene.

[0209] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0210] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which eachis attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0211] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form etheneoxo ( ), cyclopropylene, or cyclobutylene.

[0212] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0213] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH,–CH2CHOHCH3, cyclopropyl, and cyclobutyl or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0214] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl or two RDgroups are taken together with the carbon atom or carbon atoms to which eachis attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0215] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which eachis attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0216] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0217] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0218] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0219] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0220] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0221] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0222] In some embodiments,is selected from the group consisting of.

[0224] In some embodiments,is selected from the group consisting of, , , , ,.

[0225] In some embodiments,is selected from the group consisting of,

[0226] In some embodiments,is selected from the group consisting of,

[0227] In some embodiments,is selected from the group consisting of,

[0240] In some embodiments,.In some embodiments,some embodiments, RE1is. , .

[0247] In some embodiments RE1is:..

[0249] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0250] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0251] In some embodiments,.

[0252] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4cycloalkylene.

[0253] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form 3- to 5-membered heterocyclylene with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0254] In some embodiments,.

[0255] In some embodiments, RE1is CRC4RC5RC6.

[0256] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C4cycloalkylene.

[0257] In some embodiments, RC6is cyano or C1-C3haloalkyl.

[0258] In some embodiments, RC4and RC5together form, wherein RD2aand RD2bare each independently hydrogen and C1-C6alkyl.

[0259] In some embodiments, RC6is halogen.

[0260] In some embodiments,

[0261] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0262] In some embodiments,In some embodiments, RE1is optionally substituted.

[0263] In some embodiments, RE1is optionally substituted, , or

[0266] In some embodiments, RE1is optionally substituted

[0267] In some embodiments, RE1iswherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0268] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0269] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0270] In some embodiments, RE1. In some embodiments, RE1is optionally substituted, where Wmis as described above and defined herein. In some. In some embodiments, RE1is . In some embodiments, RE1is. , .

[0271] In some embodiments, RE1is an optionally substituted ring selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0273] In some embodiments, RE1is:

[0274] In some embodiments, RE1is selected from the groups depicted in the compounds in Table 1. Ring E2

[0275] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0276] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0277] In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0278] In some embodiments, Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

[0279] In some embodiments, Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl. In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is optionally substituted pyridinyl.

[0280] In some embodiments, Ring, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; represents a bond to Ring E; a is 0, 1, 2, 3, 4, 5, or 6; and each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0281] In some embodiments, Ring E2 is phenyl.

[0282] In some embodiments, Ring E2 is 6-membered monocyclic carbocyclyl.

[0283] In some embodiments, Ring E2 is 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 5-membered monocyclic heteroaryl with 1-4nitrogen atoms. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0284] In some embodiments, Ring E2 is 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms.

[0285] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0286] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0287] In some embodiments, Ring E2 is selected from the group consisting of phenyl, cyclohexyl, cyclohexenyl, pyrazole, and pyridinyl.

[0288] In some embodiments, a is 0.

[0289] In some embodiments, a is 1, 2, 3, or 4. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0290] In some embodiments, each RAis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1.

[0291] In some embodiments, each RAis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0292] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0293] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0294] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3,or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0295] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0296] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0297] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0298] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0299] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0300] In some embodiments, each RAis independently selected from the group consisting of –F, cyano, and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0301] In some embodiments, each RAis independently selected from the group consisting of –F and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene., whereinrepresents a bond to Ring E.

[0304] The compound of any one of claims 1-17, wherein Ring,w e e represents a bond to Ring E .

[0305] In some embodiments, Ring E2 is selected from the groups depicted in the compounds in Table 1. Ring E

[0306] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0307] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0308] In some embodiments, Ring E is optionally substituted phenyl. In some embodiments, Ring E is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0309] In some embodiments, Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl.

[0310] In some embodiments, Ring, wherein Ring E is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;represents a bond to LE; b is 0, 1, 2, 3, 4, 5, or 6; each RBis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1; or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0311] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0312] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0313] In some embodiments, Ring E is phenyl. In some embodiments, Ring E is 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0314] In some embodiments, Ring E is selected from the group consisting of phenyl, pyridinyl, and piperidinyl.

[0315] In some embodiments, b is 0.

[0316] In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4.

[0317] In some embodiments, each RBis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0318] In some embodiments, each RBis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0319] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0320] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0321] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0322] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0323] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0324] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0325] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0326] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and – CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0327] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0328] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0329] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0330] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et,or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0331] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et.

[0332] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et.

[0333] In some embodiments, wherein. , or ,,r, wherein represents a bond to LE.whereinrepresents a bond to LE.

[0337] In some embodiments, Ring E is

[0339] In some embodiments, Ring E is, , , ,

[0341] In some embodiments, Ring E is selected from the groups depicted in the compounds in Table 1. y2

[0342] In some embodiments, y2 is 0. In some embodiments, y2 is 1. e2

[0343] In some embodiments, e2 is 0. In some embodiments, e2 is 1. In some embodiments, e2 is 2. In some embodiments, e2 is 3. In some embodiments, e2 is 4. In some embodiments, e2 is 5. In some embodiments, e2 is 6. RE14

[0344] In some embodiments, each RE14is independently halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy.

[0345] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0346] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0347] In some embodiments, each each RE14is independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1- C6 hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1.

[0348] In some embodiments, each RE14is independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0349] In some embodiments, each RE14is independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0350] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0351] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0352] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0353] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0354] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3.

[0355] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and –CH2CF3.

[0356] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0357] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0358] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0359] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0360] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0361] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0362] In some embodiments, RE14is selected from the groups depicted in the compounds in Table 1. y1

[0363] In some embodiments, y1 is 0. In some embodiments, y1 is 1. Ring E1

[0364] In some embodiments, Ring E1, along with its RE8and R13substituents,, ,

[0365] In some embodiments, Ring E1, along with its RE8and R13substituents,.

[0366] In some embodiments, Ring E1, along with its RE8and R13substituents, is, , , ,

[0367] In some embodiments, Ring E1, along with its RE8and R13substituents, is oris

[0369] In some embodiments, Ring E1, along with its RE8and R13substituents, is selected from the groups depicted in the compounds in Table 1. e1

[0370] In some embodiments, e1 is 0. In some embodiments, e1 is 1. In some embodiments, e1 is 2. In some embodiments, e1 is 3. In some embodiments, e1 is 4. RE8

[0371] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)NRE9RE10or –NRE11C(O)RE12.

[0372] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0373] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 14 heteroatoms independently selected from nitrogen oxygen and sulfur oroptionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 3- to 7- membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0374] In some embodiments,In someembodiments, RE8isoptionally substituted.

[0375] In some embodiments, RE8is optionally substituted, , or

[0377] In some such embodiments, R° is hydrogen or C1-6 aliphatic.

[0378] In some embodiments, RE8is optionally substituted, ,wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen,and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0380] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0381] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0382] In some embodiments, RE8is. In some embodiments, RE8is optionally substituted, where Wmis as described above and defined herein. In some embodiments,. In some embodiments, RE8is optionally substituted. so e e o e s, s .

[0383] In some embodiments, RE8is an optionally substituted ring selected from:

[0384] In some embodiments, RE8is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0385] In some embodiments, RE8is:

[0386] In some embodiments, RE8is selected from the groups depicted in the compounds in Table 1. RE9

[0387] In some embodiments, RE9is hydrogen. In some embodiments, RE9is C1-C6alkyl. In some embodiments, RE9is optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0388] In some embodiments, RE8is selected from the groups depicted in the compounds in Table 1. RE10

[0389] In some embodiments, RE10is hydrogen. In some embodiments, RE10is C1-C6alkyl.

[0390] In some embodiments, RE10is selected from the groups depicted in the compounds in Table 1. RE11

[0391] In some embodiments, RE11is hydrogen. In some embodiments, RE11is C1-C6alkyl.

[0392] In some embodiments, RE11is selected from the groups depicted in the compounds in Table 1. RE12

[0393] In some embodiments, RE12is C1-C6alkyl. In some embodiments, RE12is C1-C6haloalkyl.

[0394] In some embodiments, RE12is selected from the groups depicted in the compounds in Table 1. RE13

[0395] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, – S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0396] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, – S(O)2NRN1RN2, –NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, or – NRN3C(O)RC3.

[0397] In some embodiments, RE13is selected from the groups depicted in the compounds in Table 1. RN1and RN2

[0398] In some embodiments, each of RN1and RN2is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0399] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0400] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0401] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0402] In some embodiments, RN1is selected from the group consisting of hydrogen and C1-C6alkyl.

[0403] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0404] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0405] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0406] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0407] In some embodiments, RN1is hydrogen or –Me.

[0408] In some embodiments, RN1is hydrogen.

[0409] In some embodiments, RN1is –Me.

[0410] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0411] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0412] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0413] In some embodiments, RN2is selected from the group consisting of hydrogen and C1-C6alkyl.

[0414] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0415] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0416] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0417] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0418] In some embodiments, RN2is hydrogen or –Me.

[0419] In some embodiments, RN2is hydrogen.

[0420] In some embodiments, RN2is –Me.

[0421] In some embodiments, RN1is selected from the groups depicted in the compounds in Table 1.

[0422] In some embodiments, RN2is selected from the groups depicted in the compounds in Table 1. RN3

[0423] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0424] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0425] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0426] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0427] In some embodiments, RN3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0428] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0429] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0430] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0431] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0432] In some embodiments, RN3is hydrogen or –Me.

[0433] In some embodiments, RN3is hydrogen.

[0434] In some embodiments, RN3is –Me.

[0435] In some embodiments, RN3is selected from the groups depicted in the compounds in Table 1. RN4

[0436] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0437] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0438] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0439] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0440] In some embodiments, RN4is selected from the group consisting of hydrogen and C1-C6alkyl.

[0441] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0442] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0443] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0444] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0445] In some embodiments, RN4is hydrogen or –Me.

[0446] In some embodiments, RN4is hydrogen.

[0447] In some embodiments, RN4is –Me.

[0448] In some embodiments, RN4is selected from the groups depicted in the compounds in Table 1. RN5

[0449] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0450] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0451] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0452] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0453] In some embodiments, RN5is selected from the group consisting of hydrogen and C1-C6alkyl.

[0454] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0455] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0456] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0457] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0458] In some embodiments, RN5is hydrogen or –Me.

[0459] In some embodiments, RN5is hydrogen.

[0460] In some embodiments, RN5is –Me.

[0461] In some embodiments, RN5is selected from the groups depicted in the compounds in Table 1. RN7

[0462] each of RN1, RN2, RN3, and RN4is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0463] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0464] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0465] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0466] In some embodiments, RN7is selected from the group consisting of hydrogen and C1-C6alkyl.

[0467] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0468] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0469] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0470] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0471] In some embodiments, RN7is hydrogen or –Me.

[0472] In some embodiments, RN7is hydrogen.

[0473] In some embodiments, RN7is –Me.

[0474] In some embodiments, RN7is selected from the groups depicted in the compounds in Table 1.

[0475] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0476] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0477] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0478] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0479] In some embodiments, RC3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0480] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0481] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0482] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0483] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0484] In some embodiments, RC3is hydrogen or –Me.

[0485] In some embodiments, RC3is hydrogen.

[0486] In some embodiments, RC3is –Me.

[0487] In some embodiments, RC3is selected from the groups depicted in the compounds in Table 1. RD1

[0488] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0489] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0490] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0491] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0492] In some embodiments, RD1is selected from the group consisting of hydrogen and C1-C6alkyl.

[0493] In some embodiments, RD1 is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0494] In some embodiments, RD1 is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0495] In some embodiments, RD1 is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0496] In some embodiments, RD1 is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0497] In some embodiments, RD1 is hydrogen or –Me.

[0498] In some embodiments, RD1 is hydrogen.

[0499] In some embodiments, RD1 is –Me.

[0500] In some embodiments, RD1 is selected from the groups depicted in the compounds in Table1. Table 1

[0501] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceuticallyacceptable salt thereof. Table 1. Exemplary Compounds

[0502] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. For example, in some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I as defined above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0503] In some embodiments, the present disclosure provides a compound of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, and subformulas thereof, as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, and subformulas thereof, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0504] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0505] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0506] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof.

[0507] Disclosed herein, in some embodiments, is a method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0508] Disclosed herein, in some embodiments, is a method of treating a STAT-6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0509] In some embodiments, the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder. Formula M-I’’-A’’ and Related Formulas Formula M-I’’-A’’

[0510] Disclosed herein, in some embodiments, is a compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatomsRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0511] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof. Formula M-I’-A’

[0512] Disclosed herein, in some embodiments, is a compound of Formula M-I’-A’:or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1C6alkyl C(O) C1C6alkyl C3C5carbocyclyl and 3to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; orRN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0513] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof. Formula M-I’

[0514] Disclosed herein, in some embodiments, is a compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independentlyLEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0515] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof. LE

[0516] In some embodiments, LEis –G–LE1–LE2–GS–. In some embodiments, LEis –GS–LE2–LE1– G–.

[0517] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent.

[0518] I b di t G i NRNG

[0519] In some embodiments, LE1is –C(O)–.

[0520] In some embodiments, LE2is –NRN6.

[0521] In some embodiments, RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0522] In some embodiments, LEis an optionally substitutedIn some embodiments, LEis an optionally substituted

[0523] In some embodiments, LEis optionally substituted, or [

[0525] In some such embodiments, R° is hydrogen or C1-6 aliphatic.

[0526] In some embodiments, LE is an optionally substitute

[0527] In some embodiments, LEiswherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen,and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0528] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0529] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0530] In some embodiments, LEis. In some embodiments, LEis optionally substituted, where Wmis as described above and defined herein. In some embodiments, LEis. In some embodiments, LEis optionally substituted. In some embodiments, LEis. In some embodiments, LEis . In someembodiments,.

[0531] In some embodiments, LEis an optionally substituted ring selected from:, , wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0533] In some embodiments, LEis: ,wherein each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; e2 is 0, 1, 2, 3, 4, 5 or 6; andrepresents a bond to Ring E.

[0535] In some embodiments, LEis selected from the groups depicted in the compounds in Table 2. Formula M-I

[0536] Disclosed herein, in some embodiments, is a compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- N1 N2 N1 N1 N2 N1 N2alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y2 is 0 or 1; and e2 is 0, 1, 2, 3, 4, 5 or 6.

[0537] Disclosed herein, in some embodiments, is an inhibitor compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof.Formula M-II

[0538] Disclosed herein, in some embodiments, is a compound of Formula M-II:Formula M-II, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A

[0539] Disclosed herein, in some embodiments, is a compound of Formula M-II-A:Formula M-II- A, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-1

[0001] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-1:Formula M-II-A-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-2

[0002] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-2:Formula M-II-A-2, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-3

[0003] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-3:Formula M-II-A-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-4

[0004] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-4:Formula M-II-A-4,or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-5

[0005] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-5:Formula M-II-A-5, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-6

[0006] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-6:Formula M-II-A-6, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-7

[0007] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-7:Formula M-II-A-7, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-8

[0008] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-8:Formula M-II-A-8, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-9

[0009] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-9:Formula M-II-A-9, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-10

[0010] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-10:Formula M-II-A-10, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-A-11

[0011] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-11:Formula M-II-A-11, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-12

[0012] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-12:Formula M-II-A-12, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-13

[0013] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-13:Formula M-II-A-13, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-14

[0014] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-14:Formula M-II-A-14, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-15

[0015] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-15:Formula M-II-A-15, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-16

[0016] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-16:Formula M-II-A-16, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-17

[0017] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-17:Formula M-II-A-17, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-18

[0018] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-18:Formula M-II-A-18, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-19

[0019] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-19:Formula M-II-A-19, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-20

[0020] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-20:Formula M-II-A-20, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-21

[0021] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-21:Formula M-II-A-21, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-22

[0022] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-22:Formula M-II-A-22, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-23

[0023] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-23:Formula M-II-A-23, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-24

[0024] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-24:Formula M-II-A-24, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-25

[0025] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-25:Formula M-II-A-25, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-26

[0026] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-26:Formula M-II-A-26, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-27

[0027] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-27:Formula M-II-A-27, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-28

[0028] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-28:Formula M-II-A-28, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-29

[0029] Disclosed herein, in some embodiments, is a compound of Formula M-II-A-29:Formula M-II-A-29, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-30

[0030] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-30:Formula M-II-A-30, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-31

[0031] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-31:Formula M-II-A-31, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-A-32

[0032] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-A-32:Formula M-II-A-32, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.

[0033] Disclosed herein, in some embodiments, is a compound of Formula M-II-B:Formula M-II-B, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-1

[0034] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-1:Formula M-II-B-1, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-2

[0035] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula M-II-B-2:Formula M-II-B-2, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-II-B-3

[0036] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-B-3:Formula M-II-B-3, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-II-B-4

[0037] Disclosed herein, in some embodiments, is a compound or an inhibitor compound ofFormula M-II-B-4:Formula M-II-B-4, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-III

[0038] Disclosed herein, in some embodiments, is a compound of Formula M-III:Formula M-III, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein.Formula M-IV

[0039] Disclosed herein, in some embodiments, is a compound of Formula M-TV:Formula M-IV, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. Formula M-V

[0040] Disclosed herein, in some embodiments, is a compound of Formula M-V:Formula M-V, or a pharmaceutically acceptable salt thereof, wherein each of the variables are as defined herein. RE1

[0041] In some embodiments, RE1is optionally substituted monocyclic ring selected from 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –C(O)-NRN1RN2, or –NRN3C(O)RC1.

[0042] In some embodiments, RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6cycloalkoxy, C1-C6amine, and C1-C6haloalkyl.

[0043] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms independentlyindependently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, or – NRN3C(O)RC1, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0044] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0045] In some embodiments, RE1is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0046] In some embodiments, RE1is 6-membered heteroaryl with 1-3 nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

[0047] In some embodiments, RE1is 5-membered heterocyclyl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0048] In some embodiments, RE1is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0049] In some embodiments, RE1is 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0050] In some embodiments, RE1is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0051] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and – NRN3C(O)NRN1RN2, wherein Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl; d is 0, 1, 2, 3, 4, 5, or 6; and each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5-membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form etheneoxo3- to 5-membered monocycliccarbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0052] In some embodiments, RE1is selected from the group consisting NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, – C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3NRN3C(O)NRN1RN2.

[0053] In some embodiments,.

[0054] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and pyridonyl.

[0055] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0056] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered

[0057] In some embodiments, Ring F2 is selected from the group consisting of 4- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0058] In some embodiments, Ring F2 is selected from the group consisting of 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0059] In some embodiments, Ring F2 is selected from the group consisting of 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, d is 0. In some embodiments, d is 1, 2, 3, 4, 5, or 6. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 5. In some embodiments, d is 6.

[0061] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene, oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0062] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0063] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0064] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –(3- to 5- membered carbocyclyl), and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attachedto form ethene ( ), oxo ( ), 3- to 5-membered monocyclic carbocyclylene, or 3- to5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0065] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl), or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0066] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, and –(3- to 5-membered carbocyclyl).

[0067] In some embodiments, each RDis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0068] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, and –(3- to 5-membered carbocyclyl).

[0069] In some embodiments, each RDis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0070] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0071] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0072] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2,–Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0073] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0074] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0075] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0076] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0077] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0078] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0079] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0080] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl.

[0081] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0082] In some embodiments, two RDgroups are taken together with the carbon atom or carbonatoms to which each is attached to form ethene ( ), oxo ( ), 3- to 5-membered monocycliccarbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0083] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0084] In some embodiments, two RDgroups are taken together with the carbon atom or carbonatoms to which each is attached to form ethene), oxo ( ), cyclopropylene, orcyclobutylene.

[0085] In some embodiments, two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0086] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene ( ), oxo ( ), cyclopropylene, or cyclobutylene.

[0087] In some embodiments, each RDis independently selected from the group consisting of –F,–Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which eachis attached to form etheneoxo ( ), cyclopropylene, or cyclobutylene.

[0088] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form etheneoxo ( ), cyclopropylene, or cyclobutylene.

[0089] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH,–CH2CHOHCH3, cyclopropyl, and cyclobutyl or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene), cyclopropylene, or cyclobutylene.

[0090] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene, cyclopropylene, or cyclobutylene.

[0091] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, –CH2CHOHCH3, cyclopropyl, and cyclobutyl, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form ethene, cyclopropylene, or cyclobutylene.

[0092] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0093] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu,–CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3. or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0094] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0095] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0096] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, – CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0097] In some embodiments, each RDis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, – CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RDgroups are taken together with the carbon atom or carbon atoms to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0100] In some embodiments,is selected from the group consisting of

[0101] In some embodiments,is selected from the group consisting of,

[0102] In some embodiments,is selected from the group consisting of,

[0103] In some embodiments,is selected from the group consisting of,,[

[0106] In some embodiments,is selected from the group consisting of, [[[[,, ,,In some embodiments,some embodiments, RE1is. , .

[0123] In some embodiments RE1is:..

[0125] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0126] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0127] In some embodiments,.

[0128] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4cycloalkylene.

[0129] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form 3- to 5-membered heterocyclylene with 1- 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments,.

[0131] In some embodiments, RE1is CRC4RC5RC6.

[0132] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C4cycloalkylene.

[0133] In some embodiments, RC6is cyano or C1-C3haloalkyl.

[0134] In some embodiments, RC4and RC5together form, wherein RD2aand RD2bare each independently hydrogen and C1-C6alkyl.

[0135] In some embodiments, RC6is halogen.

[0136] In some embodiments,

[0137] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0138] In some embodiments,In some embodiments, RE1is optionally substituted.

[0139] In some embodiments, RE1is optionally substituted, , or,wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] As defined above and described herein, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0145] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Xa1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, RE1. In some embodiments, RE1is optionally substituted, where Wmis as described above and defined herein. In someIn some embodiments,. In some embodimeE1nts, R is. , .

[0147] In some embodiments, RE1is an optionally substituted ring selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6 aliphatic).

[0149] In some embodiments, RE1is:

[0150] In some embodiments, RE1is selected from the groups depicted in the compounds in Table 2. Ring E2

[0151] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0152] In some embodiments, Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0153] In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0154] In some embodiments, Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

[0155] In some embodiments, Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl. In some embodiments, Ring E2 is optionally substituted phenyl. In some embodiments, Ring E2 is optionally substituted pyridinyl.

[0156] In some embodiments, Ring, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; represents a bond to Ring E; a is 0, 1, 2, 3, 4, 5, or 6; each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, –O-(3- to 5-membered carbocyclyl), RA1, and –ORA1; or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl; RA1is selected from the group consisting of phenyl, 3- to 5-membered monocyclic carbocyclyl, and 3- to 5-membered monocyclic heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RA1is unsubstituted or substituted with 1-4 occurences of RA1a; andeach RA1ais independently selected from the group consisting of halogen, C1-C6alkyl, and C1-C6haloalkyl.

[0157] In some embodiments, each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)- NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0158] In some embodiments, each RAis independently selected from the group consisting of RA1and –ORA1.

[0159] In some embodiments, each RA1ais independently selected from the group consisting of – F, –Cl, –Br, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, – CF(CH3)2, –CF2CF3, and –CH2CF3.

[0160] In some embodiments, each RA1ais independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, ,or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0161] In some embodiments, Ring, wherein Ring E2 is selected from the group consisting of phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms;each RAis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0162] In some embodiments, Ring E2 is phenyl.

[0163] In some embodiments, Ring E2 is 6-membered monocyclic carbocyclyl.

[0164] In some embodiments, Ring E2 is 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 5-membered monocyclic heteroaryl with 1-4 nitrogen atoms. In some embodiments, Ring E2 is 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0165] In some embodiments, Ring E2 is 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms.

[0166] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0167] In some embodiments, Ring E2 is selected from the group consisting of phenyl and 6- membered monocyclic heteroaryl with 1-4 nitrogen atoms.

[0168] In some embodiments, Ring E2 is selected from the group consisting of phenyl, cyclohexyl, cyclohexenyl, pyrazole, and pyridinyl.

[0169] In some embodiments, a is 0.

[0170] In some embodiments, a is 1, 2, 3, or 4. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, a is 4.

[0171] In some embodiments, each RAis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1.

[0172] In some embodiments, each RAis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0173] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0174] In some embodiments, two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0175] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0176] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0177] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0178] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0179] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0180] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0181] In some embodiments, each RAis independently selected from the group consisting of –F, cyano, and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0182] In some embodiments, each RAis independently selected from the group consisting of –F and –OH, or two RAgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.wherein represents a bond to Ring E.

[0184] In some embodiments, Ring E2 is, , ,, , , , , ,whereinrepresents a bond to Ring E .

[0186] In some embodiments, Ring E2 is selected from the groups depicted in the compounds in Table 2. Ring E

[0187] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0189] In some embodiments, Ring E is optionally substituted phenyl. In some embodiments, Ring E is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatomsoptionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0190] In some embodiments, Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, or optionally substituted piperidinyl.

[0191] In some embodiments, Ring, wherein Ring E is selected from the group consisting of phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; represents a bond to LE; b is 0, 1, 2, 3, 4, 5, or 6; each RBis independently selected from the group consisting of halogen, cyano, nitro, –ORO1, – NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –(C1-C6alkyl)-NRN1RN2, and –(C1-C6alkyl)-ORO1; or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0192] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0193] In some embodiments, Ring E is selected from the group consisting of phenyl, 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen oxygen and sulfur

[0194] In some embodiments, Ring E is phenyl. In some embodiments, Ring E is 5- to 6- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E is 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0195] In some embodiments, Ring E is selected from the group consisting of phenyl, pyridinyl, and piperidinyl.

[0196] In some embodiments, b is 0.

[0197] In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. In some embodiments, b is 4.

[0198] In some embodiments, each RBis independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0199] In some embodiments, each RBis independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0200] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, 3- to 5-membered monocyclic carbocyclylene, or 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the 3- to 5-membered monocyclic carbocyclylene and the 3- to 5-membered monocyclic heterocyclylene with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C6alkyl and C1-C6haloalkyl.

[0201] In some embodiments, two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0202] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0203] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2,–Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0204] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0205] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0206] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and –CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0207] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3 and – CH2CF3, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0208] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et,or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0209] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo, cyclopropylene, or cyclobutylene.

[0210] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0211] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et, or two RBgroups are taken together with the carbon atom to which each is attached to form oxo or cyclopropylene.

[0212] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, cyano, –Me, and –Et.

[0213] In some embodiments, each RBis independently selected from the group consisting of –F, –Cl,–Br, –Me, and –Et.

[0214] In some embodiments, wherein. , or, wherein represents a bond to LE.wherein represents a bond to LE. ,,whereinrepresents a bond to LE.

[0218] In some embodiments, Ring E isw ee represents a bond to LE.

[0219] In some embodiments, Ring E is

[0222] In some embodiments, Ring E is selected from the groups depicted in the compounds in Table 2. y2

[0223] In some embodiments, y2 is 0. In some embodiments, y2 is 1. e2

[0224] In some embodiments, e2 is 0. In some embodiments, e2 is 1. In some embodiments, e2 is 2. In some embodiments, e2 is 3. In some embodiments, e2 is 4. In some embodiments, e2 is 5. In some embodiments, e2 is 6. RE14

[0225] In some embodiments, each RE14is independently halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy.

[0226] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0227] In some embodiments, each RE14is independently halogen, cyano, C1-C6alkyl, or C1-C6alkoxy.

[0228] In some embodiments, each each RE14is independently selected from the group consisting of halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1- N1 N2 O1

[0229] In some embodiments, each RE14is independently selected from the group consisting of halogen, cyano, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0230] In some embodiments, each RE14is independently selected from the group consisting of halogen, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, and C1-C6hydroxyalkyl.

[0231] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0232] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0233] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, – C(CH3)2OH, and –CH2CHOHCH3.

[0234] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, –Et, –C(O)Me, –C(O)Et, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH, –CH2CH2OH, –C(CH3)2OH, and –CH2CHOHCH3.

[0235] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, – NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, – C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3.

[0236] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, – C(O)nBu, –C(O)iBu, –C(O)sBu, –C(O)tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3and –CH2CF3.

[0237] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, cyano, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0238] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl, –Br, –OH, –OMe, –OEt, –NH2, –NHMe, –NMe2, –Me, and –Et.

[0239] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0240] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0241] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, cyano, –Me, and –Et.

[0242] In some embodiments, each RE14is independently selected from the group consisting of – F, –Cl,–Br, –Me, and –Et.

[0243] In some embodiments, RE14is selected from the groups depicted in the compounds in Table 2. Ring E1

[0244] In some embodiments, Ring.

[0245] In some embodiments, Ring.

[0246] In some embodiments, Ring E1 is.

[0247] In some embodiments, Ring E1 is, , .

[0248] In some embodiments, Ring E1 is.

[0249] In some embodiments, Ring E1 is selected from the groups depicted in the compounds in Table 2.

[0250] In some embodiments, XE1is N. In some embodiments, XE1is CRE18.

[0251] In some embodiments, XE1is selected from the groups depicted in the compounds in Table 2. RE15

[0252] In some embodiments, RE15is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0253] In some embodiments, RE15is hydrogen.

[0254] In some embodiments, RE15is selected from the groups depicted in the compounds in Table 2. RE16

[0255] In some embodiments, RE16is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0256] In some embodiments, RE16is hydrogen.

[0257] In some embodiments, RE16is selected from the groups depicted in the compounds in Table 2.

[0258] In some embodiments, RE17is hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1-C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl).

[0259] In some embodiments, RE17is hydrogen.

[0260] In some embodiments, RE17is selected from the groups depicted in the compounds in Table 2. RE18

[0261] In some embodiments, RE18is hydrogen or C1-C6alkyl.

[0262] In some embodiments, RE18is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0263] In some embodiments, RE18is hydrogen or –Me.

[0264] In some embodiments, RE18is hydrogen.

[0265] In some embodiments, RE18is selected from the groups depicted in the compounds in Table 2. RN1and RN2

[0266] In some embodiments, each of RN1and RN2is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0267] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0268] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0269] In some embodiments, RN1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0270] In some embodiments, RN1is selected from the group consisting of hydrogen and C1-C6alkyl.

[0271] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0272] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0273] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0274] In some embodiments, RN1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0275] In some embodiments, RN1is hydrogen or –Me.

[0276] In some embodiments, RN1is hydrogen.

[0277] In some embodiments, RN1is –Me.

[0278] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0279] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0280] In some embodiments, RN2is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0281] In some embodiments, RN2is selected from the group consisting of hydrogen and C1-C6alkyl.

[0282] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0283] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0284] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0285] In some embodiments, RN2is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0286] In some embodiments, RN2is hydrogen or –Me.

[0287] In some embodiments, RN2is hydrogen.

[0288] In some embodiments, RN2is –Me.

[0289] In some embodiments, RN1is selected from the groups depicted in the compounds in Table 2.

[0290] In some embodiments, RN2is selected from the groups depicted in the compounds in Table 2.

[0291] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0292] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0293] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0294] In some embodiments, RN3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0295] In some embodiments, RN3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0296] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0297] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0298] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0299] In some embodiments, RN3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0300] In some embodiments, RN3is hydrogen or –Me.

[0301] In some embodiments, RN3is hydrogen.

[0302] In some embodiments, RN3is –Me.

[0303] In some embodiments, RN3is selected from the groups depicted in the compounds in Table 2. RN4

[0304] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0305] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0306] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0307] In some embodiments, RN4is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0308] In some embodiments, RN4is selected from the group consisting of hydrogen and C1-C6alkyl.

[0309] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0310] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0311] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0312] In some embodiments, RN4is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0313] In some embodiments, RN4is hydrogen or –Me.

[0314] In some embodiments, RN4is hydrogen.

[0315] In some embodiments, RN4is –Me.

[0316] In some embodiments, RN4is selected from the groups depicted in the compounds in Table 2. RN5

[0317] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0318] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0319] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0320] In some embodiments, RN5is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0321] In some embodiments, RN5is selected from the group consisting of hydrogen and C1-C6alkyl.

[0322] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0323] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0324] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0325] In some embodiments, RN5is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0326] In some embodiments, RN5is hydrogen or –Me.

[0327] In some embodiments, RN5is hydrogen.

[0328] In some embodiments, RN5is –Me.

[0329] In some embodiments, RN5is selected from the groups depicted in the compounds in Table 2. RN7

[0330] each of RN1, RN2, RN3, and RN4is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0331] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0332] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0333] In some embodiments, RN7is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0334] In some embodiments, RN7is selected from the group consisting of hydrogen and C1-C6alkyl.

[0335] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0336] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0337] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0338] In some embodiments, RN7is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0339] In some embodiments, RN7is hydrogen or –Me.

[0340] In some embodiments, RN7is hydrogen.

[0341] In some embodiments, RN7is –Me.

[0342] In some embodiments, RN7is selected from the groups depicted in the compounds in Table 2. RC3

[0343] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0344] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0345] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0346] In some embodiments, RC3is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0347] In some embodiments, RC3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0348] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0349] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0350] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0351] In some embodiments, RC3is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0352] In some embodiments, RC3is hydrogen or –Me.

[0353] In some embodiments, RC3is hydrogen.

[0354] In some embodiments, RC3is –Me.

[0355] In some embodiments, RC3is selected from the groups depicted in the compounds in Table 2. RD1

[0356] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0357] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C(O)-C1-C6alkyl, 3- to 5- membered carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0358] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)-C1-C6alkyl.

[0359] In some embodiments, RD1is selected from the group consisting of hydrogen, C1-C6alkyl, and C1-C6haloalkyl.

[0360] In some embodiments, RD1is selected from the group consisting of hydrogen and C1-C6alkyl.

[0361] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –C(O)Me, –C(O)Et, –C(O)nPr, –C(O)iPr, –C(O)nBu, –C(O)iBu, –C(O)sBu, and –C(O)tBu.

[0362] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0363] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, and – CH2CF3.

[0364] In some embodiments, RD1is selected from the group consisting of hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, and –tBu.

[0365] In some embodiments, RD1is hydrogen or –Me.

[0366] In some embodiments, RD1is hydrogen.

[0367] In some embodiments, RD1is –Me.

[0368] In some embodiments, RD1is selected from the groups depicted in the compounds in Table 2. Table 2

[0369] Disclosed herein, in some embodiments, is a compound of Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Exemplary Compounds

[0370] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. For example, in some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I as defined above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0371] In some embodiments, the present disclosure provides a compound of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, or Formula M-V, or a subformula thereof, as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula X-I’’-A’’,Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, or Formula M-V, or a subformula thereof, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0372] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0373] In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein and / or in a method for treating a STAT6-mediated disorder as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for modulating STAT6 as described herein. In some embodiments, the present disclosure also provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0374] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof.

[0375] Disclosed herein, in some embodiments, is a method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0376] Disclosed herein, in some embodiments, is a method of treating a STAT-6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0377] In some embodiments, the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated withproliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder. Pharmaceutical Compositions

[0378] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are administered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients.

[0379] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient (i.e., one or more pharmaceutically acceptable excipients).

[0380] The compounds disclosed herein are used in free base forms, salt forms, or solvate forms, or as prodrugs. All forms are within the compositions (e.g., pharmaceutical compositions) described herein. The disclosed compounds, or salts, solvates, or prodrugs thereof, are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.

[0381] Pharmaceutical compositions described herein are preferably formulated for administration to a subject (e.g., a human) in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’- A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are useful for treating a disease or disorder or symptoms thereof described herein

[0382] The dosage of the compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) in the pharmaceutical compositions, as well as the amount of the pharmaceutical composition administered to a subject, can vary depending on factors such characteristics of the subject (e.g., age, health, weight, and gender); the nature and extent of the symptoms; the frequency of treatment; the mode of administration of the pharmaceutical compositions; the solubility of the compounds in the pharmaceutical compositions; the potency and activity of the compounds; and the pharmacodynamic properties of the compound. The dosage of the compounds disclosed here (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) or compositions comprising compounds disclosed herein are varied to achieve a desired therapeutic response for a particular subject, composition, or mode of administration, without being toxic to the subject.

[0383] The present disclosure also provides kits including pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’- A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0384] Disclosed herein, in some embodiments, is a process for providing a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, andMethods of Use and Treatment

[0385] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) and compositions comprising said compounds as described herein are generally useful for modulation of STAT6 protein activity (e.g., inhibition of STAT6 protein activity) including phosphorylated or activated STAT6 protein (e.g., pSTAT6) activity.

[0386] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6, or a mutant thereof, activity in a biological sample, wherein the method comprises contacting said biological sample with a compound disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’- A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), or a composition comprising said compound.

[0387] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from a subject (e.g., a patient).

[0388] Modulation (e.g., inhibition) of STAT6, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0389] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6, or a mutant thereof, activity in a subject (e.g., a patient), the method comprising administering to said subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X- I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, andcompounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), or a composition comprising said compound or pharmaceutically acceptable salt thereof.

[0390] Disclosed herein, in some embodiments, is a method for treating a disease or disorder mediated by STAT6 or a mutant thereof, in a subject (e.g., a patient) in need thereof, the method comprising administering to said subject a compound disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), or a pharmaceutically acceptable composition thereof. Exemplary diseases and disorders are described in herein.

[0391] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6 in a subject (e.g., a patient), wherein the method comprises administering to said subject a compound disclosed herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), wherein the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0392] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6 in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’- A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to an untreated subject with the same STAT6-mediated disorder, disease, or condition. In some embodiments, the STAT6 is from abiological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0393] Disclosed herein, in some embodiments, is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X- I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0394] Disclosed herein, in some embodiments, is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof; and wherein the method results in the subject having a reduced STAT6 level relative to an untreated subject with the same STAT6-meditated disorder, disease, or condition. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein.

[0395] The activity of a compound described herein as a modulator (e.g., an inhibitor) of STAT6 or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the activity and / or the subsequent functional consequences of activated STAT6 protein or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to STAT6 protein. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / STAT6 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with STAT6 protein bound to known radioligands. Detailed conditions for assaying a compound utilized in the present disclosure as a modulator (e.g., an inhibitor) of STAT proteins, or a mutant thereof, are set forth in the Examples below.

[0396] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0397] Compounds disclosed herein are modulators (e.g., inhibitors) of STAT6 protein and are therefore useful for treating one or more disorders associated with activity of STAT6 protein. Thus, disclosed herein, in some embodiments, is a method for treating a STAT6-mediated disorder or disease comprising administering to a subject in need thereof (e.g., a patient) a compound disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof), or pharmaceutically acceptable composition thereof.

[0398] As used herein, the term “STAT6-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which STAT6 or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which STAT6 or a mutant thereof, are known to play a role.

[0399] STAT6 functions as a transcription factor to induce gene expression and plays an important role in the IL-4 / IL-13 signaling pathway and thus is critical in IL-4 / IL-13 mediated biological responses including in human malignancies (e.g., Patel, B.K.R., et al. "Localization of the human stat6 gene to chromosome 12q13. 3–q14. 1, a region implicated in multiple solid tumors." Genomics 52.2 (1998): 192-200). The STAT6-mediated signaling pathway has been shown to be required for the development of T-helper type 2 (Th2) cells and Th2 immune response and plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma (e.g., Walford, H. H. and Doherty, T. A. “STAT6 and lung inflammation.” Jak-stat 2.4 (2013): e25301). It has been found that STAT6 induces the expression of BCL2L1 / BCL-X(L), which is responsible for the anti-apoptotic activity of IL-4 andis shown to play a prominent role in adaptive immunity such as providing innate immune signaling in response to virus infection (e.g., Chen, H., et al. “Activation of STAT6 by STING is critical for antiviral innate immunity.” Cell 147.2 (2011): 436-446). Knockout studies in mice have suggested the role STAT6 in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins. Activation of STAT6 signaling pathway is necessary in tumor-associated macrophages (TAMs) and is implicated in the treatment of cancers and atherosclerosis (e.g., Binnemars‐Postma, K., et al. “Targeting the Stat6 pathway in tumor‐ associated macrophages reduces tumor growth and metastatic niche formation in breast cancer.” The FASEB Journal 32.2 (2018): 969-978; Gong, M., et al. “STAT6 upregulation promotes M2 macrophage polarization to suppress atherosclerosis.” Medical science monitor basic research 23 (2017): 240). STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation. STAT6 is also required for the development of IL-9-secreting T cells. STAT6 is also involved in IL4 signaling in B cells, and STAT6 determines the levels of CD20 on the surface of normal and malignant B lymphocytes (e.g., Sandova, V., et al. “IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3Kδ inhibitor idelalisib.” haematologica 106.11 (2021): 2995).

[0400] In some embodiments, biomarkers associated with the IL-4 / 13 pathway include IgE, Thymus and activation regulated chemokine (TARC), CD23, periostin, and eisinophils. TARC is a serum TH2 biomarker and chemoattractant for TH2 cell. CD23 is a B cell activation marker and correlates with IgE class switch. Periostin is a serum TH2 biomarker and ECM protein associated with tissue remodeling in atopic diseases.

[0401] In some embodiments, treatment with provided a compound results in lesser IL-4 induced TARC release compared to a reference or standard level. In some embodiments, treatment with provided a compound results in lesser IL-13 induced CD23 expression compared to a reference or standard level. In some embodiments, treatment with provided a compound results in lesser IL- 13 induced periostin release compared to a reference or standard level.

[0402] In some embodiments, treatment with provided a compound inhibits IL-4 induced TARC release. In some embodiments, treatment with provided a compound inhibits IL-13 induced CD23 expression. ISE, treatment with provided a compound inhibits IL-13 induced periostin release.

[0403] Disclosed herein, in some embodiments, is a method for treating one or more disorders, diseases, and / or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder a hormone related disease a metabolic disorder conditions associated withorgan transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[0404] Diseases and conditions treatable according to the methods disclosed herein include, but are not limited to, cancer, cardiovascular disease, viral disease, autoimmune diseases, autoinflammatory syndromes, atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological disorders, metabolic syndrome, immunodeficiency disorders such as AIDS and HIV, destructive bone disorders, osteoarthritis, proliferative disorders, infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders in a patient. In one embodiment, a human patient is treated with a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably modulate (e.g., inhibit) STAT6 or a mutant thereof

[0405] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present disclosure is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma exacerbated or induced following bacterial or viral infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[0406] Disclosed herein, in some embodiments, is a method of treating an allergic or inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure to the subject. The disease may be a lung disease such as, e.g., asthma, airway hyperresponsiveness (AHR), an allergic disease, allergic rhinitis, emphysema,chronic obstructive pulmonary disease (COPD), reactive airway disease, chronic rhinosinusitis, or essentially any other disease of the upper or lower airways that produces airflow obstruction.

[0407] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4 to 6 am, i.e., at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[0408] In some embodiments, STAT6, via its Src homology 2 (SH2) domain, is recruited to the phosphotyrosine residues and is phosphorylated on Tyr641. In some embodiments, STAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the nucleus, and participates in the expression of genes leading to asthma and airway hyperresponsiveness (AHR).

[0409] Disclosed herein, in some embodiments, is a method of treating asthma in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0410] Disclosed herein, in some embodiments, is a method of treating airway hyperresponsiveness (AHR) in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0411] Disclosed herein, in some embodiments, is a method of treating allergic rhinitis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0412] In some embodiments, the present disclosure provides a method of treating allergic asthma in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0413] Disclosed herein, in some embodiments, is a method of treating emphysema in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0414] Disclosed herein, in some embodiments, is a method of treating chronic rhinosinusitis (e.g., with nasal polyposis) in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0415] Disclosed herein, in some embodiments, is a method of treating atopic dermatitis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0416] Disclosed herein, in some embodiments, is a method of treating COPD in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0417] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) can be used for other inflammatory or obstructive airways diseases and conditions to which the present disclosure is applicable and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The present disclosure is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present disclosure is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0418] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M V and subformulas thereof and compounds of Table 1 and Table 2 andpharmaceutically acceptable salts thereof) are also useful in the treatment of eosinophil related disorders, e.g., eosinophilia, in particular eosinophil related disorders of the airways (e.g., involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and / or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, esophagitis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[0419] Disclosed herein, in some embodiments, is a method of treating eosinophilic esophagitis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0420] Disclosed herein, in some embodiments, is a method of treating prurigo nodularis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0421] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’, Formula M-I’, Formula M-I, Formula M-II, Formula M-III, Formula M-IV, and Formula M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are also useful in the treatment of inflammatory or allergic conditions of the skin. Disclosed herein, in some embodiments, is a method of treating inflammatory or allergic conditions of the skin in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments the inflammatory disease of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0423] Compounds disclosed herein (e.g., compounds of Formula X-I’’-A’’, Formula X-I’-A’, Formula X-I’, Formula X-I, Formula I’’-A’’, Formula I’-A’, Formula I’, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula M-I’’-A’’, Formula M-I’-A’,M-V, and subformulas thereof, and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, reti...

Claims

CLAIMS What is claimed:

1. An inhibitor compound of Formula X-I’’-A’’:Formula X-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, orRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

2. An inhibitor compound of Formula X-I’-A’:Formula X-I’-A’or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatomseach RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independentlyRNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

3. An inhibitor compound of Formula X-I’:Formula X-I’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is C(O) S(O)12 or CH2 ;G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RO2is hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

4. An inhibitor compound of Formula X-I:or a pharmaceutically acceptable salt thereof, wherein:RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, or –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, –ORO2, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen,oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; RO2is hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6.

5. An inhibitor compound of Formula I’’-A’’:Formula I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen oxygen and sulfur 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic carbocyclyl, and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is optionally substituted 6-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, –CH(COORE9)(NRE9RE10), – C(O)ORE9, –CRC4RC5RC6, –C(O)NRE9RN6, –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, optionally substituted 3- to 4 membered carbocyclyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl;RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

6. An inhibitor compound of Formula I’-A’:Formula I’-A’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , whereD2a D2bin each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

7. An inhibitor compound of Formula I’:Formula I’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; Ring E1 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy;each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; y1 is 0 or 1; and e1 is 0, 1, 2, 3, or 4.

8. The inhibitor compound of any one of claims 1 to 7, wherein,, wherein each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; e2 is 0, 1, 2, 3, 4, 5 or 6; and represents a bond to Ring E.

9. An inhibitor compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E1 is an optionally substituted ring selected from phenyl and 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; RE9is hydrogen, C1-C6alkyl, or optionally substituted 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE10and RE11is independently hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; each RE13is independently halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy,–C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y1 is 0 or 1; y2 is 0 or 1; e1 is 0, 1, 2, 3, or 4; and e2 is 0, 1, 2, 3, 4, 5 or 6.

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

11. The inhibitor compound of any one of claims 1 to 9, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6cycloalkoxy, C1-C6amine and C1-C6haloalkyl.

12. The inhibitor compound of any one of claims 1 to 9, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-3 substituents, each independently selected from oxo, C1-C6alkyl and C1-C6haloalkyl.

15. The inhibitor compound of any one of claims 1 to 9, wherein RE1is,16. The inhibitor compound of any one of claims 1 to 9, wherein RE1is.

17. The inhibitor compound of any one of claims 1 to 9, wherein RE1is.

18. The inhibitor compound of any one of claims 1-17, wherein Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

19. The inhibitor compound of any one of claims 1-17, wherein Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl.

20. The inhibitor compound of any one of claims 1-17, wherein Ring,21. The inhibitor compound of any one of claims 1-17, wherein Ring,w ere n represen s a bond to Ring E .

22. The compound of any one of claims 1-21, wherein Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, optionally substituted pyridazinyl, or optionally substituted piperidinyl.

23. The inhibitor compound of any one of claims 1-21, wherein Ring,whereinrepresents a bond to LE.

24. The inhibitor compound of any one of claims 1-21, wherein Ring,25. The inhibitor compound of any one of claims 1-21, wherein Ring,26. The inhibitor compound of any one of claims 1-21, wherein Ringwhereinrepresents a bond to LE.

27. The inhibitor compound of any one of claims 1 to 26, wherein Ring E1, along with its28. The inhibitor compound of any one of claims 1 to 26, wherein Ring E1, along with its RE8and R13substituents,.

29. The inhibitor compound of any one of claims 1 to 26, wherein Ring E1, along with its30. The inhibitor compound of any one of claims 1 to 26, wherein Ring E1, along with its31. The inhibitor compound of any one of claims 1 to 26, wherein Ring E1, along with its.

32. The inhibitor compound of any one of claims 1 to 31, wherein y1 is 1.

33. The inhibitor compound of any one of claims 1 to 32, wherein y2 is 0.

34. The inhibitor compound of any one of claims 1 to 32, wherein y2 is 1.

35. An inhibitor compound selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

36. An inhibitor compound of Formula M-I’’-A’’:Formula M-I’’-A’’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6- membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1,C6 alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

37. An inhibitor compound of Formula M-I’-A’:Formula M-I’-A’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl, 6-membered monocyclic carbocyclyl, 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms, and 6-membered monocyclic heterocyclyl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 3- to 7-membered monocyclic carbocyclyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O–G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, orRC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

38. An inhibitor compound of Formula M-I’:Formula M-I’, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1- 2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;r Ring E2; Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6 alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC4, RC5, and RC6is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNLis hydrogen or optionally substituted C1-C6alkyl; RN6is hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RNGis hydrogen or optionally substituted C1-C6alkyl; and RCGis hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring. .

39. The inhibitor compound of any one of claims 36 to 38, wherein,, wherein each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy; e2 is 0, 1, 2, 3, 4, 5 or 6; and represents a bond to Ring E.

40. An inhibitor compound of Formula M-I:Formula M-I, or a pharmaceutically acceptable salt thereof, wherein: RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, – C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, –CRC4RC5RC6, –S(O)1-2-NRN1RN2, –NRN3S(O)1-2RC2, and –NRN3C(O)NRN1RN2;Ring E2 is an optionally substituted ring selected from phenyl and 6-membered monocyclic heteroaryl with 1-4 nitrogen atoms; Ring E is an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3-7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RingXE1is N or CRE18; each of RE15, RE16, and RE17is, independently, hydrogen, halogen, halogen, cyano, nitro, –ORO1, –NRN1RN2, C1-C6alkyl, –C(O)-C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, –O-(C1- C6alkyl)-NRN1RN2, –NRN1-(C1-C6alkyl)-NRN1RN2, –(C1-C6alkyl)-NRN1RN2, –O-(C1-C6alkyl)-ORO1, –NRN1-(C1-C6alkyl)-ORO1, –(C1-C6alkyl)-ORO1, and –O-(3- to 5-membered carbocyclyl); RE18is hydrogen, halogen, or C1-C6alkyl; each RE14is independently, halogen, cyano, or an optionally substituted group selected from C1- C6 alkyl and C1-C6alkoxy; each RN1, RN2, RN3, RN4, RN5, RN7, RC3and RD1is, independently, hydrogen or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur or an optionally substituted 5- to 6- membered heteroaryl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC1and RC2is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RC3, RC4, and RC5is independently hydrogen, halogen, cyano, or an optionally substitutedRC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; y2 is 0 or 1; and e2 is 0, 1, 2, 3, 4, 5 or 6.

41. The inhibitor compound of any one of claims 36 to 40, wherein RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

42. The inhibitor compound of any one of claims 36 to 40, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-4 substituents, each independently selected from oxo, hydroxy, cyano, C1-C6alkyl, C2-C6 alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6cycloalkoxy, C1-C6amine and C1-C6haloalkyl.

43. The inhibitor compound of any one of claims 36 to 40, wherein RE1is 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RE1is substituted with 0-3 substituents, each independently selected from oxo, C1-C6alkyl and C1-C6haloalkyl.

44. The inhibitor compound of any one of claims 36 to 40, wherein RE1is,45. The inhibitor compound of any one of claims 36 to 40, wherein RE1is,46. The inhibitor compound of any one of claims 36 to 40, wherein RE1is,47. The inhibitor compound of any one of claims 36 to 40, wherein RE1isor.

48. The inhibitor compound of any one of claims 36 to 40, wherein RE1is.

49. The inhibitor compound of any one of claims 36 to 48, wherein Ring E2 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted pyrazole, or optionally substituted pyridinyl.

50. The inhibitor compound of any one of claims 36 to 48, wherein Ring E2 is optionally substituted phenyl or optionally substituted pyridinyl.

51. The inhibitor compound of any one of claims 36 to 48, wherein Ring E2 iswhereinrepresents a bond to Ring E .

53. The inhibitor compound of any one of claims 36 to 52, wherein Ring E is optionally substituted phenyl, optionally substituted or pyridinyl, optionally substituted pyridazinyl, or optionally substituted piperidinyl.

54. The inhibitor compound of any one of claims 36 to 52, wherein Ring,wherein represents a bond to LE.whereinrepresents a bond to LE.. The inhibitor compound of any one of claims 36 to 52, wherein Ring,57. The inhibitor compound of any one of claims 36 to 52, wherein Ring,58. The inhibitor compound of any one of claims 36 to 52, wherein Ring E1 is.

59. The inhibitor compound of any one of claims 36 to 52, wherein Ring E1 is.

60. The inhibitor compound of any one of claims 36 to 52, wherein Ring E1.

61. The inhibitor compound of any one of claims 36 to 52, wherein Ring E1,62. The inhibitor compound of any one of claims 36 to 52, wherein Ring E1.

63. The inhibitor compound of any one of claims 36 to 62, wherein y2 is 0.

64. The inhibitor compound of any one of claims 36 to 62, wherein y2 is 1.

65. An inhibitor compound selected from any one of the compounds of Table 2, or a pharmaceutically acceptable salt thereof.

66. A pharmaceutical composition comprising an inhibitor compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

67. A method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample v a pharmaceutical composition of claim 66.

68. A method of treating a STAT-6-mediated disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject an inhibitor compound of any one of claims 1 to 65 or a pharmaceutical composition of claim 66.

69. The method of claim 68, wherein the STAT6-mediated disease or disorder is a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

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