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 / 645,838, filed May 10, 2024; U.S. Provisional Application No. 63 / 645,836, filed May 10, 2024; U.S. Provisional Application No. 63 / 657,707, filed June 7, 2024; U.S. Provisional Application No.63 / 670,763, filed July 12, 2024; U.S. Provisional Application No.63 / 681,714, filed August 9, 2024; and U.S. Provisional Application No. 63 / 767,224, filed March 5, 2024, 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 (Goenka and Kaplan. "Transcriptional regulation bySTAT6." Immunologic research 50.1 (2011): 87-96.). There is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases and cancers (Glosson et al. "Wheezing and itching: The requirement for STAT proteins in allergic inflammation." Jak- Stat 1.1 (2012): 3-15; Loh et al. "Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication." Frontiers in oncology 9 (2019): 48).

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

[0006] Disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', or Formula IV:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0007] Also disclosed herein, in some embodiments, is a compound or an inhibitor compound of Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0008] 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.

[0009] 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

[0010] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula AA', Formula AA, Formula A, Formula A-l, Formula I'", Formula I", Formula I', Formula I, Formula 11"', Formula II", Formula II', Formula II, Formula III'", Formula III", Formula III', Formula III, Formula IV, Formula IV, Formula IV-1, Formula 1-1', Formula 1-1, Formula l-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, 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

[0011] 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 tofacilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure

[0012] 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.

[0013] 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.

[0014] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge and is substituted or unsubstituted. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are wellknown 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:

[0015] 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.

[0016] 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 C1-4straight or branched alkyl group that is substituted with one or more halogen atoms. The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0017] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0018] 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.

[0019] 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.

[0020] 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:.

[0021] The term “halogen” means –F, –Cl, –Br, or –I.

[0022] 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.

[0023] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –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, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0029] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, – (CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, – (CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR , –(C1–4straight 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0030] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] 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, whereineach R is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the aliphatic group of R†are independently halogen, – R●, -(haloR●), –OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] 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 compoundsformed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0035] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0036] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species set forth herein.

[0037] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits STAT6 protein with measurable affinity. In certain embodiments, an inhibitor has an IC50and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0038] 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 compound has an IC50and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0039] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in STAT6 protein activity between a sample comprising a compound of the present disclosure, or composition thereof, and STAT6 protein, and an equivalent sample comprising STAT6 protein, in the absence of said compound, or composition thereof.

[0040] 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

[0041] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0042] Compounds disclosed herein (e.g., compounds of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II,and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, 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 AA'

[0043] Disclosed herein, in some embodiments, is a compound of Formula AA':or a pharmaceutically acceptable salt thereof, wherein Ring E is wherein indicateEs bond to L ;within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring E2 isor an optionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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-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 whereinD2a D2beach R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

[0044] Disclosed herein, in some embodiments, is an inhibitor compound of Formula AA':or a pharmaceutically acceptable salt thereof, wherein Ring E is wherein inEdicates bond to L ; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring E2 isor an optionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

[0045] In some embodiments, Ring E2 is an optionally substituted 5- to 6- membered heterocyclic with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] In some embodiments, Ring E2 isE5 E1In some embodiments, Y is CR . In some embodiments, YE5is N.

[0047] In some embodiments, when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl.

[0048] In some embodiments, Ring E2 is

[0049] In some embodiments, the compound or the inhibitor compound is of Formula AA:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0050] In some embodiments, the compound or the inhibitor compound is of Formula AA:or a pharmaceutically acceptable salt thereof, wherein: Ring E is wheEreinindicates bond to L ; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

[0051] In some embodiments, the compound or the inhibitor compound is of Formula A:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0052] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10, –NRE11C(O)RE12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0053] In some embodiments, the compound or the inhibitor compound is of Formula A-1:or a pharmaceutically acceptable salt thereof, wherein: Ring E1 isRE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl;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, –C(O)-NRN1RN2, and –NRN3C(O)RC1; and LEis –C(O)NRN6– or –NRN6C(O)–.

[0054] In some embodiments, m is 0, p is 1, and XE5is CRE6, N, O, or S.

[0055] In some embodiments, m is 0. In some embodiments, m is 1.

[0056] In some embodiments, p is 0. In some embodiments, p is 1.

[0057] In some embodiments m is 0 and p is 1. In some embodiments, m is 1 and p is 0. In some embodiments, m is 0 and p is 0. In some embodiments, m is 1 and p is 1.

[0058] In some embodiments, m is 0 and p is 1, and each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S. In some embodiments, XE1is N. In some embodiments, XE1is CRE6. In some embodiments, XE1is NRE4. In some embodiments, XE1is O. In some embodiments, XE1is S. In some embodiments, XE2is N. In some embodiments, XE2is CRE6. In some embodiments, XE2is NRE4. In some embodiments, XE2is O. In some embodiments, XE2is S. In some embodiments, XE3is N. In some embodiments, XE3is CRE6. In some embodiments, XE3is NRE4. In some embodiments, XE3is O. In some embodiments, XE3is S. In some embodiments, XE4is N. In some embodiments, XE4is CRE6. In some embodiments, XE4is NRE4. In some embodiments, XE4is O. In some embodiments, XE4is S. In some embodiments, XE5is N. In some embodiments, XE5is CRE6. In some embodiments, XE5is NRE4. In some embodiments, XE5is O. In some embodiments, XE5is S.

[0059] In some embodiments, Xais C. In some embodiments, Xbis C. In some embodiments, Xcis C. In some embodiments, Xdis C. In some embodiments, Xais N. In some embodiments, Xbis N. In some embodiments, Xcis N.

[0060] In some embodiments, the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresentswherein indicatesbond to LE.

[0061] In some embodiments, m is 1 and p is 0, and each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S. In some embodiments, XE1is N. In some embodiments, XE1is CRE6. In some embodiments, XE1is NRE4. In some embodiments, XE1is O. In some embodiments, XE1is S. In some embodiments, XE3is N. In some embodiments, XE3is CRE6. In some embodiments, XE3is NRE4. In some embodiments, XE3is O. In some embodiments, XE3is S. In some embodiments, XE4is N. In some embodiments, XE4is CRE6. In some embodiments, XE4is NRE4. In some embodiments, XE4is O. In some embodiments, XE4is S. In some embodiments, XE5is N. In some embodiments, XE5is CRE6. In some embodiments, XE5is NRE4. In some embodiments, XE5is O. In some embodiments, XE5is S. In some embodiments, XE5is S. In some embodiments, XE6is N. In some embodiments, XE6is CRE6. In some embodiments, XE6is NRE4. In some embodiments, XE6is O. In some embodiments, XE6is S.

[0062] In some embodiments, Xais C. In some embodiments, Xbis C. In some embodiments, Xcis C. In some embodiments, Xdis C. In some embodiments, Xais N. In some embodiments, Xbis N. In some embodiments, Xdis N.

[0063] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswherein iEndicates bond to L .

[0064] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswhereinindicates bond to LE.

[0065] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents wherein inEdicates bond to L .

[0066] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents wEhereinindicates bond to L .

[0067] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, whereinEindicates bond to L . In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, whereinEindicates bond to L .

[0068] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents wherein iEndicates bond to L .

[0069] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, whereinEindicates bond to L .

[0070] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and XdrepresentswhereinEindicates bond to L .

[0071] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswherein indicates bond toEL .

[0072] Disclosed herein, in some embodiments, is a compound of Formula I''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S;each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclylwith 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0073] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic;Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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-C6carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RC4and RC5are optionally taken together to formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0074] In some embodiments, the compound or the inhibitor compound is of Formula I'':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl;each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0075] In some embodiments, XE5is CRE6, N, O, or S.

[0076] In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 6-membered heteroaryl with 1-2 nitrogen atoms.

[0077] In some embodiments, Ring E1 is an optionally substituted 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 9- membered bicyclic heteroaryl with 1-2 nitrogen atoms.

[0078] In some embodiments, Ring E1 is an optionally substituted phenyl.

[0079] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, –C(O)- C1-C6alkyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,–C(O)- NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10, –NRE11C(O)RE12, - C(O)OH, ; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0080] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and – C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10, – NRE11C(O)RE12, or -C(O)OH; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0081] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10, –NRE11C(O)RE12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0082] In some embodiments, Ring E1 is whereinRE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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;RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0083] In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0084] In some embodiments, RE8is –NRE11C(O)RE12. In some embodiments, RE11is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE12is optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or optionally substituted C1-C6alkyl; RE12is optionally substituted C1-C6alkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; andRN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0086] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0087] In some embodiments, Ring E1, along with its RE8and R13substituents, is.

[0088] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0089] In some embodiments, RE9is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl.

[0090] In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0091] In some embodiments, RE11is hydrogen or an optionally substituted group selected from C1-C6alkyl, 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.

[0092] In some embodiments, RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0093] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, RE8is optionally substituted

[0095] In some embodiments, RE8is optionally substitutedor.

[0096] In some embodiments, RE8iswherein R° is as defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0097] In some such embodiments, R° is hydrogen or C1-6 aliphatic.

[0098] In some embodiments, RE8is optionally substituted, ,

[0099] In some embodiments, RE8iswherein 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.

[0100] 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.

[0101] 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.

[0102] In some embodiments, RE8is In soE8me embodiments, R is optionally

[0103] In some embodiments, RE8is an optionally substituted ring selected from:

[0104] In some embodiments, RE8is selected from:, wherein each R° is as defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0105] In some embodiments, RE8is:

[0106] 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.

[0107] In some embodiments, each RE13is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0108] In some embodiments, LEis –G–LE1–LE2–GS–, wherein G and GSare each absent.

[0109] In some embodiments, LEis –GS–LE2–LE1–G–, wherein G and GSare each absent.

[0110] In some embodiments, GSis –CH2CH2–. In some embodiments, G is –CH2CH2–. In some embodiments, GSis –CH2–. In some embodiments, G is –CH2–.

[0111] In some embodiments, LEis –LE1–LE2–.

[0112] In some embodiments, LE1is –C(O)–.

[0113] In some embodiments, LE2is –NRN6–.

[0114] In some embodiments, LEis –C(O)NRN6–. In some embodiments, LEis –C(O)NH–.

[0115] In some embodiments, LEis an optionally substitutedsome embodiments, LEis an optionally substituted.

[0116] In some embodiments, LEis optionally substituted

[0117] In some embodiments, LEis

[0118] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0119] In some embodiments, LEis an optionally substitute

[0120] 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.

[0121] 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.

[0122] 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.

[0123] In some embodiments, LEis. In some embodiments, LEis optionally substituted whmere W is as described above and defined herein. In someembodiments, LEisIn some embodiments, LEis optionally substituted

[0124] In some embodiments, LEis an optionally substituted ring selected from:

[0125] In some embodiments, LEis:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0126] In some embodiments, LEis:

[0127] In some embodiments, YE3is CRE2.

[0128] In some embodiments, YE4is CRE3. Formula I'

[0129] Disclosed herein, in some embodiments, is a compound of Formula I':or a pharmaceutically acceptable salt thereof, wherein: Ring E is 9-membered bicyclic ring having the structure ofwherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein each independently represents a single or double bond, wherein Ring E3 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E4 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, whereinindicates bond to LE1;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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of XE1, XE2, XE3, XE4, and XE5is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0130] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I':or a pharmaceutically acceptable salt thereof, wherein: Ring E is 9-membered bicyclic ring having the structure ofwherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein each independently represents a single or double bond, wherein Ring E3 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E4 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, wherein indi E1cates bond to L ;RE1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with 1-4 heteroatoms independentlyselected 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of XE1, XE2, XE3, XE4, and XE5is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl. Formula I

[0131] In some embodiments, the compound or the inhibitor compound is of Formula I:or a pharmaceutically acceptable salt thereof.

[0132] Disclosed herein, in some embodiments, is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of XE1, XE2, XE3, XE4, and XE5is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0133] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of XE1, XE2, XE3, XE4, and XE5is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy,wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0134] In some embodiments, XE1is N. In some embodiments, XE1is CRE6.

[0135] In some embodiments, XE2is N. In some embodiments, XE2is CRE6.

[0136] In some embodiments, XE3is N. In some embodiments, XE3is CRE6.

[0137] In some embodiments, XE4is N. In some embodiments, XE4is CRE6.

[0138] In some embodiments, XE5is N. In some embodiments, XE5is CRE6.

[0139] In some embodiments, Ring E is

[0140] Disclosed herein, in some embodiments, is a compound of Formula II''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0141] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl;each of XE1, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0142] In some embodiments, the compound or the inhibitor compound is of Formula II'':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresentsthat said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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;each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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.

[0143] In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 6-membered heteroaryl with 1-2 nitrogen atoms.

[0144] In some embodiments, Ring E1 is an optionally substituted 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 9- membered bicyclic heteroaryl with 1-2 nitrogen atoms.

[0145] In some embodiments, Ring E1 is an optionally substituted phenyl.

[0146] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, –C(O)- C1-C6alkyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,–C(O)- NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10, –NRE11C(O)RE12, - C(O)OH, ; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0147] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and – C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10– NRE11C(O)RE12, or -C(O)OH; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0148] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10, –NRE11C(O)RE12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0149] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0150] In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0151] In some embodiments, RE8is –NRE11C(O)RE12. In some embodiments, RE11is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE12is optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0152] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or optionally substituted C1-C6alkyl; RE12is optionally substituted C1-C6alkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0153] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0154] In some embodiments, Ring E1, along with its RE8and R13substituents, is.

[0155] 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.

[0156] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0157] In some embodiments, RE9is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl.

[0158] In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0159] In some embodiments, RE11is hydrogen or an optionally substituted group selected from C1-C6alkyl, 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.

[0160] In some embodiments, RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0161] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8isoptionally 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.

[0162] In some embodiments, RE8is optionally substitutedIn

[0163] In some embodiments, RE8is optionally substitutedor

[0164] In some embodiments, RE8is

[0165] In some such embodiments, R° is hydrogen or C1-6 aliphatic.

[0166] In some embodiments, RE8is optionally substituted

[0167] In some embodiments, RE8iswherein 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.

[0168] 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.

[0169] 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.

[0170] In some embodiments, RE8isE8In some embodiments, R is optionally substitutedwhere Wmis as described above and defined herein. In some embodiments, RE8isIn some embodiments, RE8is optionally substituted

[0171] In some embodiments, RE8is an optionally substituted ring selected from:

[0172] In some embodiments, RE8is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0173] In some embodiments, RE8is:

[0174] 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.

[0175] In some embodiments, each RE13is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0176] In some embodiments, LEis –G–LE1–LE2–GS–, wherein G and GSare each absent.

[0177] In some embodiments, LEis –GS–LE2–LE1–G–, wherein G and GSare each absent.

[0178] In some embodiments, GSis –CH2CH2–. In some embodiments, G is –CH2CH2–. In some embodiments, GSis –CH2–. In some embodiments, G is –CH2–.

[0179] In some embodiments, LEis –LE1–LE2–.

[0180] In some embodiments, LE1is –C(O)–.

[0181] In some embodiments, LE2is –NRN6–.

[0182] In some embodiments, LEis –C(O)NRN6–. In some embodiments, LEis –C(O)NH–.

[0183] In some embodiments, LEis an optionally substitutedIn some embodiments, LEis an optionally substituted

[0184] In some embodiments, LEis optionally substituted

[0185] In some embodiments, LEis

[0186] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0187] In some embodiments, LE is an optionally substitute

[0188] 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.

[0189] 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 monocyclicheteroaryl 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.

[0190] 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.

[0191] In some embodiments, LEis. In some embodiments, LEis optionally substitutedwhere Wmis as described above and defined herein. In some embodiments, LEis In some embodEiments, L is optionally substituted

[0192] In some embodiments, LEis an optionally substituted ring selected from:

[0193] In some embodiments, LEis:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0194] In some embodiments, LEis:

[0195] In some embodiments, YE3is CRE2.

[0196] In some embodiments, YE4is CRE3. Formula II'

[0197] Disclosed herein, in some embodiments, is a compound of Formula II':or a pharmaceutically acceptable salt thereof, wherein:Ring E is 8-membered bicyclic ring having the structure ofwherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein eachindependently represents a single or double bond, wherein Ring E5 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E6 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, whereinindicates bond to LE1;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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0198] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II':or a pharmaceutically acceptable salt thereof, wherein:Ring E is 8-membered bicyclic ring having the structure ofwherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein eachindependently represents a single or double bond, wherein Ring E5 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E6 is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, whereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl. Formula II

[0199] In some embodiments, the compound or the inhibitor compound is of Formula II:or a pharmaceutically acceptable salt thereof.

[0200] Disclosed herein, in some embodiments, is a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–;each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0201] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy;RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0202] In some embodiments, ZE1is N. In some embodiments, ZE1is CRE6.

[0203] In some embodiments, ZE2is N. In some embodiments, ZE2is CRE6.

[0204] In some embodiments, ZE3is N. In some embodiments, ZE3is CRE6.

[0205] In some embodiments, Ring E is

[0206] Disclosed herein, in some embodiments, is a compound of Formula III''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent;each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0207] Disclosed herein, in some embodiments, is an inhibitor compound of Formula III''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0208] In some embodiments, the compound or the inhibitor compound is of Formula III'':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, whereinLE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring;each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0209] In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 6-membered heteroaryl with 1-2 nitrogen atoms.

[0210] In some embodiments, Ring E1 is an optionally substituted 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 8- to 10-membered bicyclic heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 9- membered bicyclic heteroaryl with 1-2 nitrogen atoms.

[0211] In some embodiments, Ring E1 is an optionally substituted phenyl.

[0212] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, –C(O)- C1-C6alkyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,–C(O)- NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10, –NRE11C(O)RE12, - C(O)OH, ; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl;each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0213] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and – C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10– NRE11C(O)RE12, or -C(O)OH; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0214] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10, –NRE11C(O)RE12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0215] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0216] In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0217] In some embodiments, RE8is –NRE11C(O)RE12. In some embodiments, RE11is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE12is optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0218] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or optionally substituted C1-C6alkyl; RE12is optionally substituted C1-C6alkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0219] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0220] In some embodiments, Ring E1, along with its RE8and R13substituents, is.

[0221] 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.

[0222] 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.

[0223] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0224] In some embodiments, RE9is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl.

[0225] In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0226] In some embodiments, RE11is hydrogen or an optionally substituted group selected from C1-C6alkyl, 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.

[0227] In some embodiments, RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0228] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0229] In some embodiments, RE8is optionally substitutedIn some embodiments, RE8is optionally substituted

[0230] In some embodiments, RE8is optionally substitutedor

[0231] In some embodiments, RE8is

[0232] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0233] In some embodiments, RE8is optionally substituted

[0234] In some embodiments, RE8iswherein 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.

[0235] 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.

[0236] 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.

[0237] In some embodiments, RE8isE8In some embodiments, R is optionally substituted whmere W is as described above and defined herein. In someembodiments, RE8is. In some embodiments, RE8is optionally substituted In some embodiments, RE8is IE8n some embodiments, R is. In some embodiments, RE8is

[0238] In some embodiments, RE8is an optionally substituted ring selected from:

[0239] In some embodiments, RE8is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0240] In some embodiments, RE8is:

[0241] 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.

[0242] In some embodiments, each RE13is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0243] In some embodiments, LEis –G–LE1–LE2–GS–, wherein G and GSare each absent.

[0244] In some embodiments, LEis –GS–LE2–LE1–G–, wherein G and GSare each absent.

[0245] In some embodiments, GSis –CH2CH2–. In some embodiments, G is –CH2CH2–. In some embodiments, GSis –CH2–. In some embodiments, G is –CH2–.

[0246] In some embodiments, LEis –LE1–LE2–.

[0247] In some embodiments, LE1is –C(O)–.

[0248] In some embodiments, LE2is –NRN6–.

[0249] In some embodiments, LEis –C(O)NRN6–. In some embodiments, LEis –C(O)NH–.

[0250] In some embodiments, LEis an optionally substitutedsome embodiments, LEis an optionally substituted.

[0251] In some embodiments, LEis optionally substituted

[0252] In some embodiments, LEis

[0253] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0254] In some embodiments, LEis an optionally substitute

[0255] 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.

[0256] 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.

[0257] 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.

[0258] In some embodiments, LEis .EIn some embodiments, L is optionally substituted where Wmis as described above and defined herein. In someembodiments, LEisIn some embodiments, LEis optionally substituted In some embodiments, LEis. In some embodiments, LEis. In some embodiments, LEis

[0259] In some embodiments, LEis an optionally substituted ring selected from:

[0260] In some embodiments, LEis:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0261] In some embodiments, LEis:

[0262] In some embodiments, YE3is CRE2.

[0263] In some embodiments, YE4is CRE3.Formula III'

[0264] Disclosed herein, in some embodiments, is a compound of Formula III':or a pharmaceutically acceptable salt thereof, wherein: Ring E is 10-membered bicyclic ring having the structure ofor, wherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein eachindependently represents a single or double bond, wherein Ring E7 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring E8 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy,wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, whereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0265] Disclosed herein, in some embodiments, is an inhibitor compound of Formula III':or a pharmaceutically acceptable salt thereof, wherein: Ring E is 10-membered bicyclic ring having the structure oforwherein z is an atom, each of which is independently selected from carbon, nitrogen, oxygen, and sulfur, wherein each independently represents a single or double bond, wherein Ring E7 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring E8 is phenyl, 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 6-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein e0 is 0, 1, 2, 3, 4, or 5, wherein each RE0is, independently, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl, whereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl. Formula III

[0266] In some embodiments, the compound or the inhibitor compound is of Formula III:or a pharmaceutically acceptable salt thereof.

[0267] Disclosed herein, in some embodiments, is a compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl;RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0268] Disclosed herein, in some embodiments, is an inhibitor compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein: Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of ZE1, ZE2, ZE3, ZE4, ZE5, and ZE6is, independently, N or CRE6;RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0269] In some embodiments, ZE1is N. In some embodiments, ZE1is CRE6.

[0270] In some embodiments, ZE2is N. In some embodiments, ZE2is CRE6.

[0271] In some embodiments, ZE3is N. In some embodiments, ZE3is CRE6.

[0272] In some embodiments, ZE4is N. In some embodiments, ZE4is CRE6.

[0273] In some embodiments, ZE5is N. In some embodiments, ZE5is CRE6.

[0274] In some embodiments, ZE5is N. In some embodiments, ZE5is CRE6.

[0275] In some embodiments, ZE6is N. In some embodiments, ZE6is CRE6.

[0276] In some embodiments, Ring E is

[0277] Disclosed herein, in some embodiments, is a compound of Formula IV':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 fromnitrogen, 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 or –NRN3C(O)NRN1RN2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

[0278] Disclosed herein, in some embodiments, is an inhibitor compound of Formula IV':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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 or –NRN3C(O)NRN1RN2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl;each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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.

[0279] In some embodiments, the compound or the inhibitor compound is of Formula IV:or a pharmaceutically acceptable salt thereof, wherein:within the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy;RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formwherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl.

[0280] In some embodiments, the compound or the inhibitor compound is of Formula IV-1:or a pharmaceutically acceptable salt thereof, wherein: Ring E1 isRE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl;RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl;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, –C(O)-NRN1RN2, and –NRN3C(O)RC1; and LEis –C(O)NRN6– or –NRN6C(O)–.

[0281] In some embodiments, XE1is N. In some embodiments, XE1is CRE6. In some embodiments, XE1is NRE4. In some embodiments, XE1is O. In some embodiments, XE1is S. In some embodiments, XE3is N. In some embodiments, XE3is CRE6. In some embodiments, XE3is NRE4. In some embodiments, XE3is O. In some embodiments, XE3is S. In some embodiments, XE4is N. In some embodiments, XE4is CRE6. In some embodiments, XE4is NRE4. In some embodiments, XE4is O. In some embodiments, XE4is S. In some embodiments, XE5is N. In some embodiments, XE5is CRE6. In some embodiments, XE5is NRE4. In some embodiments, XE5is O. In some embodiments, XE5is S. In some embodiments, XE5is S. In some embodiments, XE6is N. In some embodiments, XE6is CRE6. In some embodiments, XE6is NRE4. In some embodiments, XE6is O. In some embodiments, XE6is S.

[0282] In some embodiments, Xais C. In some embodiments, Xbis C. In some embodiments, Xcis C. In some embodiments, Xdis C. In some embodiments, Xais N. In some embodiments, Xbis N. In some embodiments, Xdis N.

[0283] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswherein indicates bond toEL . In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswhereinindicatesbond to LE. In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents wherein indicates bEond to L .

[0284] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswhereinindicates bond to LE. In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, wherein indicates bond to LE.E1In some embodiments, the bicyclic ring containing X , XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, whereinindicates bond to LE. In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and XdrepresentsEwhereinindicates bond to L .In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents, whereinEindicates bond to L .

[0285] In some embodiments, the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswherein indicates boE E1nd to L . In some embodiments, the bicyclic ring containing X , XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresentswherein indicates bond to LE.

[0286] In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 5- to 6-membered heteroaryl with 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 6-membered heteroaryl with 1-2 nitrogen atoms.

[0287] In some embodiments, Ring E1 is an optionally substituted 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring E1 is an optionally substituted 8- to 10-membered bicyclic heteroarylwith 1-2 nitrogen atoms. In some embodiments, Ring E1 is an optionally substituted 9- membered bicyclic heteroaryl with 1-2 nitrogen atoms.

[0288] In some embodiments, Ring E1 is an optionally substituted phenyl.

[0289] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, –C(O)- C1-C6alkyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,–C(O)- NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10, –NRE11C(O)RE12, - C(O)OH, ; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0290] In some embodiments, Ring E1 is phenyl optionally substituted with 1-5 substituents each independently selected from halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and – C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, thiazolyl, –C(O)NRE9RE10– NRE11C(O)RE12, or -C(O)OH; wherein RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; and RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0291] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10, –NRE11C(O)RE12, optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 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; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0292] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- memberedheterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE12is an optionally substituted group selected from C1-C6alkyl, 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; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0293] In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0294] In some embodiments, RE8is –NRE11C(O)RE12. In some embodiments, RE11is hydrogen or optionally substituted C1-C6alkyl. In some embodiments, RE12is optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0295] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or optionally substituted C1-C6alkyl; RE12is optionally substituted C1-C6alkyl; e1 is 0, 1, 2, 3, or 4;each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1-C6alkoxy, and –C(O)-C1-C6alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0296] In some embodiments, Ring E1 iswherein RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and RN4, RN5, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

[0297] In some embodiments, Ring E1, along with its RE8and R13substituents, is.

[0298] 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.

[0299] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0300] In some embodiments, RE9is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE9is hydrogen or optionally substituted C1-C6alkyl.

[0301] In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl, 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE10is hydrogen or an optionally substituted group selected from C1-C6alkyl and 5- to 6- membered heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6- membered heteroaryl is optionally substituted with C1-C6alkyl or C3-C5cycloalkyl. In some embodiments, RE10is hydrogen or optionally substituted C1-C6alkyl.

[0302] In some embodiments, RE11is hydrogen or an optionally substituted group selected from C1-C6alkyl, 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.

[0303] In some embodiments, RE12is an optionally substituted group selected from C1-C6alkyl, 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.

[0304] In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RE8is optionally substituted 3- to 7-membered monocyclic heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0305] In some embodiments, RE8is optionally substitutedIn some embodiments, RE8is optionally substituted.

[0306] In some embodiments, RE8is optionally substituted, , or

[0307] In some embodiments, RE8is

[0308] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0309] In some embodiments, RE8is optionally substituted

[0310] In some embodiments, RE8iswherein 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.

[0311] 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.

[0312] 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.

[0313] In some embodiments, RE8is. In some embodiments, RE8is optionally substituted, where Wmis as described above and defined herein. In some embodiments, RE8is. In some embodiments, RE8is optionally substituted In some embodiments, RE8is. In some embodiments, RE8is. In some embodiments, RE8is

[0314] In some embodiments, RE8is an optionally substituted ring selected from:

[0315] In some embodiments, RE8is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0316] In some embodiments, RE8is:

[0317] 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.

[0318] In some embodiments, each RE13is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0319] In some embodiments, LEis –G–LE1–LE2–GS–, wherein G and GSare each absent.

[0320] In some embodiments, LEis –GS–LE2–LE1–G–, wherein G and GSare each absent.

[0321] In some embodiments, GSis –CH2CH2–. In some embodiments, G is –CH2CH2–. In some embodiments, GSis –CH2–. In some embodiments, G is –CH2–.

[0322] In some embodiments, LEis –LE1–LE2–.

[0323] In some embodiments, LE1is –C(O)–.

[0324] In some embodiments, LE2is –NRN6–.

[0325] In some embodiments, LEis –C(O)NRN6–. In some embodiments, LEis –C(O)NH–.

[0326] In some embodiments, LEis an optionally substitutedIn some embodiments, LEis an optionally substituted.

[0327] In some embodiments, LEis optionally substituted

[0328] In some embodiments, LEis

[0329] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0330] In some embodiments, LEis an optionally substitute

[0331] 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.

[0332] 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.

[0333] 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.

[0334] In some embodiments, LEis. In some embodiments, LEis optionally substitutedwhere Wmis as described above and defined herein. In some embodiments, LEis In some embodimentsE, L is optionally substituted In some embodiments, LEis In some embodimentEs, L is. In some embodiments, LEis

[0335] In some embodiments, LEis an optionally substituted ring selected from:

[0336] In some embodiments, LEis:, , wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0337] In some embodiments, LEis:

[0338] In some embodiments, YE3is CRE2.

[0339] In some embodiments, YE4is CRE3.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] In some embodiments, RE1is

[0350] In some embodiments, RE1is:.

[0351] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0352] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0353] 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.

[0354] 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.

[0355] In some embodiments, RE1is

[0356] In some embodiments, RE1is CRC4RC5RC6.

[0357] 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.

[0358] In some embodiments, RC6is cyano or C1-C3haloalkyl.

[0359] In some embodiments, RC4and RC5together form whD2a D2berein R and R are each independently hydrogen and C1-C6alkyl.

[0360] In some embodiments, RC6is halogen.

[0361] In some embodiments, RE1is

[0362] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0363] In some embodiments, RE1is optionally substitutedIn some embodiments, RE1is optionally substituted

[0364] In some embodiments, RE1is optionally substitutedor

[0365] In some embodiments, RE1is

[0366] In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0367] In some embodiments, RE1is optionally substituted

[0368] 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.

[0369] 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 monocyclicheteroaryl 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.

[0370] 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.

[0371] In some embodiments, RE1is

[0372] In some embodiments, RE1is an optionally substituted ring selected from:

[0373] In some embodiments, RE1is selected from:, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0374] In some embodiments, RE1is:

[0375] In some embodiments, RE2is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F, –CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE2is hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0376] In some embodiments, RE3is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE3is hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0377] In some embodiments, YE1is N. In some embodiments, YE1is CRE7.

[0378] In some embodiments, YE2is N. In some embodiments, YE2is CRE7.

[0379] In some embodiments, RE4is hydrogen. In some embodiments, each RE4is, independently, optionally substituted C1-C6alkyl. In some embodiments, each RE4is, independently, C1-C6alkyl or C1-C6alkyl-C3-C6cycloalkyl. In some embodiments, RE4is C1- C6alkyl. In some embodiments, RE4is –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE4is –Me or –Et. In some embodiments, RE4is –Me. In some embodiments, RE4is –Et. is In some embodiments, RE4is –C1-C6alkyl-C3-C6cycloalkyl. In some embodiments, RE4is

[0380] In some embodiments, LE1is –C(O)–, –S(O)1-2–, or –CH2–, and LE2is –NRN6– or –O–.

[0381] In some embodiments, LE1is –C(O)–. In some embodiments, LE1is –S(O)1-2–. In some embodiments, LE1is –CH2–. In some embodiments, LE2is –NRN6–. In some embodiments, LE2is –O–.

[0382] In some embodiments, LE1is –NRN6– or –O–, and LE2is –C(O)–, –S(O)1-2–, or –CH2–. In some embodiments, LE1is –NRN6–. In some embodiments, LE1is –O–. In some embodiments, LE2is –C(O)–. In some embodiments, LE2is –S(O)1-2–. In some embodiments, LE2is –CH2–.

[0383] In some embodiments, RN6is hydrogen or C1-C6alkyl. In some embodiments, RN6is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN6is hydrogen.

[0384] In some embodiments, each RE6is, independently, hydrogen, halogen, or an optionally substituted group selected from C1-C6alkyl and C1-C6alkoxy. In some embodiments, each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1- 3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments, each RE6is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each RE6is, independently, hydrogen, –F, –Cl, – CF3, –Me, or –Et. In some embodiments, each RE6is, independently, hydrogen, –F, –CF3, or – Me.

[0385] In some embodiments, each RE7is, independently, hydrogen, halogen, and an optionally substituted group selected from C1-C6alkyl, phenyl, 6- membered heteroaryl with 1-2 nitrogen atoms, and C3-C6cycloalkyl.

[0386] In some embodiments, each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1- C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy.

[0387] In some embodiments, each RE7is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, – CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

[0388] In some embodiments, each RE7is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl.

[0389] In some embodiments, each RE7is, independently, hydrogen, –F, –CF3, –Me, phenyl,, cyclohexyl, or pyridyl.

[0390] In some embodiments, each RE7is, independently, hydrogen, –F, –CF3, –Me, or pyridyl.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, 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.

[0395] In some embodiments, RE13is halogen.

[0396] In some embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is – NRE11C(O)RE12.

[0397] In some embodiments, RE9is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE9is hydrogen. In some embodiments, RE9is –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE9is hydrogen or –Me.

[0398] In some embodiments, RE10is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE10is hydrogen. In some embodiments, RE10is –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu. In some embodiments, RE10is hydrogen or –Me.

[0399] In some embodiments, RE11is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RE11is hydrogen. In some embodiments, RE10is –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu. In some embodiments, RE11is hydrogen or –Me.

[0400] In some embodiments,

[0401] In some embodiments, each of RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0402] In some embodiments, each of RN1, RN2, RN3, RN7, and RD1is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RN1, RN2, RN3, RN7, and RD1is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0403] In some embodiments, each of RC1and RC2is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RC1and RC2is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0404] In some embodiments, RN3is hydrogen or C1-C6alkyl. In some embodiments, RN3is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN3is hydrogen.

[0405] In some embodiments, RC3is C1-C6 alkyl. In some embodiments, RC3is –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

[0406] In some embodiments, RN4is hydrogen or C1-C6alkyl. In some embodiments, RN4is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN4is hydrogen.

[0407] In some embodiments, RN5is hydrogen or C1-C6alkyl. In some embodiments, RN5is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN5is hydrogen.

[0408] In some embodiments, the compound is of any one of Formula I-a-1 to Formula I-a- 4:or a pharmaceutically acceptable salt thereof.

[0409] In some embodiments, the compound is of any one of Formula II-a-1 to Formula II- a-4:or a pharmaceutically acceptable salt thereof.

[0410] In some embodiments, the compound is of any one of Formula III-a-1 to Formula III-a-4:or a pharmaceutically acceptable salt thereof.

[0411] In some embodiments, the compound is of any one of Formula IV-a-1 to Formula IV- a-6:or a pharmaceutically acceptable salt thereof. Exemplary Compounds

[0412] Disclosed herein, in some embodiments, is a compound of Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt thereof.

[0413] Disclosed herein, in some embodiments, is an inhibitor compound of Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt thereof.

[0414] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0415] Disclosed herein, in some embodiments, is an inhibitor compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0416] In some embodiments, the compound or the inhibitor compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary Compounds

[0417] Disclosed herein, in some embodiments, is a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0418] Disclosed herein, in some embodiments, is an inhibitor compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0419] In some embodiments, the compound or the inhibitor compound is a compound of Table 2, or a pharmaceutically acceptable salt thereof. Table 2. Exemplary Compounds

[0420] Disclosed herein, in some embodiments, is a compound of Table 3, or a pharmaceutically acceptable salt thereof.

[0421] Disclosed herein, in some embodiments, is an inhibitor compound of Table 3, or a pharmaceutically acceptable salt thereof.

[0422] In some embodiments, the compound or the inhibitor compound is a compound of Table 3, or a pharmaceutically acceptable salt thereof.Table 3. Exemplary Compounds

[0423] Disclosed herein, in some embodiments, is a compound of Table 4, or a pharmaceutically acceptable salt thereof.

[0424] Disclosed herein, in some embodiments, is an inhibitor compound of Table 4, or a pharmaceutically acceptable salt thereof.

[0425] In some embodiments, the compound or the inhibitor compound is a compound of Table 4, or a pharmaceutically acceptable salt thereof.Table 4. Exemplary Compounds

[0426] 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 AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', or Formula IV, or a subformula thereof, or a pharmaceutically acceptable salt thereof, 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, Table 2, Table 3, or Table 4 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,Table 2, Table 3, or Table 4 above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0427] In some embodiments, the present disclosure provides a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', or Formula IV, or a subformula thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', or Formula IV, or a subformula thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0428] 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.

[0429] 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.

[0430] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof.

[0431] 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.

[0432] 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.

[0433] 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 1-I'

[0434] Disclosed herein, in some embodiments, is a compound of Formula 1-I':or a pharmaceutically acceptable salt thereof, wherein: RS11is 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)-NRN11RN12, or – NRN13C(O)RC11, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl; RS12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl;or RS11and RS12, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC12; RS13is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS11and YS12is, independently, N or CRS17; XS11is N or CRS15; XS12, XS13, and XS14are each, independently, N or CRS16, LS11is –C(O)– or –CH2–; LS12is –NRN16– or –O–; RS14is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS14is optionally substituted with cyano; RS15is hydrogen or halogen; RS16is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS16is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS17is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolyl; each of RN11, RN12, RN13, RN14, RN16, RC11, RC12, and RC13is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN15is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN15is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0435] Disclosed herein, in some embodiments, is an inhibitor compound of Formula 1-I':or a pharmaceutically acceptable salt thereof, wherein: RS11is 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)-NRN11RN12, or – NRN13C(O)RC11, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl; RS12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS11and RS12, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC12; RS13is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS11and YS12is, independently, N or CRS17; XS11is N or CRS15; XS12, XS13, and XS14are each, independently, N or CRS16, LS11is –C(O)– or –CH2–; LS12is –NRN16– or –O–; RS14is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS14is optionally substituted with cyano; RS15is hydrogen or halogen; RS16is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS16is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS17is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolyl;each of RN11, RN12, RN13, RN14, RN16, RC11, RC12, and RC13is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN15is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN15is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0436] In some embodiments, YS11is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy.

[0437] In some embodiments, YS12is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy.

[0438] In some embodiments, Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is fused with a ring to form 8- to 10-membered aryl or 8- to 10- membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN11RN12C(O)RC13, imidazolyl, and thiazolyl.

[0439] In some embodiments, (i) YS11is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (ii) YS12is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (iii) Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is fused with a ring to form 8- to 10-membered aryl or 8- to 10- membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN11RN12C(O)RC13, imidazolyl, and thiazolyl.

[0440] In some embodiments, the compound or the inhibitor compound is of Formula 1-I:or a pharmaceutically acceptable salt thereof, wherein: RS11is 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)-NRN11RN12, or – NRN13C(O)RC11, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl; RS12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS11and RS12, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC12; RS13is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS11and YS12is, independently, N or CRS17; XS11is N or CRS15;XS12, XS13, and XS14are each, independently, N or CRS16, LS11is –C(O)– or –CH2–; LS12is –NRN16– or –O–; RS14is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS14is optionally substituted with cyano; RS15is hydrogen or halogen; RS16is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS16is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS17is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolyl; each of RN11, RN12, RN13, RN14, RN16, RC11, RC12, and RC13is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN15is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN15is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3, provided that:(i) YS11is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (ii) YS12is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (iii) Ring S11 phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is fused with a ring to form 9-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolylIn some embodiments, RS11is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

[0441] In some embodiments, RS11is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein said 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and

[0442] wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

[0443] In some embodiments, RS11is 6-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein said 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

[0444] In some embodiments, RS11is

[0445] In some embodiments, RS11is –C(O)-NRN11RN12or –NRN13C(O)RC11. In some embodiments, each of RN11, RN12, RN13, and RC11is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RN11, RN12, RN13, and RC11is, independently, hydrogen, –Me, – Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0446] In some embodiments, RS12is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F, –CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RS12is hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0447] In some embodiments, RS13is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RS13is hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0448] In some embodiments, RS14is C1-C6alkyl. In some embodiments, RS14is –Me or –Et. In some embodiments, RS14is –C1-C6alkyl-C3-C6cycloalkyl. In some embodiments, RS14is.

[0449] In some embodiments, LS11is –C(O)–.

[0450] In some embodiments, LS12is –NRN16–.

[0451] In some embodiments, RN16is hydrogen or C1-C6alkyl. In some embodiments, RN16is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN16is hydrogen.

[0452] In some embodiments, XS12is CRS16.

[0453] In some embodiments, XS13is CRS16.

[0454] In some embodiments, XS14is CRS16.

[0455] In some embodiments, each RS16is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each RS16is, independently, hydrogen, –F, –CF3, or – Me.

[0456] In some embodiments, XS14is N.

[0457] In some embodiments, YS11is CRS17.

[0458] In some embodiments, YS12is CRS17.

[0459] In some embodiments, each RS17is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, – CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl. In some embodiments, each RS17is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl. In some embodiments, each RS17is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

[0460] In some embodiments, Ring S11 is 9-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)- NRN14RN15, –NRN11RN12C(O)RC13, imidazolyl, and thiazolyl.

[0461] In some embodiments, Ring S11 is, , ,, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0462] In some embodiments, Ring S11 is, , , or, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

[0463] In some embodiments, the compound or the inhibitor compound is of any one of Formula 1-I-a-1 to 1-I-a-4:or a pharmaceutically acceptable salt thereof.Formula 1-II

[0464] Disclosed herein, in some embodiments, is a compound of Formula 1-II:or a pharmaceutically acceptable salt thereof, wherein: RS21is 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)-NRN21RN22, or – NRN23C(O)RC21, wherein RS1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; s21 is an integer selected from 0-4; s22 is an integer selected from 0-6; each RS22is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC22; XS21is N or CRS25, XS22, XS23, and XS24are each, independently, N or CRS26, LS21is –C(O)– or –CH2–; LS22is –NRN26– or –O–; RS24is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS24is optionally substituted with cyano; RS25is hydrogen or halogen;RS26is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS26is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each of YS21and YS22is, independently, N or CRS27; each RS27is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S21 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S21 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl; each RN21, RN22, RN23, RN24, RN26, RC21, RC22, and RC23is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN25is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN25is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0465] Disclosed herein, in some embodiments, is an inhibitor compound of Formula 1-II:or a pharmaceutically acceptable salt thereof, wherein: RS21is 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)-NRN21RN22, or – NRN23C(O)RC21, wherein RS1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; s21 is an integer selected from 0-4; s22 is an integer selected from 0-6; each RS22is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC22; XS21is N or CRS25, XS22, XS23, and XS24are each, independently, N or CRS26, LS21is –C(O)– or –CH2–; LS22is –NRN26– or –O–; RS24is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS24is optionally substituted with cyano; RS25is hydrogen or halogen; RS26is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl,wherein RS26is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each of YS21and YS22is, independently, N or CRS27; each RS27is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S21 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S21 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl; each RN21, RN22, RN23, RN24, RN26, RC21, RC22, and RC23is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN25is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN25is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0466] In some embodiments, RS21is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RS21is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0467] In some embodiments, RS21is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RS21is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0468] In some embodiments, RS21is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RS21is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0469] In some embodiments, RS21isIn some embodiments, RS21isIn some embodiments, RS21is

[0470] In some embodiments, RS21is –C(O)-NRN21RN22or –NRN23C(O)RC21.

[0471] In some embodiments, each of RN21, RN22, RN23, and RC21is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RN21, RN22, RN23, and RC21is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0472] In some embodiments, s21 is 1, 2, or 3.

[0473] In some embodiments, s22 is 0, 1, or 2. In some embodiments, s22 is 2, 3, or 4.

[0474] In some embodiments, each RS22is, independently, –F, –Cl, –CF3, –CHF2, –CH2F,– CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7-membered carbocyclyl.

[0475] In some embodiments, each RS22is, independently, –F, –Cl, –CF3, –CHF2, –CH2F,– CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 4- to 5-membered carbocyclyl.

[0476] In some embodiments,In some embodiments,

[0477] In some embodiments, RS24is C1-C6alkyl. In some embodiments, RS24is –Me or –Et. In some embodiments, RS24is –C1-C6alkyl-C3-C6cycloalkyl. In some embodiments, RS24is.

[0478] In some embodiments, LS21is –C(O)–.

[0479] In some embodiments, LS22is –NRN26–.

[0480] In some embodiments, RN26is hydrogen or C1-C6alkyl. In some embodiments, RN26is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN26is hydrogen.

[0481] In some embodiments, XS22is CRS26.

[0482] In some embodiments, XS23is CRS26.

[0483] In some embodiments, XS24is CRS26.

[0484] In some embodiments, each RS26is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each RS26is, independently, hydrogen, –F, –CF3, or – Me.

[0485] In some embodiments, XS24is N.

[0486] In some embodiments, YS11is CRS27.

[0487] In some embodiments, YS12is CRS27.

[0488] In some embodiments, each RS27is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, – CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl. In some embodiments, each RS27is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl. In some embodiments, each RS27is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

[0489] In some embodiments, Ring S21 is 9-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionallysubstituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)- NRN14RN15, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

[0490] In some embodiments, Ring S21 is, , ,, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0491] In some embodiments, Ring S21 is, , , or, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

[0492] In some embodiments, Ring S21 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, – S(O)2NRN21RN22, –NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN21RN22, –C(O)- NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

[0493] In some embodiments, Ring S21 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, – S(O)2NRN21RN22, –NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN21RN22, –C(O)- NRN24RN25, and –NRN23C(O)RC23.

[0494] In some embodiments, Ring S21 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from –C(O)-NRN24RN25and – NRN21RN22C(O)RC23.

[0495] In some embodiments, Ring S21 is phenyl, wherein Ring S21 is substituted with –C(O)- NRN24RN25or –NRN21RN22C(O)RC23.

[0496] In some embodiments, Ring S21 is,

[0497] In some embodiments, Ring S21 is

[0498] In some embodiments, RN23is hydrogen or C1-C6alkyl. In some embodiments, RN23is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN23is hydrogen.

[0499] In some embodiments, RC23is C1-C6alkyl. In some embodiments, RC23is –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0500] In some embodiments, RN24is hydrogen or C1-C6alkyl. In some embodiments, RN24is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN24is hydrogen.

[0501] In some embodiments, RN25is hydrogen or C1-C6alkyl. In some embodiments, RN25is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN25is hydrogen.

[0502] In some embodiments, the compound or the inhibitor compound is of any one of Formula 1-II-a-1 to Formula 1-II-a-4:or a pharmaceutically acceptable salt thereof. Formula 1-III

[0503] Disclosed herein, in some embodiments, is a compound of Formula 1-III:or a pharmaceutically acceptable salt thereof, wherein: RS31is 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)-NRN31RN32, or – NRN33C(O)RC31, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; Ring S32 isRS32ais hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS31and RS32a, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC32; RS33is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS31and YS32is, independently, N or CRS37; S31 is an integer selected from 0-4; S32 is an integer selected from 0-6; RS32bis halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS32bsubstituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, and – C(O)RC32; XS31is N or CRS35; XS32, XS33, and XS34are each, independently, N or CRS36, LS31is –S(O)2– and LS32 is –NRN36–, or LS31is –NRN36– and LS32 is –S(O)2–, or LS31is –NRN36– and LS32is –C(O)–;RS34is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS34is optionally substituted with cyano; RS35is hydrogen or halogen; RS36is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS36is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS37is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S31 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S31 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S31 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN31RN32, –S(O)2NRN31RN32, – NRN33S(O)2RC33, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN31RN32, –C(O)-NRN34RN35, –NRN33C(O)RC33, imidazolyl, and thiazolyl; each RN31, RN32, RN33, RN34, RN36, RC31, RC32, and RC33is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN35is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN35is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0504] Disclosed herein, in some embodiments, is an inhibitor compound of Formula 1-III:or a pharmaceutically acceptable salt thereof, wherein: RS31is 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)-NRN31RN32, or – NRN33C(O)RC31, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; Ring S32 isRS32ais hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS31and RS32a, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC32; RS33is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS31and YS32is, independently, N or CRS37; S31 is an integer selected from 0-4; S32 is an integer selected from 0-6;RS32bis halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS32bsubstituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, and – C(O)RC32; XS31is N or CRS35; XS32, XS33, and XS34are each, independently, N or CRS36, LS31is –S(O)2– and LS32is –NRN36–, or LS31is –NRN36– and LS32is –S(O)2–, or LS31is –NRN36– and LS32is –C(O)–; RS34is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS34is optionally substituted with cyano; RS35is hydrogen or halogen; RS36is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS36is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS37is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S31 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S31 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S31 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN31RN32, –S(O)2NRN31RN32, – NRN33S(O)2RC33, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN31RN32, –C(O)-NRN34RN35, –NRN33C(O)RC33, imidazolyl, and thiazolyl;each RN31, RN32, RN33, RN34, RN36, RC31, RC32, and RC33is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN35is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN35is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

[0505] In some embodiments, RS31is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0506] In some embodiments, RS31is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0507] In some embodiments, RS31is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0508] In some embodiments, RS31isor InS31some embodiments, R isIn some embodiments, RS31is

[0509] In some embodiments, RS31is –C(O)-NRN31RN32or –NRN33C(O)RC31.

[0510] In some embodiments, each of RN31, RN32, RN33, and RC31is, independently, hydrogen or C1-C6alkyl. In some embodiments, each of RN31, RN32, RN33, and RC31is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0511] In some embodiments, Ring S32 is

[0512] In some embodiments, RS32ais hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0513] In some embodiments, RS32ais hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0514] In some embodiments, RS33is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F, –CF2CF3, – CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0515] In some embodiments, RS33is hydrogen, –F, –CF3, –CHF2, –CH2F,or –Me.

[0516] In some embodiments, YS31is CRS37.

[0517] In some embodiments, YS32is CRS37.

[0518] In some embodiments, each RS37is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, – CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

[0519] In some embodiments, each RS37is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl.

[0520] In some embodiments, each RS37is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

[0521] In some embodiments, Ring S32 is

[0522] In some embodiments, s31 is 1, 2, or 3.

[0523] In some embodiments, s32 is 0, 1, or 2. The compound of claim 117 or 118, wherein s32 is 2, 3, or 4.

[0524] In some embodiments, each RS32bis, independently, –F, –Cl, –CF3, –CHF2, –CH2F,– CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7-membered carbocyclyl.

[0525] In some embodiments, each RS32bis, independently, –F, –Cl, –CF3, –CHF2, –CH2F,– CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 4- to 5-membered carbocyclyl.

[0526] In some embodiments,

[0527] In some embodiments,

[0528] In some embodiments, RS34is C1-C6alkyl. In some embodiments, RS34is –Me or –Et. In some embodiments, RS34is –C1-C6alkyl-C3-C6cycloalkyl. In some embodiments, RS34is.

[0529] In some embodiments, LS31is –S(O)2– and LS32is –NRN36–. In some embodiments, LS31is –NRN36– and LS32is –C(O)–.

[0530] In some embodiments, RN36is hydrogen or C1-C6alkyl. In some embodiments, RN36is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN36is hydrogen.

[0531] In some embodiments, XS32is CRS36.

[0532] In some embodiments, XS33is CRS36.

[0533] In some embodiments, XS34is CRS36.

[0534] In some embodiments, each RS36is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each RS36is, independently, hydrogen, –F, –CF3, or – Me.

[0535] In some embodiments, XS34is N.

[0536] In some embodiments, Ring S31 is 9-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)- NRN14RN15, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

[0537] In some embodiments, Ring S31 is, , , or, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

[0538] In some embodiments, Ring S31 is, , ,, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F, –CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

[0539] In some embodiments, Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, – S(O)2NRN21RN22, –NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN21RN22, –C(O)- NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

[0540] In some embodiments, Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, – S(O)2NRN21RN22, –NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN21RN22, –C(O)- NRN24RN25, and –NRN23C(O)RC23.

[0541] In some embodiments, Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from –C(O)-NRN24RN25and – NRN21RN22C(O)RC23.

[0542] In some embodiments, Ring S31 is phenyl, wherein Ring S21 is substituted with –C(O)- NRN24RN25or –NRN21RN22C(O)RC23.

[0543] In some embodiments, Ring S31 is

[0544] In some embodiments, Ring S31 is

[0545] In some embodiments, RN33is hydrogen or C1-C6alkyl. In some embodiments, RN33is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN33is hydrogen.

[0546] In some embodiments, RC33is C1-C6alkyl. In some embodiments, RC33is –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

[0547] In some embodiments, RN34is hydrogen or C1-C6alkyl. In some embodiments, RN34is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN34is hydrogen.

[0548] In some embodiments, RN35is hydrogen or C1-C6alkyl. In some embodiments, RN35is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu. In some embodiments, RN35is hydrogen.

[0549] In some embodiments, the compound or the inhibitor compound is of any one of Formula 1-III-a-1 to Formula 1-III-a-6:or a pharmaceutically acceptable salt thereof. Exemplary Compounds

[0550] Disclosed herein, in some embodiments, is a compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof.

[0551] Disclosed herein, in some embodiments, is an inhibitor compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof.

[0552] Disclosed herein, in some embodiments, is a compound of Table 5, or a pharmaceutically acceptable salt thereof.

[0553] Disclosed herein, in some embodiments, is an inhibitor compound of Table 5, or a pharmaceutically acceptable salt thereof.

[0554] In some embodiments, the compound or the inhibitor compound is a compound of Table 5, or a pharmaceutically acceptable salt thereof Table 5. Exemplary Compounds

[0555] Disclosed herein, in some embodiments, is a compound of Table 6, or a pharmaceutically acceptable salt thereof.

[0556] Disclosed herein, in some embodiments, is an inhibitor compound of Table 6, or a pharmaceutically acceptable salt thereof.

[0557] In some embodiments, the compound or the inhibitor compound is a compound of Table 6, or a pharmaceutically acceptable salt thereofTable 6. Exemplary Compounds

[0558] Disclosed herein, in some embodiments, is a compound of Table 7, or a pharmaceutically acceptable salt thereof.

[0559] Disclosed herein, in some embodiments, is an inhibitor compound of Table 7, or a pharmaceutically acceptable salt thereof.

[0560] In some embodiments, the compound or the inhibitor compound is a compound of Table 7, or a pharmaceutically acceptable salt thereofTable 7. Exemplary Compounds

[0561] 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 1-1', Formula 1-1, Formula l-II, or Formula I-III, or a subformula thereof, or a compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof, 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 5, Table 6, or Table 7 above, or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 5, Table 6, or Table 7 above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0562] In some embodiments, the present disclosure provides a compound of Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0563] 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 (such as a compound of Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof), 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.

[0564] 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.

[0565] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof.

[0566] 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 thebiological sample a compound disclosed herein, or a pharmaceutical composition disclosed herein.

[0567] 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.

[0568] 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. Pharmaceutical Compositions

[0569] Compounds disclosed herein (e.g., compounds of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, and pharmaceutically acceptable salts thereof) are administered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients.

[0570] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I- III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient (i.e., one or more pharmaceutically acceptable excipients).

[0571] 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 prodrugsthereof, 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.

[0572] 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 AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, and pharmaceutically acceptable salts thereof) are useful for treating a disease or disorder, or symptoms thereof, described herein.

[0573] The dosage of the compounds disclosed herein (e.g., compounds of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, 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 AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, 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.

[0574] The present disclosure also provides kits including pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula AA', Formula AA,Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, and pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0575] Disclosed herein, in some embodiments, is a process for providing a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof), Methods of Use and Treatment

[0576] Compounds disclosed herein (e.g., compounds of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, and Formula I-III, and subformulas thereof, and compounds of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, and Table 7, 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.

[0577] 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., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof), or a composition comprising said compound.

[0578] 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).

[0579] 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.

[0580] 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., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof), or a composition comprising said compound or pharmaceutically acceptable salt thereof.

[0581] 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., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, Formula III''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable composition thereof. Exemplary diseases and disorders are described in herein.

[0582] 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., a compound of Formula AA', Formula AA, Formula A, Formula A-1, Formula I''', Formula I'', Formula I', Formula I, Formula II''', Formula II'', Formula II', Formula II, FormulaIII''', Formula III'', Formula III', Formula III, Formula IV', Formula IV, Formula IV-1, Formula 1-I', Formula 1-I, Formula 1-II, or Formula I-III, or a subformula thereof, or a compound of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7, or a pharmaceutically acceptable salt th...

Claims

1. CLAIMS What is claimed:

1. An inhibitor compound of Formula AA':or a pharmaceutically acceptable salt thereof, wherein Ring E iswherei Enindicates bond to L ;within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring E2 isor an optionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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-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 whereinD2a D2beach R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

2. The inhibitor compound of claim 1, wherein the inhibitor compound is of Formula AA:or a pharmaceutically acceptable salt thereof, wherein: Ring E is wherein indEicates bond to L ; within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE2, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl; m is 0 or 1; and p is 0 or 1.

3. The inhibitor compound of claim 2, wherein the inhibitor compound is of Formula A:or a pharmaceutically acceptable salt thereof.

4. A inhibitor compound of Formula I''':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl;each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 formD2awherein each R and RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl.

5. The inhibitor compound of claim 4, wherein the inhibitor compound is of Formula I'':or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE2, XE3, XE4, XE5, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)- NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3;each of XE1, XE2, XE3, XE4, and XE5is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 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 RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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 eacD2a D2bh R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

6. A inhibitor compound of Formula IV':or a pharmaceutically acceptable salt thereof, wherein:within the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 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; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2, the RE7and RE1or the RE2and RE1are taken together with the carbon atoms to which RE7and RE1or RE2and RE1attached to form an optionally substituted 5- to 6- membered heteroaryl; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 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; RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andeach 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 formD2awherein each R and RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl.

7. The inhibitor compound of claim 6, wherein the inhibitor compound is of Formula IV:or a pharmaceutically acceptable salt thereof, wherein: within the bicyclic ring containing XE1, XE3, XE4, XE5, XE6, Xa, Xb, Xc, and Xdrepresents that said bicyclic ring is aromatic; Ring E1 is independently an optionally substituted ring selected from phenyl, 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, naphthyl, and 8-to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; RE1is an optionally substituted monocyclic ring selected from 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur and 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-NRN1RN2, –NRN3C(O)RC1, –C(S)-NRN1RN2, –C(NRN7)-NRN1RN2, –C(NORD1)-NRN1RN2, –C(RC4RC5)-NRN1RN2, – CRC4RC5RC6, –S(O)1-2-NRN1RN2, or –NRN3S(O)1-2RC2; RE2is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, optionally substituted C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; each of XE1, XE3, XE4, XE5, and XE6is, independently, N, CRE6, NRE4, O, or S; each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, optionally substituted C1-C6alkyl, or –C1-C6alkyl- C3-C6cycloalkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6–, or –O–, or LE1is –NRN6– or –O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-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; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, 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, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each 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 formD2a D2bwherein each R and R is, independently, hydrogen or optionally substituted C1-C6alkyl.

8. The inhibitor compound of any one of claims 1-7, wherein m is 0, p is 1, and XE5is CRE6, N, O, or S.

9. The inhibitor compound of any one of claims 1-8, wherein Ring E1 is an optionally substituted phenyl.

10. The inhibitor compound of any one of claims 1-9, wherein LEis –LE1–LE2–.

11. The inhibitor compound of any one of claims 1-10, wherein YE3is CRE2.

12. The inhibitor compound of any one of claims 1-11, wherein YE4is CRE3.

13. A inhibitor compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring E iswhereinindicates bond to LE1; 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; RE2is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; RE3is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; each of YE1and YE2is, independently, N or CRE7; each of XE1, XE2, XE3, XE4, and XE5is, independently, N or CRE6; RE4is hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl; 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–; each RE6is, independently, hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy, wherein each of C1-C6alkyl, C1-C6haloalkyl, or C1-C6alkoxy is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, C1-C6alkoxy, and C3-C6cycloalkyl; each RE7is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6alkyl or C1-C6haloalkyl; e1 is 0, 1, 2, 3, or 4; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; and each RN1, RN2, RN3, RN4, RN5, RN6, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl.

14. The inhibitor compound of any one of claims 1-13, wherein XE1is N.

15. The inhibitor compound of any one of claims 1-13, wherein XE1is CRE6.

16. The inhibitor compound of any one of claims 1-5 and 7-13, wherein Ring E is.

17. The inhibitor compound of any one of claims 1-16, wherein 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.

18. The inhibitor compound of any one of claims 1-16, wherein 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.

19. The inhibitor compound of any one of claims 1-16, wherein RE1is20. The inhibitor compound of any one of claims 1-16, wherein RE1is21. The inhibitor compound of any one of claims 1-16, wherein RE1is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, whereinRE1is optionally substituted with 1-3 substituents, each independently selected from oxo, C1- C6alkyl, and C1-C6haloalkyl.

22. The inhibitor compound of any one of claims 1-16, wherein RE1is23. The inhibitor compound of any one of claims 1-16, wherein RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

24. The inhibitor compound of any one of claims 1-16, wherein each of RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen or C1-C6alkyl.

25. The inhibitor compound of any one of claims 1-16, wherein each of RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

26. The inhibitor compound of any one of claims 1-25, wherein RE2is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

27. The inhibitor compound of any one of claims 1-25, wherein RE2is hydrogen, –F, – CF3, –CHF2, –CH2F,or –Me.

28. The inhibitor compound of any one of claims 1-27, wherein RE3is hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

29. The inhibitor compound of any one of claims 1-27, wherein RE3is hydrogen, –F, – CF3, –CHF2, –CH2F,or –Me.

30. The inhibitor compound of any one of claims 1-29, wherein YE1is CRE7.

31. The inhibitor compound of any one of claims 1-30, wherein YE2is CRE7.

32. The inhibitor compound of any one of claims 1-31, wherein each RE7is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

33. The inhibitor compound of any one of claims 1-31, wherein each RE7is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,cyclohexyl, or pyridyl.

34. The inhibitor compound of any one of claims 1-31, wherein each RE7is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

35. The inhibitor compound of any one of claims 1-34, wherein RE4is C1-C6alkyl.

36. The inhibitor compound of any one of claims 1-34, wherein RE4is –Me or –Et.

37. The inhibitor compound of any one of claims 1-34, wherein RE4is –C1-C6alkyl-C3-C6cycloalkyl.

38. The inhibitor compound of any one of claims 1-34, wherein RE4is.

39. The inhibitor compound of any one of claims 1-38, wherein LE1is –C(O)–.

40. The inhibitor compound of any one of claims 1-39, wherein LE2is –NRN6–.

41. The inhibitor compound of any one of claims 1-40, wherein RN6is hydrogen or C1-C6alkyl.

42. The inhibitor compound of any one of claims 1-40, wherein RN6is hydrogen, –Me, – Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

43. The inhibitor compound of any one of claims 1-40, wherein RN6is hydrogen.

44. The inhibitor compound of any one of claims 1-43, wherein each RE6is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

45. The inhibitor compound of any one of claims 1-43, wherein each RE6is, independently, hydrogen, –F, –CF3, or –Me.

46. The inhibitor compound of any one of claims 13-45, whereinis47. The inhibitor compound of any one of claims 13-46, wherein.

48. The inhibitor compound of any one of claims 1-47, wherein RN3is hydrogen or C1-C6alkyl.

49. The inhibitor compound of any one of claims 1-47, wherein RN3is hydrogen, –Me, – Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

50. The inhibitor compound of any one of claims 1-47, wherein RN3is hydrogen.

51. The inhibitor compound of any one of claims 13-47, wherein RC3is C1-C6alkyl.

52. The inhibitor compound of any one of claims 13-47, wherein RC3is –Me, –Et, –nPr, – iPr, –nBu, –sBu, or –tBu.

53. The inhibitor compound of any one of claims 13-47, wherein RN4is hydrogen or C1- C6alkyl.

54. The inhibitor compound of any one of claims 13-47, wherein RN4is hydrogen, –Me, – Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

55. The inhibitor compound of any one of claims 13-47, wherein RN4is hydrogen.

56. The inhibitor compound of any one of claims 13-47, wherein RN5is hydrogen or C1- C6alkyl.

57. The inhibitor compound of any one of claims 13-47, wherein RN5is hydrogen, –Me, – Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

58. The inhibitor compound of any one of claims 13-47, wherein RN5is hydrogen.

59. The inhibitor compound of claim 13, wherein the inhibitor compound is of any one of Formula I-a-1 to Formula I-a-4:or a pharmaceutically acceptable salt thereof.

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

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

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

63. A inhibitor compound selected from any one of the compounds of Table 4, or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition comprising an inhibitor compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

65. A method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample an inhibitor compound of any one of claims 1-63, or a pharmaceutical composition of claim 64.

66. 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 1-63, or a pharmaceutical composition of claim 64.

67. The method of claim 66, wherein the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

68. A inhibitor compound of Formula 1-1:or a pharmaceutically acceptable salt thereof, wherein:RS11is 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)-NRN11RN12, or – NRN13C(O)RC11, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl; RS12is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS11and RS12, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC12; RS13is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS11and YS12is, independently, N or CRS17; XS11is N or CRS15; XS12, XS13, and XS14are each, independently, N or CRS16, LS11is –C(O)– or –CH2–; LS12is –NRN16– or –O–; RS14is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS14is optionally substituted with cyano; RS15is hydrogen or halogen; RS16is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS16is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS17is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S11 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolyl; each of RN11, RN12, RN13, RN14, RN16, RC11, RC12, and RC13is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN15is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN15is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3, wherein: (i) YS11is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (ii) YS12is CRS17, wherein said RS17is phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; or (iii) Ring S11 phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is fused with a ring to form 9-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, – NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN11RN12, –C(O)-NRN14RN15, –NRN13C(O)RC13, imidazolyl, and thiazolyl.

69. The inhibitor compound of claim 68, wherein RS11is 5-membered heteroaryl with 1-3 heteroatoms nitrogen atoms, wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

70. The inhibitor compound of claim 68, wherein RS11is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein said 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

71. The inhibitor compound of claim 68, wherein RS11is72. The inhibitor compound of claim 68, wherein RS11is.

73. The inhibitor compound of claim 68, wherein RS11is 6-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein said 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is substituted with 1-3 oxo substituents, and wherein RS11is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, and C1-C6haloalkyl.

74. The inhibitor compound of claim 68, wherein RS11is75. The inhibitor compound of claim 68, wherein RS11is –C(O)-NRN11RN12or – NRN13C(O)RC11.

76. The inhibitor compound of claim 68, wherein each of RN11, RN12, RN13, and RC11is, independently, hydrogen or C1-C6alkyl.

77. The inhibitor compound of claim 68, wherein each of RN11, RN12, RN13, and RC11is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

78. The inhibitor compound of any one of claims 68-77, wherein RS12is hydrogen, –F, – Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

79. The inhibitor compound of any one of claims 68-77, wherein RS12is hydrogen, –F, – CF3, –CHF2, –CH2F,or –Me.

80. The inhibitor compound of any one of claims 68-79, wherein RS13is hydrogen, –F, – Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

81. The inhibitor compound of any one of claims 68-79, wherein RS13is hydrogen, –F, – CF3, –CHF2, –CH2F,or –Me.

82. The inhibitor compound of any one of claims 68-81, wherein RS14is C1-C6alkyl.

83. The inhibitor compound of any one of claims 68-81, wherein RS14is –Me or –Et.

84. The inhibitor compound of any one of claims 68-81, wherein RS14is –C1-C6alkyl-C3- C6cycloalkyl.

85. The inhibitor compound of any one of claims 68-81, wherein RS14is.

86. The inhibitor compound of any one of claims 68-85, wherein LS11is –C(O)–.

87. The inhibitor compound of any one of claims 68-85, wherein LS12is –NRN16–.

88. The inhibitor compound of any one of claims 68-87, wherein RN16is hydrogen or C1- C6alkyl.

89. The inhibitor compound of any one of claims 68-87, wherein RN16is hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

90. The inhibitor compound of any one of claims 68-87, wherein RN16is hydrogen.

91. The inhibitor compound of any one of claims 68-90, wherein XS12is CRS16.

92. The inhibitor compound of any one of claims 68-91, wherein XS13is CRS16.

93. The inhibitor compound of any one of claims 68-92, wherein XS14is CRS16.

94. The inhibitor compound of any one of claims 68-93, wherein each RS16is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

95. The inhibitor compound of any one of claims 68-93, wherein each RS16is, independently, hydrogen, –F, –CF3, or –Me.

96. The inhibitor compound of any one of claims 68-92, wherein XS14is N.

97. The inhibitor compound of any one of claims 68-96, wherein YS11is CRS17.

98. The inhibitor compound of any one of claims 68-96, wherein YS12is CRS17.

99. The inhibitor compound of any one of claims 68-98, wherein each RS17is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

100. The inhibitor compound of any one of claims 68-98, wherein each RS17is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl.

101. The inhibitor compound of any one of claims 68-98, wherein each RS17is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

102. The inhibitor compound of any one of claims 68-101, wherein Ring S11 is 9- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC13, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl- C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)-NRN14RN15, –NRN11RN12C(O)RC13, imidazolyl, and thiazolyl.

103. The inhibitor compound of any one of claims 68-101, wherein Ring S11 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

104. The inhibitor compound of any one of claims 68-101, wherein Ring S11 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F, –CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

105. The inhibitor compound of claim 68, wherein the inhibitor compound is of any one of Formula I-a-1 through Formula I-a-4:or a pharmaceutically acceptable salt thereof.

106. A inhibitor compound of Formula 1-II:or a pharmaceutically acceptable salt thereof, wherein: RS21is 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)-NRN21RN22, or – NRN23C(O)RC21, wherein RS1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; s21 is an integer selected from 0-4; s22 is an integer selected from 0-6; each RS22is, independently, halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC22; XS21is N or CRS25, XS22, XS23, and XS24are each, independently, N or CRS26, LS21is –C(O)– or –CH2–; LS22is –NRN26– or –O–; RS24is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS24is optionally substituted with cyano; RS25is hydrogen or halogen;RS26is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS26is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each of YS21and YS22is, independently, N or CRS27; each RS27is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S21 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S21 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl; each RN21, RN22, RN23, RN24, RN26, RC21, RC22, and RC23is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN25is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN25is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

107. The inhibitor compound of claim 106, wherein RS21is 5-membered heteroaryl with 1- 3 heteroatoms nitrogen atoms, wherein RS21is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

108. The inhibitor compound of claim 106, wherein RS21is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RS21is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

109. The inhibitor compound of claim 106, wherein RS21is110. The inhibitor compound of claim 106, wherein RS21is111. The inhibitor compound of claim 106, wherein RS21is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RS21is optionally substituted with 1-3 substituents, each independently selected from oxo, C1-C6alkyl, and C1- C6haloalkyl.

112. The inhibitor compound of claim 106, wherein RS21is113. The inhibitor compound of claim 106, wherein RS21is –C(O)-NRN21RN22or – NRN23C(O)RC21.

114. The inhibitor compound of claim 106, wherein each of RN21, RN22, RN23, and RC21is, independently, hydrogen or C1-C6alkyl.

115. The inhibitor compound of claim 106, wherein each of RN21, RN22, RN23, and RC21is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

116. The inhibitor compound of any one of claims 106-115, wherein s21 is 1, 2, or 3.

117. The inhibitor compound of any one of claims 106-116, wherein s22 is 0, 1, or 2.

118. The inhibitor compound of any one of claims 106-116, wherein s22 is 2, 3, or 4.

119. The inhibitor compound of any one of claims 106-118, wherein each RS22is, independently, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7-membered carbocyclyl.

120. The inhibitor compound of any one of claims 106-118, wherein each RS22is, independently, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 4- to 5-membered carbocyclyl.

121. The inhibitor compound of any one of claims 106-120, wherein122. The inhibitor compound of any one of claims 106-120, wherein123. The inhibitor compound of any one of claims 106-122, wherein RS24is C1-C6alkyl.

124. The inhibitor compound of any one of claims 106-122, wherein RS24is –Me or –Et.

125. The inhibitor compound of any one of claims 106-122, wherein RS24is –C1-C6alkyl- C3-C6cycloalkyl.

126. The inhibitor compound of any one of claims 106-122, wherein RS24is.

127. The inhibitor compound of any one of claims 106-126, wherein LS21is –C(O)–.

128. The inhibitor compound of any one of claims 106-127, wherein LS22is –NRN26–.

129. The inhibitor compound of any one of claims 106-128, wherein RN26is hydrogen or C1-C6alkyl.

130. The inhibitor compound of any one of claims 106-128, wherein RN26is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

131. The inhibitor compound of any one of claims 106-128, wherein RN26is hydrogen.

132. The inhibitor compound of any one of claims 106-131, wherein XS22is CRS26.

133. The inhibitor compound of any one of claims 106-132, wherein XS23is CRS26.

134. The inhibitor compound of any one of claims 106-133, wherein XS24is CRS26.

135. The inhibitor compound of any one of claims 106-134, wherein each RS26is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

136. The inhibitor compound of any one of claims 106-134, wherein each RS26is, independently, hydrogen, –F, –CF3, or –Me.

137. The inhibitor compound of any one of claims 106-133, wherein XS24is N.

138. The inhibitor compound of any one of claims 106-137, wherein YS11is CRS27.

139. The inhibitor compound of any one of claims 106-138, wherein YS12is CRS27.

140. The inhibitor compound of any one of claims 106-139, wherein each RS27is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

141. The inhibitor compound of any one of claims 106-139, wherein each RS27is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl.

142. The inhibitor compound of any one of claims 106-139, wherein each RS27is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

143. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is 9- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl- C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)-NRN14RN15, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

144. The inhibitor compound of any one of claims 106-142, wherein Ring S21 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

145. The inhibitor compound of any one of claims 106-142, wherein Ring S21 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

146. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is phenyl,wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

147. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, and –NRN23C(O)RC23.

148. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from –C(O)-NRN24RN25and –NRN21RN22C(O)RC23.

149. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is phenyl, wherein Ring S21 is substituted with –C(O)-NRN24RN25or –NRN21RN22C(O)RC23.

150. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is151. The inhibitor compound of any one of claims 106-142, wherein Ring S21 is.

152. The inhibitor compound of any one of claims 106-150, wherein RN23is hydrogen or C1-C6alkyl.

153. The inhibitor compound of any one of claims 106-150, wherein RN23is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

154. The inhibitor compound of any one of claims 106-150, wherein RN23is hydrogen.

155. The inhibitor compound of any one of claims 106-150, wherein RC23is C1-C6alkyl.

156. The inhibitor compound of any one of claims 106-150, wherein RC23is –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

157. The inhibitor compound of any one of claims 106-150, wherein RN24is hydrogen or C1-C6alkyl.

158. The inhibitor compound of any one of claims 106-150, wherein RN24is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

159. The inhibitor compound of any one of claims 106-150, wherein RN24is hydrogen.

160. The inhibitor compound of any one of claims 106-150, wherein RN25is hydrogen or C1-C6alkyl.

161. The inhibitor compound of any one of claims 106-150, wherein RN25is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

162. The inhibitor compound of any one of claims 106-150, wherein RN25is hydrogen.

163. The inhibitor compound of claim 106, wherein the inhibitor compound is of any one of Formula 1-II-a-1 through Formula 1-II-a-4:or a pharmaceutically acceptable salt thereof.

164. A inhibitor compound of Formula 1-III:or a pharmaceutically acceptable salt thereof, wherein: RS31is 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)-NRN31RN32, or – NRN33C(O)RC31, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl; Ring S32 isRS32ais hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or RS31and RS32a, together with the carbon atoms to which they are attached, combine to form 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said 5- to 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with 1-3 substituents, each independently selected from C1-C6alkyl, C1-C6haloalkyl, and –C(O)RC32; RS33is hydrogen, halogen, C1-C6alkyl group, or C1-C6haloalkyl; each of YS31and YS32is, independently, N or CRS37;S31 is an integer selected from 0-4; S32 is an integer selected from 0-6; RS32bis halogen, C1-C6alkyl, or C1-C6haloalkyl; or two RS32bsubstituents, together with the carbon atoms to which they are attached, combine to form 3- to 7- membered carbocyclyl, wherein said 3- to 7-membered carbocyclyl is optionally substituted with 1-3 substituents independently selected from C1-C6alkyl, C1-C6haloalkyl, and – C(O)RC32; XS31is N or CRS35; XS32, XS33, and XS34are each, independently, N or CRS36, LS31is –S(O)2– and LS32is –NRN36–, or LS31is –NRN36– and LS32is –S(O)2–, or LS31is –NRN36– and LS32is –C(O)–; RS34is hydrogen, C1-C6alkyl, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, –C2-C6alkyl-C1- C3haloalkoxy, or –C1-C6alkyl-C3-C6cycloalkyl, wherein RS34is optionally substituted with cyano; RS35is hydrogen or halogen; RS36is hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl group, C1-C6haloalkyl, –C2-C6alkyl-C1-C3alkoxy, C3-C6cycloalkyl, or phenyl, wherein RS36is optionally substituted with 1-3 substituents, each independently selected from –OH and cyano; each RS37is, independently, hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said phenyl, C3-C7cycloalkyl, or 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur is optionally substituted with C1-C6alkoxy; Ring S31 is phenyl or 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S31 is optionally fused with a ring to form 8- to 10-membered aryl or 8- to 10-membered heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein Ring S31 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN31RN32, –S(O)2NRN31RN32, – NRN33S(O)2RC33, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN31RN32, –C(O)-NRN34RN35, –NRN33C(O)RC33, imidazolyl, and thiazolyl; each RN31, RN32, RN33, RN34, RN36, RC31, RC32, and RC33is, independently, hydrogen, C1-C6alkyl, or –C(O)-C1-C6alkyl; and RN35is H, C1-C6alkyl, –C(O)-C1-C6alkyl, or 5 to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RN35is optionally substituted with 1-3 substituents, each independently selected from cyano and –NCH3.

165. The inhibitor compound of claim 164, wherein RS31is 5-membered heteroaryl with 1- 3 heteroatoms nitrogen atoms, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

166. The inhibitor compound of claim 164, wherein RS31is 5-membered heterocyclyl with 1-3 heteroatoms nitrogen atoms, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1-C6haloalkyl.

167. The inhibitor compound of claim 164, wherein RS31is168. The inhibitor compound of claim 164, wherein RS31is169. The inhibitor compound of claim 164, wherein RS31is 6-membered heterocyclyl with 1-3 heteroatoms independently selected from nitrogen and oxygen, wherein RS31is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6alkyl, and C1- C6haloalkyl.

170. The inhibitor compound of claim 164, wherein RS31is171. The inhibitor compound of claim 164, wherein RS31is –C(O)-NRN31RN32or – NRN33C(O)RC31.

172. The inhibitor compound of claim 164, wherein each of RN31, RN32, RN33, and RC31is, independently, hydrogen or C1-C6alkyl.

173. The inhibitor compound of claim 164, wherein each of RN31, RN32, RN33, and RC31is, independently, hydrogen, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

174. The inhibitor compound of any one of claims 164-173, wherein Ring S32 is.

175. The inhibitor compound of claim 174, wherein RS32ais hydrogen, –F, –Cl, –CF3, – CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

176. The inhibitor compound of claim 174, wherein RS32ais hydrogen, –F, –CF3, –CHF2, – CH2F,or –Me.

177. The inhibitor compound of any one of claims 174 to 176, wherein RS33is hydrogen, – F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or – tBu.

178. The inhibitor compound of any one of claims 174 to 176, wherein RS33is hydrogen, – F, –CF3, –CHF2, –CH2F,or –Me.

179. The inhibitor compound of any one of claims 174 to 178, wherein YS31is CRS37.

180. The inhibitor compound of any one of claims 174 to 179, wherein YS32is CRS37.

181. The inhibitor compound of any one of claims 174 to 180, wherein each RS37is, independently, hydrogen, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, – nPr, –iPr, –nBu, –sBu, –tBu, phenyl,, cyclohexyl, or pyridyl.

182. The inhibitor compound of any one of claims 174 to 180, wherein each RS37is, independently, hydrogen, –F, –CF3, –CHF2, –CH2F,–Me, phenyl,, cyclohexyl, or pyridyl.

183. The inhibitor compound of any one of claims 174 to 180, wherein each RS37is, independently, hydrogen, –F, –CF3,–Me, phenyl,, cyclohexyl, or pyridyl.

184. The inhibitor compound of any one of claims 164-173, wherein Ring S32 is.

185. The inhibitor compound of claim 184, wherein s31 is 1, 2, or 3.

186. The inhibitor compound of claim 184 or 185, wherein s32 is 0, 1, or 2.

187. The inhibitor compound of claim 184 or 185, wherein s32 is 2, 3, or 4.

188. The inhibitor compound of any one of claims 184-187, wherein each RS32bis, independently, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 3- to 7-membered carbocyclyl.

189. The inhibitor compound of any one of claims 184-187, wherein each RS32bis, independently, –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, – nBu, –sBu, or –tBu, or two RS22substituents, together with the carbon atoms to which they are attached, combine to form 4- to 5-membered carbocyclyl.

190. The inhibitor compound of any one of claims 184-187, wherein191. The inhibitor compound of any one of claims 184-187, wherein192. The inhibitor compound of any one of claims 164-191, wherein RS34is C1-C6alkyl.

193. The inhibitor compound of any one of claims 164-191, wherein RS34is –Me or –Et.

194. The inhibitor compound of any one of claims 164-191, wherein RS34is –C1-C6alkyl- C3-C6cycloalkyl.

195. The inhibitor compound of any one of claims 164-191, wherein RS34is.

196. The inhibitor compound of any one of claims 164-195, wherein LS31is –S(O)2– and LS32is –NRN36–.

197. The inhibitor compound of any one of claims 164-195, wherein LS31is –NRN36– and LS32is –C(O)–.

198. The inhibitor compound of any one of claims 164-197, wherein RN36is hydrogen or C1-C6alkyl.

199. The inhibitor compound of any one of claims 164-197, wherein RN36is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

200. The inhibitor compound of any one of claims 164-197, wherein RN36is hydrogen.

201. The inhibitor compound of any one of claims 164-200, wherein XS32is CRS36.

202. The inhibitor compound of any one of claims 164-201, wherein XS33is CRS36.

203. The inhibitor compound of any one of claims 164-202, wherein XS34is CRS36.

204. The inhibitor compound of any one of claims 164-203, wherein each RS36is, independently, hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

205. The inhibitor compound of any one of claims 164-203, wherein each RS36is, independently, hydrogen, –F, –CF3, or –Me.

206. The inhibitor compound of any one of claims 164-202, wherein XS34is N.

207. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is 9- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –OH, cyano, –NRN11RN12, –S(O)2NRN11RN12, –NRN13S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl- C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl-NRN11RN12, –C(O)-NRN14RN15, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

208. The inhibitor compound of any one of claims 164-206, wherein Ring S31 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from halogen, C1-C6alkyl, or C1-C6haloalkyl.

209. The inhibitor compound of any one of claims 164-206, wherein Ring S31 iswherein Ring S11 is optionally substituted with 1-3 substituents, each independently selected from –F, –Cl, –CF3, –CHF2, –CH2F,–CF2CF3, –CH(CF3)2, –Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

210. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, –NRN23C(O)RC23, imidazolyl, and thiazolyl.

211. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from halogen, –OH, cyano, –NRN21RN22, –S(O)2NRN21RN22, – NRN23S(O)2RC23, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1-C6alkyl-C1-C3alkoxy, –C(O)-C1-C6alkyl, –C1-C6alkyl- NRN21RN22, –C(O)-NRN24RN25, and –NRN23C(O)RC23.

212. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is phenyl, wherein Ring S21 is optionally substituted with 1-3 substituents, each independently selected from –C(O)-NRN24RN25and –NRN21RN22C(O)RC23.

213. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is phenyl, wherein Ring S21 is substituted with –C(O)-NRN24RN25or –NRN21RN22C(O)RC23.

214. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is215. The inhibitor compound of any one of claims 164-206, wherein Ring S31 is.

216. The inhibitor compound of any one of claims 164-215, wherein RN33is hydrogen or C1-C6alkyl.

217. The inhibitor compound of any one of claims 164-215, wherein RN33is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

218. The inhibitor compound of any one of claims 164-215, wherein RN33is hydrogen.

219. The inhibitor compound of any one of claims 164-215, wherein RC33is C1-C6alkyl.

220. The inhibitor compound of any one of claims 164-215, wherein RC33is –Me, –Et, – nPr, –iPr, –nBu, –sBu, or –tBu.

221. The inhibitor compound of any one of claims 164-215, wherein RN34is hydrogen or C1-C6alkyl.

222. The inhibitor compound of any one of claims 164-215, wherein RN34is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

223. The inhibitor compound of any one of claims 164-215, wherein RN34is hydrogen.

224. The inhibitor compound of any one of claims 164-215, wherein RN35is hydrogen or C1-C6alkyl.

225. The inhibitor compound of any one of claims 164-215, wherein RN35is hydrogen, – Me, –Et, –nPr, –iPr, –nBu, –sBu, or –tBu.

226. The inhibitor compound of any one of claims 164-215, wherein RN35is hydrogen.

227. The inhibitor compound of claim 164, wherein the inhibitor compound is of any one of Formula 1-III-a-1 to Formula 1-III-a-6:or a pharmaceutically acceptable salt thereof.

228. An inhibitor compound selected from any one of the compounds of Table 5, or a pharmaceutically acceptable salt thereof.

229. An inhibitor compound selected from any one of the compounds of Table 6, or a pharmaceutically acceptable salt thereof.

230. An inhibitor compound selected from any one of the compounds of Table 7, or a pharmaceutically acceptable salt thereof.

231. A pharmaceutical composition comprising an inhibitor compound of any one of claims 68-230, and a pharmaceutically acceptable excipient thereof.

232. A method of modulating STAT6 in a subject or a biological sample, wherein the method comprises administering to the subject or the biological sample an inhibitor compound of any one of claims 68-230, or a pharmaceutical composition of claim 231.

233. 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 68-230, or a pharmaceutical composition of claim 231.

234. The method of claim 233, wherein the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive or overgrowing bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.