STAT6 inhibitors and uses thereof

Abstract

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

Description

Attorney Docket No.: KME-300WO 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 / 676,238, filed July 26, 2024, and U.S. Provisional Application No.63 / 767,230, filed March 5 5, 2025, each of which is incorporated herein by reference in its entirety. FIELD

[0002] The present disclosure relates to compounds and methods useful for modulating (e.g., inhibiting) signal transducer and activator of transcription 6 (“STAT6”). The present disclosure also provides pharmaceutically acceptable compositions comprising compounds disclosed 10 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 15 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. 20

[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 25 STAT6." Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin- 4 (IL4) and interleukin-13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema (Goenka and Kaplan. "Transcriptional regulation by 30 STAT6." Immunologic research 50.1 (2011): 87-96.). There is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases and cancers (Glosson et al. 1 IPTS / 200079038.1Attorney Docket No.: KME-300WO "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). 5

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

[0006] Disclosed herein, in some embodiments, is a compound of A compound of Formula I:10 Formula I, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0007] Disclosed herein, in some embodiments, is a compound of A compound of Formula II:15 Formula II, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein. 2 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0008] Disclosed herein, in some embodiments, is a compound of A compound of Formula III:Formula III, 5 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0009] Disclosed herein, in some embodiments, is a compound of A compound of Formula IV:Formula IV, 10 or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0010] Disclosed herein, in some embodiments, is an inhibitor compound of A compound of Formula I: 3 IPTS / 200079038.1Attorney Docket No.: KME-300WOFormula I, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0011] Disclosed herein, in some embodiments, is a compound of A compound of Formula 5 II:Formula II, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0012] Disclosed herein, in some embodiments, is an inhibitor compound of A compound of 10 Formula III: 4 IPTS / 200079038.1Attorney Docket No.: KME-300WOFormula III, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0013] Disclosed herein, in some embodiments, is an inhibitor compound of A compound of 5 Formula IV:Formula IV, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.

[0014] Compounds disclosed herein, and pharmaceutically acceptable compositions thereof, 10 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. 5 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0015] 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. 5 DETAILED DESCRIPTION

[0016] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), compositions comprising said compounds, and 10 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- 15 induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder). Definitions

[0017] 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 20 indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0018] Chemical elements are identified in accordance with the Periodic Table of the Elements, 25 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. 30

[0019] 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 6 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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, 5 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 10 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, 15 alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0020] 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 20 or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the 25 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: 7 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0021] The term “lower alkyl” refers to a C1-4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 5

[0022] The term “haloalkyl” refers to a C1-6 straight or branched alkyl group that is substituted with one or more halogen atoms and “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a 10 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)).

[0023] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0024] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or 15 branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0025] 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 20 polymethylene group in which one or more methylene hydrogen atoms are replaced with a 8 IPTS / 200079038.1Attorney Docket No.: KME-300WO substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0026] 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 5 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:.

[0027] The term “halogen” means –F, –Cl, –Br, or –I.

[0028] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or 10 “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 15 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. 20

[0029] 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 25 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, 30 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, 9 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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,” 5 “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).

[0030] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and 10 “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 15 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.

[0031] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon 20 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 25 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 30 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.

[0032] 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 10 IPTS / 200079038.1Attorney Docket No.: KME-300WO having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0033] 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 5 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 10 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.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an “optionally15 substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; – CN; –N3; –(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–20 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°; –25 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,30 C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12– 11 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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.

[0035] Suitable monovalent substituents on R° (or the ring formed by taking two independent 5 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 10 preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0036] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” 15 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, 20 or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 25

[0037] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected 30 from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include C(O)CH212 IPTS / 200079038.1Attorney Docket No.: KME-300WO wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together 5 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.

[0039] 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, 10 or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which 15 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. 20 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 25 compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all 30 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 13 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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 5 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.

[0042] As used herein, the term “provided compound” refers to any genus, subgenus, and / or 10 species set forth herein.

[0043] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits STAT6 protein with measurable affinity.

[0044] 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 15 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, 20 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 25 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 30 to an inhibitor compound as defined above. In some embodiments, an E3 ligase is a cereblon E3 ubiquitin ligase. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 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. 14 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0045] 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. 5

[0046] 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, 10 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 15 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

[0047] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. 20

[0048] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, 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. 25

[0049] Disclosed herein, in some embodiments, is a compound of Formula I: 15 IPTS / 200079038.1Attorney Docket No.: KME-300WOFormula I, or a pharmaceutically acceptable salt thereof, 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 10 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; Ringoptionally substituted 5- to 6- membered heterocyclyl with1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 15 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)- 16 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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 optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; 5 or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; 10 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; 15 each of Xa, Xb, Xc, and Xdis, independently, C or N; each of RE4is, independently, hydrogen, or optionally substituted C1-C6alkyl; 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–; 20 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 25 substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; 30 RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6 alkyl; 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, 17 IPTS / 200079038.1Attorney Docket No.: KME-300WO oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, C3-C7 cycloalkyl, 5- or 6-membered 5 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- 10 membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected 15 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- 20 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 RC425 and RC5are attached to form an optionally substituted group selected from C3-C6 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RD2aRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; 30 m is 0 or 1; and p is 0 or 1.

[0050] Disclosed herein, in some embodiments, is an inhibitor compound of Formula I: 18 IPTS / 200079038.1Attorney Docket No.: KME-300WOor a pharmaceutically acceptable salt thereof.

[0051] Disclosed herein, in some embodiments, is a compound of Formula II: 5Formula II, or a pharmaceutically acceptable salt thereof, wherein: * indicates bond toEL ; 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 19 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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 5 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; 10 RE2is hydrogen, halogen, optionally substituted C1-C6alkyl or optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; 15 YE3is N or CRE2; YE4is N or CRE3; 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; 20 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, or optionally substituted C1-C6alkyl; 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 – 25 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; 30 each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 20 IPTS / 200079038.1Attorney Docket No.: KME-300WO each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; RNLis hydrogen or optionally substituted C1-C6 alkyl; 5 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; 10 each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 15 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 20 which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; 25 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 30 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 21 IPTS / 200079038.1Attorney Docket No.: KME-300WO RD2aRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; m is 0 or 1; and p is 0 or 1. 5

[0052] Disclosed herein, in some embodiments, is an inhibitor compound of Formula II:Formula II, or a pharmaceutically acceptable salt thereof.

[0053] Disclosed herein, in some embodiments, is a compound of Formula III:10Formula 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; 22 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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- 5 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 from10 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 optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; 15 or RE2and RE3are taken together with the atoms to which they are attached to form optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; 20 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; 25 each of RE4is, independently, hydrogen, or optionally substituted C1-C6 alkyl; LEis –G–LE1–LE2–GS– or –GS–LE2–LE1–G–, wherein LE1is –C(O)–, –S(O)1-2–, or –CH2– and LE2is –NRN6– or –O–, or LE1is –NRN6– or – O– and LE2is –C(O)–, –S(O)1-2–, or –CH2–; G is –NRNG–, –(CRC7RCG)1-2–, or absent; 30 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-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 23 IPTS / 200079038.1Attorney Docket No.: KME-300WO carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; 5 RNGis hydrogen or optionally substituted C1-C6 alkyl; RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, 10 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 15 sulfur, C1-C6 alkoxy, C3-C7 carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RN1, RN2, RN3, RN6, RN7, and RD1is, independently, hydrogen, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, 20 oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 25 RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring; each RC1and RC2, is independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 carbocyclyl, and 3- to 5- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, 30 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-C6 24 IPTS / 200079038.1Attorney Docket No.: KME-300WO carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RD2aRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6alkyl; 5 m is 0 or 1; and p is 0 or 1.

[0054] Disclosed herein, in some embodiments, is an inhibitor compound of Formula III:Formula III, 10 or a pharmaceutically acceptable salt thereof.

[0055] Disclosed herein, in some embodiments, is a compound of Formula IV:25 IPTS / 200079038.1Attorney Docket No.: KME-300WO Formula IV, 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; 5 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, 10 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)-15 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 optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form 20 optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; or when YE1is CRE7or YE3is CRE2and YE5is CRE1, the RE7and RE1or the RE2and 25 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, or optionally substituted C1-C6alkyl; 30 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; 26 IPTS / 200079038.1Attorney Docket No.: KME-300WO each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, –C(O)-C1-C6 alkyl, C3-C5 5 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6 alkyl and C1-C6 alkoxy; RNGis hydrogen or optionally substituted C1-C6alkyl; 10 RNLis hydrogen or optionally substituted C1-C6alkyl; each RE6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms 15 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 20 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 25 RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to 30 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; 27 IPTS / 200079038.1Attorney Docket No.: KME-300WO each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C6 5 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or RD2aRD2bRC4and RC5are optionally taken together to form , wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; and m is 0 or 1. 10

[0056] Disclosed herein, in some embodiments, is an inhibitor compound of Formula IV:Formula IV, or a pharmaceutically acceptable salt thereof. *

[0057] In some embodiments,28 IPTS / 200079038.1Attorney Docket No.: KME-300WO , 529 IPTS / 200079038.1Attorney Docket No.: KME-300WO 5

[0064] In some embodiments, Ring E1 is optionally substituted phenyl. 30 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0065] In some embodiments, Ring E1 is , wherein: each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, –C1- 5 C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6 alkyl; and e1 is 0, 1, 2, 3, or 4. 10

[0066] In some embodiments, Ring E1 is.

[0067] In some embodiments, Ring E1 is , wherein: RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6 alkyl; 15 RE12is C1-C6 alkyl or C1-C6 haloalkyl; each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, –C1- C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; 20 each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6 alkyl, or – C(O)-C1-C6 alkyl; and e1 is 0, 1, 2, 3, or 4. 31 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0068] In some embodiments, Ring E1, along with its RE8and R13substituents, is.

[0069] 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. 5

[0070] 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.

[0071] In some embodiments, RE8is –C(O)NRE9RE10or –NRE11C(O)RE12. In some 10 embodiments, RE8is –C(O)NRE9RE10. In some embodiments, RE8is –NRE11C(O)RE12.

[0072] 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 15 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.

[0073] In some embodiments, RE8is optionally substituted20 embodiments, RE8is optionally substituted

[0074] In some embodiments, RE8is optionally substituted. 32 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0075] In some embodiments,

[0076] In some such embodiments, R° is hydrogen or C1-6 aliphatic. 5wherein 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. 10

[0079] 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 15 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.

[0080] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic 20 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. 33 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0081] In some embodiments,some embodiments, RE8is optionally O substituted, where Wmis as described above and defined herein. In some embodiments,In some embodiments, RE8is optionally substituted O # N Wm0-3 . In some embodiments,In some embodiments, RE8is 5.

[0082] In some embodiments, RE8is an optionally substituted ring selected from:

[0083] In some embodiments, RE8is selected from: 10wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0084] In some embodiments, RE8is: 34 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0085] In some embodiments, RE9is hydrogen. In some embodiments, RE9is C1-C6 alkyl. In some embodiments, RE9is optionally substituted 5-membered heteroaryl with 1-4 heteroatoms 5 independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, RE10is hydrogen. In some embodiments, RE10is C1-C6 alkyl.

[0087] In some embodiments, RE11is hydrogen. In some embodiments, RE11is C1-C6 alkyl.

[0088] In some embodiments, RE12is C1-C6alkyl. In some embodiments, RE11is C1-C6haloalkyl. 10

[0089] In some embodiments, each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, –NRN3S(O)2RC2, optionally substituted group selected from C1-C6alkyl, C1- C6 alkoxy,–C(O)-C1-C6 alkyl, –C(O)-NRN4RN5, –NRN3C(O)RC3, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, C1-C6alkoxy, C3-C7carbocyclyl, and 3- to 7-membered heterocyclyl with 1-4 15 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] 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. 20.

[0092] In some embodiments, Ring E1 is optionally substituted 8- to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0093] In some embodiments, Ring E1 is optionally substituted 9-membered bicyclic 25 heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 35 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0094] In some embodiments, Ringwherein: RE14is hydrogen, C1-C6 alkyl, –C(O)-C1-C6 alkyl, or C3-C6 cycloalkyl; each RE15is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – 5 NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6 alkyl; and 10 e2 is 0, 1, 2, 3, or 4.

[0096] In some embodiments, Ring E1 is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 15

[0097] In some embodiments, Ring E1 is optionally substituted 5-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, Ringwherein: 36 IPTS / 200079038.1Attorney Docket No.: KME-300WO RE14is hydrogen, C1-C6 alkyl, –C(O)-C1-C6 alkyl, or C3-C6 cycloalkyl; each RE15is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – 5 NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6alkyl; and e2 is 0, 1, 2, 3, or 4. 10

[0100] In some embodiments, Ring E1 is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, Ring E1 is optionally substituted 5-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.15

[0102] In some embodiments, Ring E1 is.

[0103] In some embodiments, LEis –G–LE1–LE2–GS–. In some embodiments, LEis –GS–LE2– LE1–G–.

[0104] In some embodiments, LEis –G–LE1–LE2–GS–, wherein GSis absent. In some embodiments, LEis –GS–LE2–LE1–G–, wherein GSis absent. 20

[0105] In some embodiments, G is –NRNG–.

[0106] In some embodiments, LE1is –C(O)–.

[0107] In some embodiments, LE2is –NRN6. 37 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0108] In some embodiments, RN6and RNG, or RN6and RCGare taken together with the atoms to which they are attached to form a 5- to 6-membered saturated, partially unsaturated or aromatic ring.

[0109] In some embodiments, LEis an optionally substituted5 some embodiments, LEis an optionally substituted.

[0110] In some embodiments, LEis optionally substituted,, or [

[0112] In some such embodiments, R° is hydrogen or C1-6 aliphatic. 10

[0113] In some embodiments, LEis an optionallywherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, 15 and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 38 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0115] 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. 5 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. 10

[0116] 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. 15

[0117] In some embodiments,In some embodiments, LEis optionally substituted, where Wmis as described above and defined herein. In some embodiments,. In some embodiments, LEis optionally substituted. In some embodiments, LEis20

[0118] In some embodiments, LEis an optionally substituted ring selected from: 39 IPTS / 200079038.1Attorney Docket No.: KME-300WO 5, wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic.

[0120] In some embodiments, LEis: 10 [40 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0122] In some embodiments, Ringsome embodiments, Ring E2 isoptionally substituted 5- to 6- membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0123] In some embodiments, YE5is N. In some embodiments, YE5is CRE1. 5

[0124] In some embodiments, YE1is N. In some embodiments, YE1is CRE7.

[0125] In some embodiments, YE2is N. In some embodiments, YE2is CRE7.

[0126] In some embodiments, YE3is N. In some embodiments, YE3is CRE2;

[0127] In some embodiments, YE4is N. In some embodiments, YE4is CRE3. 1041 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0130] In some embodiments, RE1is optionally substituted,N, or

[0132] In some such embodiments, R° is hydrogen or C1-6aliphatic. 5wherein Ring Xa1is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms selected from nitrogen, oxygen, 10 and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0135] 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 15 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 20 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, Ring Xa1an optionally substituted 5 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 42 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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.

[0137] In some embodiments,some embodiments, RE1is optionally O 5 substituted, where Wmis as described above and defined herein. In some embodiments,In some embodiments, RE1is optionally substituted. In some embodiments, RE1is.

[0138] In some embodiments, RE1is an optionally substituted ring selected from: 10

[0139] In some embodiments, RE1is selected from: 15wherein each R° is a defined above and described herein (e.g., hydrogen or C1-6aliphatic). 43 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0140] In some embodiments, RE1is:

[0141] In some embodiments, RE1is optionally substituted monocyclic ring selected from 5- 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.

[0142] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5- to 6-membered heterocyclyl with10 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, pyridonyl, –C(O)-wherein RE1is optionally substituted with 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl.

[0143] In some embodiments, RE1is 5-membered heteroaryl with 1-4 heteroatoms nitrogen atoms, wherein RE1is optionally substituted with 1-6 substituents, each independently selected 15 from oxo, C1-C6alkyl, and C1-C6haloalkyl.

[0144] 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.

[0145] In some embodiments, RE1is 6-membered heteroaryl with 1-3 nitrogen atoms, wherein 20 RE1is optionally substituted with 1-3 substituents, each independently selected from C1-C6 alkyl, and C1-C6haloalkyl.

[0146] 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. 25

[0147] 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.

[0148] In some embodiments, RE1is 6-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen and oxygen, wherein RE1is optionally substituted with 30 1-6 substituents, each independently selected from oxo, C1-C6 alkyl, and C1-C6 haloalkyl. 44 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0149] 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.

[0150] In some embodiments,5embodiments, In some embodiments,some O O O embodiments, RE1is. In some embodiments, RE1is. 10

[0151] In some embodiments, RE1is: ,. 45 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0152] In some embodiments, RE1is –C(O)-NRN1RN2or –NRN3C(O)RC1.

[0153] In some embodiments, RE1is -C(RC4RC5)NRN1RN2.

[0154] In some embodiments, RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form C3-C4 cycloalkylene. 5

[0155] 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.

[0156] In some embodiments,.

[0157] In some embodiments, RE1is CRC4RC5RC6. 10

[0158] 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.

[0159] In some embodiments, RC6is cyano or C1-C3 haloalkyl. RD2a

[0160] In some embodiments, R and R together formRD2b C4 C5, wherein RD2aand RD2b15 are each independently hydrogen and C1-C6alkyl.

[0161] In some embodiments, RC6is halogen.

[0162] In some embodiments,

[0163] In some embodiments, RE1is –NRN3C(O)NRN1RN2.

[0164] In some embodiments, RN1is hydrogen, or an optionally substituted group selected from20 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.

[0165] In some embodiments, RN2is hydrogen, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C5carbocyclyl, and 3- to 5-membered heterocyclyl with 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 25

[0166] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 46 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0167] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 5

[0168] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 7- membered monocyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0169] In some embodiments, RN1and RN2on the same nitrogen atom are taken together with 10 the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 8- to 10- membered bicyclic heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. 15.

[0171] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceutically acceptable salt thereof. 47 IPTS / 200079038.1Attorney Docket No.: KME-300WO Table 1. Exemplary Compounds48 IPTS / 200079038.1Attorney Docket No.: KME-300WO49 IPTS / 200079038.1Attorney Docket No.: KME-300WO O NH2N O N NH I-9 N O N N N N 50 IPTS / 200079038.1Attorney Docket No.: KME-300WO51 IPTS / 200079038.1Attorney Docket No.: KME-300WO52 IPTS / 200079038.1Attorney Docket No.: KME-300WO53 IPTS / 200079038.1Attorney Docket No.: KME-300WO54 IPTS / 200079038.1Attorney Docket No.: KME-300WO55 IPTS / 200079038.1Attorney Docket No.: KME-300WO56 IPTS / 200079038.1Attorney Docket No.: KME-300WO57 IPTS / 200079038.1Attorney Docket No.: KME-300WO58 IPTS / 200079038.1Attorney Docket No.: KME-300WO59 IPTS / 200079038.1Attorney Docket No.: KME-300WO60 IPTS / 200079038.1Attorney Docket No.: KME-300WO61 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0172] 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 5 embodiments, the present disclosure provides a pharmaceutical composition comprising a 62 IPTS / 200079038.1Attorney Docket No.: KME-300WO compound disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I as defined above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In 5 some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. 10

[0173] In some embodiments, the present disclosure provides a compound of Formula I, Formula II, Formula III, or Formula IV, or a subformula thereof, as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, or Formula IV, or a subformula thereof, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically 15 acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0174] 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 20 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.

[0175] In some embodiments, the present disclosure also provides a compound described 25 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 30 provides a compound described herein, or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.

[0176] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable excipient thereof. 63 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0177] 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. 5

[0178] 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.

[0179] In some embodiments, the STAT6-mediated disease or disorder is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, 10 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. 15 Pharmaceutical Compositions

[0180] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are administered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically 20 acceptable excipients.

[0181] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient (i.e., one or more 25 pharmaceutically acceptable excipients).

[0182] The compounds disclosed herein are used in free base forms, salt forms, or solvate forms, or as prodrugs. All forms are within the compositions (e.g., pharmaceutical compositions) described herein. The disclosed compounds, or salts, solvates, or prodrugs thereof, are administered to a subject in a variety of forms depending on the selected route of 30 administration, as will be understood by those skilled in the art.

[0183] 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 64 IPTS / 200079038.1Attorney Docket No.: KME-300WO (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful for treating a disease or disorder, or symptoms thereof, described herein.

[0184] The dosage of the compounds disclosed herein (e.g., compounds of Formula I, 5 Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, 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 10 pharmaceutical compositions; the solubility of the compounds in the pharmaceutical compositions; the potency and activity of the compounds; and the pharmacodynamic properties of the compound. The dosage of the compounds disclosed here (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) or compositions comprising 15 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.

[0185] The present disclosure also provides kits including pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and 20 pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0186] Disclosed herein, in some embodiments, is a process for providing a pharmaceutical composition comprising a compound disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 25 1, and pharmaceutically acceptable salts thereof). Methods of Use and Treatment

[0187] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) and compositions comprising said compounds as 30 described herein are generally useful for modulation of STAT6 protein activity (e.g., inhibition 65 IPTS / 200079038.1Attorney Docket No.: KME-300WO of STAT6 protein activity) including phosphorylated or activated STAT6 protein (e.g., pSTAT6) activity.

[0188] 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 5 contacting said biological sample with a compound disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), or a composition comprising said compound.

[0189] The term “biological sample”, as used herein, includes, without limitation, cell cultures 10 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).

[0190] Modulation (e.g., inhibition) of STAT6, or a mutant thereof, activity in a biological 15 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.

[0191] 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 20 administering to said subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), or a composition comprising said compound or pharmaceutically acceptable salt thereof.

[0192] Disclosed herein, in some embodiments, is a method for treating a disease or disorder 25 mediated by STAT6 or a mutant thereof, in a subject (e.g., a patient) in need thereof, the method comprising administering to said subject a compound disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), or a pharmaceutically acceptable composition thereof. Exemplary diseases and disorders are described in herein. 30

[0193] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6 in a subject (e.g., a patient), wherein the method comprises administering to said subject a compound disclosed herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), wherein 66 IPTS / 200079038.1Attorney Docket No.: KME-300WO the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the 5 polypeptide described herein.

[0194] Disclosed herein, in some embodiments, is a method of modulating (e.g., inhibiting) STAT6 in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and 10 subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to an untreated subject with the same STAT6-mediated disorder, disease, or condition. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide 15 described herein.

[0195] Disclosed herein, in some embodiments, is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof, (e.g., compounds of Formula I, Formula II, Formula III, and 20 Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof); and wherein the method results in the subject having a reduced STAT6 level relative to the subject prior to administering the compound described herein, or a pharmaceutical acceptable salt thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some 25 embodiments, the STAT6 is the polypeptide described herein.

[0196] Disclosed herein, in some embodiments, is a method of treating a STAT6-mediated disorder, disease, or condition in a subject in need thereof (e.g., a patient), wherein the method comprises administering to said subject a compound described herein, or a pharmaceutical acceptable salt thereof; and wherein the method results in the subject having a reduced STAT6 30 level relative to an untreated subject with the same STAT6-meditated disorder, disease, or condition. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from the subject. In some embodiments, the STAT6 is the polypeptide described herein. 67 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0197] The activity of a compound described herein as a modulator (e.g., an inhibitor) of STAT6 or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the activity and / or the subsequent functional consequences of activated STAT6 protein or a mutant thereof. Alternate in vitro assays 5 quantitate the ability of the inhibitor to bind to STAT6 protein. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / STAT6 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with STAT6 protein bound to known radioligands. Detailed conditions for assaying a compound 10 utilized in the present disclosure as a modulator (e.g., an inhibitor) of STAT proteins, or a mutant thereof, are set forth in the Examples below.

[0198] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be 15 administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. 20

[0199] Compounds disclosed herein are modulators (e.g., inhibitors) of STAT6 protein and are therefore useful for treating one or more disorders associated with activity of STAT6 protein. Thus, disclosed herein, in some embodiments, is a method for treating a STAT6-mediated disorder or disease comprising administering to a subject in need thereof (e.g., a patient) a compound disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and 25 Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof), or pharmaceutically acceptable composition thereof.

[0200] As used herein, the term “STAT6-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which STAT6 or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present disclosure 30 relates to treating or lessening the severity of one or more diseases in which STAT6 or a mutant thereof, are known to play a role.

[0201] STAT6 functions as a transcription factor to induce gene expression and plays an important role in the IL-4 / IL-13 signaling pathway and thus is critical in IL-4 / IL-13 mediated biological responses including in human malignancies (e.g., Patel, B.K.R., et al. "Localization 68 IPTS / 200079038.1Attorney Docket No.: KME-300WO of the human stat6 gene to chromosome 12q13.3–q14.1, a region implicated in multiple solid tumors." Genomics 52.2 (1998): 192-200). The STAT6-mediated signaling pathway has been shown to be required for the development of T-helper type 2 (Th2) cells and Th2 immune response and plays a critical role in Th2 lung inflammatory responses including clearance of 5 parasitic infections and in the pathogenesis of asthma (e.g., Walford, H. H. and Doherty, T. A. “STAT6 and lung inflammation.” Jak-stat 2.4 (2013): e25301). It has been found that STAT6 induces the expression of BCL2L1 / BCL-X(L), which is responsible for the anti-apoptotic activity of IL-4 and is shown to play a prominent role in adaptive immunity such as providing innate immune signaling in response to virus infection (e.g., Chen, H., et al. “Activation of10 STAT6 by STING is critical for antiviral innate immunity.” Cell 147.2 (2011): 436- 446). Knockout studies in mice have suggested the role STAT6 in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins. Activation of STAT6 signaling pathway is necessary in tumor-associated macrophages (TAMs) and is implicated in the treatment of cancers and atherosclerosis (e.g., Binnemars‐Postma, K., et al. 15 “Targeting the Stat6 pathway in tumor‐associated macrophages reduces tumor growth and metastatic niche formation in breast cancer.” The FASEB Journal 32.2 (2018): 969-978; Gong, M., et al. “STAT6 upregulation promotes M2 macrophage polarization to suppress atherosclerosis.” Medical science monitor basic research 23 (2017): 240). STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation. 20 STAT6 is also required for the development of IL-9-secreting T cells. STAT6 is also involved in IL4 signaling in B cells, and STAT6 determines the levels of CD20 on the surface of normal and malignant B lymphocytes (e.g., Sandova, V., et al. “IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3Kδ inhibitor idelalisib.” haematologica 106.11 (2021): 2995). 25

[0202] In some embodiments, biomarkers associated with the IL-4 / 13 pathway include IgE, Thymus and activation regulated chemokine (TARC), CD23, periostin, and eisinophils. TARC is a serum TH2 biomarker and chemoattractant for TH2 cell. CD23 is a B cell activation marker and correlates with IgE class switch. Periostin is a serum TH2 biomarker and ECM protein associated with tissue remodeling in atopic diseases. 30

[0203] In some embodiments, treatment with provided a compound results in lesser IL-4 induced TARC release compared to a reference or standard level. In some embodiments, treatment with provided a compound results in lesser IL-13 induced CD23 expression compared to a reference or standard level. In some embodiments, treatment with provided a 69 IPTS / 200079038.1Attorney Docket No.: KME-300WO compound results in lesser IL-13 induced periostin release compared to a reference or standard level.

[0204] In some embodiments, treatment with provided a compound inhibits IL-4 induced TARC release. In some embodiments, treatment with provided a compound inhibits IL-13 5 induced CD23 expression. ISE, treatment with provided a compound inhibits IL-13 induced periostin release.

[0205] Disclosed herein, in some embodiments, is a method for treating one or more disorders, diseases, and / or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, 10 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. 15

[0206] Diseases and conditions treatable according to the methods disclosed herein include, but are not limited to, cancer, cardiovascular disease, viral disease, autoimmune diseases, autoinflammatory syndromes, atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological disorders, metabolic syndrome, immunodeficiency disorders such as AIDS and HIV, destructive bone 20 disorders, osteoarthritis, proliferative disorders, infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders in a patient. In one embodiment, a human patient is treated with a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably modulate (e.g., inhibit) STAT6 or a mutant 25 thereof

[0207] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways 30 inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present disclosure is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma exacerbated or induced following bacterial or viral 70 IPTS / 200079038.1Attorney Docket No.: KME-300WO infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics. 5

[0208] Disclosed herein, in some embodiments, is a method of treating an allergic or inflammatory disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure to the subject. The disease may be a lung disease such as, e.g., asthma, airway hyperresponsiveness (AHR), an allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD), reactive airway 10 disease, chronic rhinosinusitis, or essentially any other disease of the upper or lower airways that produces airflow obstruction.

[0209] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be 15 evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the 20 hours of about 4 to 6 am, i.e., at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[0210] In some embodiments, STAT6, via its Src homology 2 (SH2) domain, is recruited to the phosphotyrosine residues and is phosphorylated on Tyr641. In some embodiments, STAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the 25 nucleus, and participates in the expression of genes leading to asthma and airway hyperresponsiveness (AHR).

[0211] Disclosed herein, in some embodiments, is a method of treating asthma in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. 30

[0212] Disclosed herein, in some embodiments, is a method of treating airway hyperresponsiveness (AHR) in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. 71 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0213] Disclosed herein, in some embodiments, is a method of treating allergic rhinitis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the present disclosure provides a method of treating allergic 5 asthma in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0215] Disclosed herein, in some embodiments, is a method of treating emphysema in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. 10

[0216] Disclosed herein, in some embodiments, is a method of treating chronic rhinosinusitis (e.g., with nasal polyposis) in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0217] Disclosed herein, in some embodiments, is a method of treating atopic dermatitis in a patient in need thereof, comprising administering a compound of the present disclosure, or a 15 pharmaceutically acceptable salt thereof.

[0218] Disclosed herein, in some embodiments, is a method of treating COPD in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0219] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula 20 III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) can be used for other inflammatory or obstructive airways diseases and conditions to which the present disclosure is applicable and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis 25 or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The present disclosure is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present 30 disclosure is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. 72 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0220] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are also useful in the treatment of eosinophil related 5 disorders, e.g., eosinophilia, in particular eosinophil related disorders of the airways (e.g., involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and / or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), 10 bronchopulmonary aspergillosis, esophagitis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[0221] Disclosed herein, in some embodiments, is a method of treating eosinophilic esophagitis in a patient in need thereof, comprising administering a compound of the present 15 disclosure, or a pharmaceutically acceptable salt thereof.

[0222] Disclosed herein, in some embodiments, is a method of treating prurigo nodularis in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0223] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula 20 III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) are also useful in the treatment of inflammatory or allergic conditions of the skin. Disclosed herein, in some embodiments, is a method of treating inflammatory or allergic conditions of the skin in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt 25 thereof.

[0224] In some embodiments the inflammatory disease of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, 30 paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0225] Compounds disclosed herein (e.g., compounds of Formula I, Formula II, Formula III, and Formula IV, and subformulas thereof, and compounds of Table 1, and pharmaceutically acceptable salts thereof) may also be used for the treatment of other diseases 73 IPTS / 200079038.1Attorney Docket No.: KME-300WO or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or 5 having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis 10 and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal 15 keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, 20 complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non- allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute 25 respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia 30 gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, prurigo nodularis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, 74 IPTS / 200079038.1Attorney Docket No.: KME-300WO epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, 5 pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0226] Disclosed herein, in some embodiments, is a method of treating an autoimmune disease selected from encephalomyelitis, systemic sclerosis, idiopathic pulmonary fibrosis (IPF), 10 inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, graft versus host disease (acute and chronic), and other tissue fibrosis diseases.

[0227] Disclosed herein, in some embodiments, is a method of treating idiopathic interstitial pneumonia(s) (IIPs), including any type of lung fibrosis, either interstitial lung disease associated with rheumatic disease (including SSc) or IPF itself, in a patient in need thereof, 15 comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments the inflammatory disease which can be treated according to the methods of the present disclosure is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, 20 systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), and osteoarthritis.

[0229] In some embodiments the inflammatory disease which can be treated according to the methods of the present disclosure is a TH17 mediated disease or TH17-associated disease. In some embodiments the TH17 mediated disease or TH17-associated disease is selected from 25 psoriasis, psoriatric arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis), or graft-versus- host disease.

[0230] In some embodiments the inflammatory disease which can be treated according to the methods of the present disclosure is selected from Sjogren’s syndrome, allergic disorders, 30 osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0231] In some embodiments, the present disclosure provides a method of treating an autoimmune disease or inflammatory disorder is selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic autoimmune hepatitis, progressive 75 IPTS / 200079038.1Attorney Docket No.: KME-300WO fibrosis associated interstitial lung disease, pulmonary arterial hypertension (PAH), immunoglobulin G4-related disease (IgG4-RD), chronic organ rejection (e.g., lung transplant), vasculitides (e.g., vasculitides), and STAT6 gain of function (GOF) mutations.

[0232] In some embodiments, the present disclosure provides a method of treating STAT6 gain 5 of function (GOF) mutations in a patient in need thereof, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT6 GOF mutation is STAT6VT.

[0233] In some embodiments, the cardiovascular disease which can be treated according to the methods of the present disclosure include, but are not limited to, restenosis, cardiomegaly, 10 atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

[0234] In some embodiments, the neurodegenerative disease which can be treated according 15 to the methods of the present disclosure include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease. 20

[0235] Disclosed herein, in some embodiments, is a method of treating, preventing or lessening the severity of Alzheimer’s disease comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt or composition thereof.

[0236] Disclosed herein, in some embodiments, is a method of treating a disease or condition commonly occurring in connection with transplantation. In some embodiments, the disease or 25 condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease.

[0237] Disclosed herein, in some embodiments, is a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity. 30

[0238] Disclosed herein, in some embodiments, is a method of treating a viral disease. In some embodiments, the viral infection is HIV or COVID19 infection.

[0239] In some embodiments, the aberrant activation of STAT6 which can be treated according to the methods disclosed herein is a human cancer. In some embodiments, the human cancer which can be treated according to the methods of the present disclosure include benign or 76 IPTS / 200079038.1Attorney Docket No.: KME-300WO malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon 5 carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkin’s and Non-Hodgkin’s, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, 10 seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, Smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, 15 Waldenström’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[0240] Disclosed herein, in some embodiments, is a method of treating a cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve shealth tumors (MPNST), pancreatic 20 cancer, non-small cell lung cancer (NSCLC) including EGFR-mutant NSCLC, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes.

[0241] Disclosed herein, in some embodiments, is a method of treating a JAK-associated 25 disease. In some embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia Such as acute lymphoblastic leukemia 30 (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Example CTCLs include Sezary syndrome and mycosis fungoides.

[0242] Disclosed herein, in some embodiments, is a method of treating a hematologic malignancy selected from LGL leukemia (T and NK cell), cutaneous T cell lymphoma (CTCL), 77 IPTS / 200079038.1Attorney Docket No.: KME-300WO peripheral T cell lymphomas (PTCL, all subtypes including ALCL), diffuse large B cell lymphoma (DLBCL), acute myelogenous leukemia, multiple myeloma, and myelofibrosis.

[0243] Disclosed herein, in some embodiments, use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation 5 of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation. EXAMPLES 10

[0244] The compounds disclosed may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds. General Synthetic Methods

[0245] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not 15 mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. 20

[0246] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed.1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic 25 synthesis methods known to one of ordinary skill in the art as shown in the following examples.

[0247] All reactions are carried out under nitrogen or argon unless otherwise stated.

[0248] Proton NMR (1H NMR) is conducted in deuterated solvent. In certain compounds disclosed herein, one or more1H shifts overlap with residual proteo solvent signals; these signals have not been reported in the experimental provided hereinafter. 30 Table 2. Analytical instruments78 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0249] For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC / MSD or Shimadzu LCMS2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH+] and equipped with Chromolith Flash RP-18e 25*2.0 mm, eluting with 5 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS was recorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector. The column used was BEH C1850*2.1 mm, 1.7 micron. Column flow was 0.55 ml / min and mobile phase were used (A) 2 mM Ammonium Acetate in 0.1% Formic Acid in Water and (B) 0.1 % Formic Acid in Acetonitrile. 10

[0250] For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC / MSD or Shimadzu LCMS 2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH+] and equipped with Xbridge C18, 2.1X50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C18 2.1X30mm columns packed with 5 mm C18- coated silica, eluting with 0.05 vol% NH3·H2O in water (solvent A) and acetonitrile (solvent 15 B).

[0251] HPLC Analytical Method: HPLC was carried out on X Bridge C18150*4.6 mm, 5 micron. Column flow was 1.0 ml / min and mobile phase were used (A) 0.1 % Ammonia in water and (B) 0.1 % Ammonia in Acetonitrile.

[0252] Prep HPLC Analytical Method: The compound was purified on Shimadzu LC-20AP 20 and UV detector. The column used was X-BRIDGE C18 (250*19)mm, 5μ. Column flow was 16.0 mL / min. Mobile phase were used (A) 0.1% Formic Acid in Water and (B) Acetonitrile Basic method used (A) 5mM ammonium bicarbonate and 0.1% NH3 in Water and (B) 79 IPTS / 200079038.1Attorney Docket No.: KME-300WO Acetonitrile or (A) 0.1% Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra were recorded at 202 nm and 254 nm.

[0253] NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz / 5 mm Probe (BBFO). The chemical shifts are reported in part-per-million. 5

[0254] In some instances, intermediates and compounds described in the examples comprise one or more stereocenters and more than one enantiomer / diastereomer was produced. In some embodiments, these enantiomers / diastereomers were separated and isolated, although stereochemistry was not resolved. Unless otherwise stated, stereochemistry was assigned arbitrarily. For intermediates, each enantiomer / diastereomer with arbitrarily assigned 10 stereochemistry may result in a final compound (e.g., assigned a “I-” number), which also maintains the arbitrarily assigned stereochemistry. Accordingly, any compound with arbitrarily assigned stereochemistry or produced from an intermediate with arbitrarily assigned stereochemistry may be depicted herein as a certain stereoisomer, but it is understood that such compound may be the other stereoisomer (i.e., enantiomer or diastereomer). 15

[0255] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described 20 herein. Example 1. Synthesis of Intermediates 1-(4-Chloro-1-methyl-1H-indazol-3-yl)-N-methylmethanamine (Intermediate A)Step 1- 3-bromo-4-chloro-1-methyl-1H-indazole 25

[0256] A mixture of 4-chloro-1-methyl-1H-indazole (10.0 g, 60.0 mmol, CAS# 162502-53-6), NBS (11.7 g, 66.0 mmol), 2,4,6-trimethylanaline (162 mg, 1.20 mmol, 168 μL) in DCE (100 80 IPTS / 200079038.1Attorney Docket No.: KME-300WO mL) was degassed and purged with N2 three times. Then the mixture was stirred at 40 °C for 2 hrs under N2 atmosphere. On completion, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was 5 concentrated in vacuo to give the crude residue. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (4.80 g) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.72 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H). Step 2 - Tert-butyl ((4-chloro-1-methyl-1H-indazol-3-yl)methyl)carbamate 10

[0257] A mixture of 3-bromo-4-chloro-1-methyl-1H-indazole (2.90 g, 11.8 mmol), potassium (tert-butoxycarbonylamino)methyl-trifluoro-boranuide (3.08 g, 12.9 mmol, CAS# 1314538- 55-0), Cs2CO3 (11.5 g, 35.4 mmol), BrettPhos Pd G3 (1.07 g, 1.18 mmol) and bis(1- adamantyl)-butyl-phosphane (423 mg, 1.18 mmol, CAS# 321921-71-5) in dioxane (30 mL) and H2O (6 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 15 90 °C for 2 hrs under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude residue. The crude residue was purified by reverse-phase HPLC (0.8g / L ammonium bicarbonate) to give the title compound (1.30 g, 80% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.59 (d, J = 8.4 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H), 5.77 - 5.75 (m, 1H), 4.66 - 4.57 (m, 2H), 20 4.00 (s, 3H), 1.39 (s, 9H). Step 3 - Tert-butyl ((4-chloro-1-methyl-1H-indazol-3-yl)methyl)(methyl)carbamate

[0258] To a solution of tert-butyl ((4-chloro-1-methyl-1H-indazol-3-yl)methyl)carbamate (1.30 g, 4.40 mmol) in DMF (13 mL) was added NaH (351 mg, 8.79 mmol, 60% dispersion in mineral oil) and MeI (935 mg, 6.59 mmol, 410 μL) at 0 °C under N2 atmosphere. The mixture 25 was then stirred at 0 °C for 2 hrs. On completion, the reaction mixture was quenched / diluted with sat.NH4Cl (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=100 / 1 to 1 / 1) to give the tittle 30 compound (1.00 g, 73% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.61 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 5.75 (s, 1H), 4.90 (s, 2H), 4.02 (s, 3H), 2.79 (s, 3H), 1.45 - 1.32 (m, 9H). Step 4 - 1-(4-Chloro-1-methyl-1H-indazol-3-yl)-N-methylmethanamine 81 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0259] A mixture of tert-butyl N-[(4-chloro-1-methyl-indazol-3-yl)methyl]-N-methyl- carbamate (1.00 g, 3.23 mmol) in DCM (10 mL) and HCl / dioxane (3 mL) was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the tittle compound (740 mg, HCl salt) as a yellow solid. LC-MS (ESI+) m / z 210.1 (M+H)+. 5 2-Methyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3-carboxylic acid (Intermediate B)Step 1 - Methyl 2-methyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3-carboxylate compound with methane 10

[0260] A mixture of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2- one (300 mg, 1.04 mmol, CAS# 1003309-09-8), methyl 6-bromo-2-methyl-2H-indazole-3- carboxylate (281 mg, 1.04 mmol, CAS# 1216852-55-9), Cs2CO3(1.02 g, 3.13 mmol), and Pd(dppf)Cl2•CH2Cl2 (85.3 mg, 104 μmol) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2three times. Then the mixture was stirred at 80 °C for 2 hrs under N215 atmosphere. On completion, the crude product was triturated with water at 25 °C for 0.5 hrs, then the mixture was filtered and the filter cake was concentrated in vacuo to give the title compound (250 mg, 59% yield) as a black solid. LC-MS (ESI+) m / z 350.1 (M+H)+. Step 2 - 2-methyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3-carboxylic acid

[0261] A mixture of methyl 2-methyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3- 20 carboxylate compound with methane (1:1) (200 mg, 572 μmol) and LiOH•H2O (72.0 mg, 1.72 mmol) in THF (2 mL) and H2O (2 mL) was stirred at 25 °C for 2 hrs. On completion, to the reaction mixture was added HCl (1N) until the pH was 4. Then the mixture was filtered and the filter cake was dried in vacuo to give the title compound (100 mg) as a white solid. LC-MS (ESI+) m / z 336.1 (M+H)+. 82 IPTS / 200079038.1Attorney Docket No.: KME-300WO N-methylmethanamine (HCl, CAS# 506-59-2) (Intermediate C)4-(3-(((4-Chloro-1-methyl-1H-indazol-3-yl)methyl)(methyl)carbamoyl)-2-methyl-2H- indazol-6-yl)-3-methylbenzoic acid (Intermediate E) 5Step 1 - Methyl 4-(3-(((4-chloro-1-methyl-1H-indazol-3-yl)methyl)(methyl)carbamoyl)-2- methyl-2H-indazol-6-yl)-3-methylbenzoate

[0262] A mixture of 6-bromo-N-((4-chloro-1-methyl-1H-indazol-3-yl)methyl)-N,2-dimethyl- 2H-indazole-3-carboxamide (with methane) (100 mg, 224 μmol, Intermediate G), (4- 10 (methoxycarbonyl)-2-methylphenyl)boronic acid (52.1 mg, 268 μmol, CAS# 158429-38-0), Cs2CO3 (218 mg, 671 μmol), and Pd(dppf)Cl2•CH2Cl2 (18.2 mg, 22.3 μmol) in dioxane (1.5 mL) and H2O (0.5 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 80 °C for 2 hrs under N2atmosphere. On completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined 15 organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude residue. The crude residue was purified by reverse-phase HPLC (0.8g / L ammonium bicarbonate) to give the title compound (50.0 mg, 43% yield) as a yellow solid. LC-MS (ESI+) m / z 516.1 (M+H)+. Step 2 - 4-(3-(((4-Chloro-1-methyl-1H-indazol-3-yl)methyl)(methyl)carbamoyl)-2-methyl-2H- 20 indazol-6-yl)-3-methylbenzoic acid

[0263] A mixture of methyl 4-(3-(((4-chloro-1-methyl-1H-indazol-3- yl)methyl)(methyl)carbamoyl)-2-methyl-2H-indazol-6-yl)-3-methylbenzoate (50.0 mg, 96.9 83 IPTS / 200079038.1Attorney Docket No.: KME-300WO μmol) and LiOH•H2O (20.3 mg, 484 μmol) in THF (1 mL) and H2O (1 mL) was stirred at 40 °C for 2 hrs. On completion, to the reaction mixture was added HCl (1N) until the pH was 6. On completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo to give the title compound (50.0 mg, 93% yield) as a yellow solid. LC-MS (ESI+) m / z 502.2 (M+H) 5+. [4-(Dimethylcarbamoyl)phenyl]boronic acid (CAS# 405520-68-5) (Intermediate F)F 6-Bromo-N-((4-chloro-1-methyl-1H-indazol-3-yl)methyl)-N,2-dimethyl-2H-indazole-3- carboxamide (Intermediate G) 10

[0264] To a solution of 6-bromo-2-methyl-indazole-3-carboxylic acid (1.8 g, 7.1 mmol, CAS# 1021859-33-5) in DMF (20 mL) was added HATU (3.22 g, 8.47 mmol), HOBt (1.91 g, 14.1 mmol) and DIEA (3.65 g, 28.2 mmol). Then 1-(4-chloro-1-methyl-indazol-3-yl)-N-methyl- methanamine (1.80 g, 8.58 mmol, Intermediate A) was added and the mixture was stirred at 15 25 °C for 10 mins. On completion, the mixture was diluted with H2O (40 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with aqueous NaCl (15 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / 1 to 1 / 1) to afford the title compound (3.4 g, 97% yield) as an orange solid. LC-MS 20 (ESI+) m / z 446.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 7.97 - 7.90 (m, 1H), 7.74 - 7.54 (m, 2H), 7.46 - 7.08 (m, 3H), 5.40 - 4.99 (m, 2H), 4.20 (s, 3H), 4.11 - 4.00 (m, 3H), 3.17 - 2.94 (m, 3H). 3-Fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate H) 84 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0265] To a solution of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.5 g, 1.88 mmol, CAS# 1050423-87-4), and N-methylmethanamine hydrochloride (153 mg, 1.88 mmol, CAS# 506-59-2) in DMF (5 mL) was added HATU (929 mg, 2.44 mmol) and 5 DIEA (729 mg, 5.64 mmol, 982 μL). The mixture was stirred at 25 °C for 0.2 hr. Upon completion, the mixture was quenched with H2O (20 mL), and then diluted with EA (20 mL) and extracted with EA (40 mL × 2). The combined organic layers were washed with NaCl (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl 10 acetate=20 / 1 to 2 / 1) to give the title compound (0.55 g, 45% yield) as a white solid. LC-MS (ESI+) m / z 293.8 (M+H)+. 3-Chloro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate I)15

[0266] To a solution of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.5 g, 1.78 mmol, CAS# 904310-72-1) N-methylmethanamine;hydrochloride (144 mg, 1.77 mmol) in DMF (6 mL) was added HATU (875 mg, 2.30 mmol) and DIEA (686 mg, 5.31 mmol, 925 μL). Then the mixture was stirred at 25 °C for 0.2 hr. Upon completion, the mixture was quenched with H2O (20 mL), and then diluted with EA (20 mL) and extracted with EA (40 mL 20 × 2). The combined organic layers were washed with NaCl (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 2 / 1) to give the title compound (500 mg, 79% yield) as a white solid. LC-MS (ESI+) m / z 310.1 (M+H)+. 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazol- 25 5(4H)-one (Intermediate J) 85 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0267] A mixture of 4-(4-bromophenyl)-2-methyl-1,2,4-triazol-3-one (0.5 g, 2.0 mmol, CAS# 530080-66-1), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (999 mg, 3.94 mmol, CAS# 73183-34-3), Pd(dppf)Cl2·CH2Cl2(241 mg, 295 5 μmol), KOAc (579 mg, 5.90 mmol) in dioxane (6 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 80 °C for 5 hrs under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 3 / 1) to give the title compound (480 mg, 75% yield) as an off-white solid. LC-MS (ESI+) m / z 302.2 10 (M+H)+. N-((4-chloro-1-methyl-1H-indazol-3-yl)methyl)-N,2-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2H-indazole-3-carboxamide (Intermediate K)

[0268] A mixture of 6-bromo-N-[(4-chloro-1-methyl-indazol-3-yl)methyl]-N,2-dimethyl-15 indazole-3-carboxamide (1.5 g, 3.4 mmol, Intermediate G), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.56 g, 10.0 mmol, CAS# 73183- 34-3), KOAc (988 mg, 10.0 mmol) and Pd(dppf)Cl2.CH2Cl2 (274 mg, 335 μmol) in dioxane (20 mL) was degassed and purged with N2three times. Then the mixture was stirred at 80 °C for 12 hrs under N2atmosphere. Upon completion, the mixture was concentrated under reduced 20 pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=30 / 1 to 1 / 1) to afford the title compound (1.6 g, 79% yield) as a brown solid. LC-MS (ESI+) m / z 494.2 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 8.01 (d, J = 1.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.43 - 7.31 (m, 2H), 7.25 - 7.07 86 IPTS / 200079038.1Attorney Docket No.: KME-300WO (m, 1H), 5.36 - 5.08 (m, 2H), 4.23 (s, 3H), 4.10 - 4.03 (m, 3H), 3.16 - 2.98 (m, 3H), 1.31 (s, 12H). 4-(4-Bromophenyl)-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate L)5 Step 1 - Ethyl 4-(4-bromophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one

[0269] To a solution of 4-bromoaniline (20 g, 116 mmol, CAS# 106-40-1) in n-BuOH (100 mL) was added methyl hydrazinecarboxylate (12.5 g, 139 mmol, CAS# 6294-89-9), 1,1,1- triethoxyethane (22.6 g, 139 mmol, 25.5 mL) and TsOH (2.00 g, 11.6 mmol). The reaction was then stirred at 120 °C for 12 hrs under N2 atmosphere. On completion, the reaction mixture was10 concentrated in vacuo to give the crude residue. The crude residue was purified by reverse- phase HPLC (0.1% FA condition) to give the title compound (17 g, 51% yield) as a white solid. LC-MS (ESI+) m / z 254.0 (M+H)+. Step 2 - 4-(4-Bromophenyl)-1,3-dimethyl-1H-1,2,4-triazol-5(4H)-one

[0270] To a solution of 4-(4-bromophenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one (3.5 g, 14 15 mmol) in DMF (30 mL) was added NaH (826 mg, 20.6 mmol, 60% dispersion in mineral oil) at 0 °C. The reaction was then stirred at 0 °C for 1 hr. Then MeI (2.93 g, 20.6 mmol, 1.29 mL) was added into the mixture at 0 °C and the reaction was stirred at 25 °C for 1 hr. On completion, the reaction mixture was quenched with NH4Cl (50mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous 20 sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound (3.5 g) as a yellow solid. LC-MS (ESI+) m / z 268.0 (M+H)+. 1-(7-Methoxy-1-methyl-1H-indazol-3-yl)-N-methylmethanamine (Intermediate M) 87 IPTS / 200079038.1Attorney Docket No.: KME-300WOStep 1 - 3-Bromo-7-methoxy-1-methyl-1H-indazole

[0271] To a solution of 3-bromo-1H-indazol-7-ol (2 g, 10 mmol) in ACN (20 mL) was added MeI (2.67 g, 18.8 mmol, 1.17 mL) and K2CO3(3.89 g, 28.2 mmol). The mixture was then 5 stirred at 80 °C for 12 hrs. On completion, the reaction mixture was filtered and the filter cake was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=1 / 0 to 5 / 1) to give a title compound (1.2 g, 50% yield) as a white solid. LC-MS (ESI+) m / z 241.0 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ = 7.17 - 7.06 (m, 2H), 6.94 (d, J = 7.2 Hz, 1H), 4.19 (s, 3H), 3.95 (s, 3H). 10 Step 2 - Tert-butyl ((7-methoxy-1-methyl-1H-indazol-3-yl)methyl)(methyl)carbamate

[0272] 3-Bromo-7-methoxy-1-methyl-1H-indazole (1 g, 4 mmol), 2-((tert- butoxycarbonyl)(methyl)amino)acetic acid (1.18 g, 6.22 mmol, CAS# 13734-36-6), BTMG (1.07 g, 6.22 mmol, CAS# 29166-72-1) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl]phenyl]iridium(1+) 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine15 hexafluorophosphate (93.1 mg, 83.0 μmol, CAS# 870987-63-6), 4-tert-butyl-2-(4-tert-butyl-2- pyridyl)pyridine dichloronickel (82.5 mg, 207 μmol, CAS# 1034901-50-2) and isoindoline- 1,3-dione (610 mg, 4.15 mmol, CAS# 85-41-6) in DMSO (40 mL) was pumped by Pump 1 { S1,P1,0.554 mL / min } to flow reactor 1 { FLR1, FEP, Coils reactor, 3.175(1 / 8’’) mm, 49.853 mL, 50 °C }. The residence time of flow reactor 1 was {FLR 1, 90 min} with a 455nm, 400W 20 light. The reaction mixture was collected after running 3 hrs through the flow reactor. On completion, the reaction mixture was quenched with water (80 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the crude residue. The residue was purified by column chromatography (SiO2, Petroleum25 ether: Ethyl acetate=1 / 0 to 10 / 1) to give a title compound (1 g, 78% yield) as a yellow oil. LC- 88 IPTS / 200079038.1Attorney Docket No.: KME-300WO MS (ESI+) m / z 306.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 7.24 (br d, J = 8.0 Hz, 1H), 7.00 (br s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H), 4.20 - 4.13 (m, 3H), 3.93 (s, 3H), 3.26 (s, 3H), 1.43 (s, 9H). Step 3 - 1-(7-Methoxy-1-methyl-1H-indazol-3-yl)-N-methylmethanamine 5

[0273] To a solution of tert-butyl ((7-methoxy-1-methyl-1H-indazol-3- yl)methyl)(methyl)carbamate (1 g, 3 mmol) in DCM (10 mL) was added HCl / dioxane (8 M, 10 mL). The mixture was then stirred at 25 °C for 10 min. On completion, the reaction mixture was concentrated in vacuo to give the title compound (600 mg) as a white solid. 6-(4-(Dimethylcarbamoyl)phenyl)-2-methyl-2H-indazole-3-carboxylic acid 10 (IntermediateStep 1 - Methyl 6-(4-(dimethylcarbamoyl)phenyl)-2-methyl-2H-indazole-3-carboxylate

[0274] To a solution of N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (300 mg, 1.09 mmol, CAS# 400727-57-3) and methyl 6-bromo-2-methyl- 15 indazole-3-carboxylate (300 mg, 1.11 mmol, CAS# 1216852-55-9) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppf)Cl2.CH2Cl2 (89.04 mg, 109.0 μmol) and Cs2CO3 (1.07 g, 3.27 mmol). The mixture was then stirred at 80 °C for 2 hr. Upon completion, the solution was filtered, and the solvent removed in vacuo. The crude was purified by column chromatography (SiO2, PE / EA=10 / 1 to 3 / 1) to give the title compound (280 mg, 72% yield) as a yellow solid. 20 LC-MS (ESI+) m / z 338.0 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 8.09 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 1.2, 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 4.46 (s, 3H), 4.00 (s, 3H), 2.99 (d, J = 10.0 Hz, 6H). Step 2 - 6-(4-(Dimethylcarbamoyl)phenyl)-2-methyl-2H-indazole-3-carboxylic acid

[0275] To a solution of methyl 6-[4-(dimethylcarbamoyl)phenyl]-2-methyl-indazole-3- 25 carboxylate (280 mg, 830 μmol) in H2O (5 mL) and THF (5 mL) was added LiOH.H2O (174.14 89 IPTS / 200079038.1Attorney Docket No.: KME-300WO mg, 4.15 mmol). The mixture was then stirred at 20 °C for 2 hr. Upon completion, the organic solvent was removed in vacuo. Then, 1M HCl was added to acidify the solution, followed by extraction with EtOAC (3×10mL). The organic layer was then dried with Na2SO4, filtered and the solvent removed in vacuo to give the title compound (200 mg, 74% yield) as a white solid. 5 LC-MS (ESI+) m / z 324.1 (M+H)+. 1-(4-Bromophenyl)imidazolidine-2,4-dione (CAS# 32547-34-1) (Intermediate O)(4-Chloro-1-methyl-1H-indazol-3-yl)methanamine (CAS# 1033693-10-5) (Intermediate R)10RExample 2. (Method 1): Synthesis of N-((4-chloro-1-methyl-1H-indazol-3-yl)methyl)- N,2-dimethyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3-carboxamide (Compound I-46)15

[0276] A mixture of 2-methyl-6-(4-(2-oxopyrrolidin-1-yl)phenyl)-2H-indazole-3-carboxylic acid (80.0 mg, 238 μmol, Intermediate B), 1-(4-chloro-1-methyl-1H-indazol-3-yl)-N- methylmethanamine (60.0 mg, 286 μmol, Intermediate A), HATU (108 mg, 286 μmol), and DIEA (154 mg, 1.19 mmol, 207 μL) in DMF (1 mL) was at 25 °C for 2 hours. On completion, the crude residue was purified by reverse-phase HPLC (0.8g / L ammonium bicarbonate) to give 20 the title compound (25.0 mg) as a white solid. LC-MS (ESI+) m / z 527.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 8.25 - 7.89 (m, 2H), 7.89 - 7.64 (m, 5H), 7.53 (s, 2H), 7.36 - 7.07 90 IPTS / 200079038.1Attorney Docket No.: KME-300WO (m, 1H), 5.40 - 5.14 (m, 2H), 4.22 (s, 3H), 4.09 (s, 3H), 3.94 - 3.84 (m, 2H), 3.44 - 3.38 (m, 3H), 3.13 - 3.01 (m, 2H), 2.39 - 2.02 (m, 2H). Table 3: Compounds synthesized via Method 1, coupling of the corresponding amines and carboxylic acids5aThe coupling was run under standard conditions for 1-2 hrs at rt. Purification of the final compounds via standard techniques including reverse-phase HPLC and prep-HPLC. Example 3. (Method 2): Synthesis of N-((4-chloro-1-methyl-1H-indazol-3-yl)methyl)- N,2-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-3- carboxamide (Compound I-47) 1091 IPTS / 200079038.1Attorney Docket No.: KME-300WO

[0277] A mixture of 6-bromo-N-[(4-chloro-1-methyl-indazol-3-yl)methyl]-N,2-dimethyl- indazole-3-carboxamide (110 mg, 246 μmol, Intermediate G), [4- (dimethylcarbamoyl)phenyl]boronic acid (142 mg, 738 μmol, CAS# 405520-68-5, Intermediate F), K2CO3 (102 mg, 738 μmol) and Pd(dppf)Cl2.CH2Cl2 (20.1 mg, 24.6 μmol) in 5 dioxane (1 mL) and H2O (0.2 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 80 °C for 2 hrs under N2atmosphere. Upon completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (column: CD01-Phenomenex luna C18150*25*10um;mobile phase: [water(FA)-ACN];gradient:32%-62% B over 10 min) to afford the title compound 10 (88.46 mg, 67% yield) as a yellow solid. LC-MS (ESI+) m / z 515.1 (M+H)+;1H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.0 Hz, 3H), 7.69 - 7.59 (m, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.43 - 7.32 (m, 1H), 7.28 - 7.09 (m, 1H), 5.36 - 5.14 (m, 2H), 4.23 (s, 3H), 4.08 (d, J = 1.6 Hz, 3H), 3.14 (s, 3H), 2.99 (s, 6H). Table 4: Compounds synthesized via Method 2, the cross coupling of the corresponding 15 bromides and boronic acids92 IPTS / 200079038.1Attorney Docket No.: KME-300WO aThe cross coupling was run under standard conditions for 1-2 hrs at 80 ºC. Boronic acids or esters were used as the coupling partners. Purification of the final compounds via standard techniques including reverse-phase HPLC and prep-HPLC.bThe product of the coupling was further deprotected with TFA in DCM at rt for 2 hr. The final compound was purified by 5 reverse phase HPLC. Example 4. Homogenous Time-Resolved Fluorescence (HTRF) Binding Assay

[0278] HTRF binding assays were performed using 2 nM biotinylated STAT6 (aa1-847) purified from BV (baculovirus expression system), 1X Streptavidin-terbium (Revvity) prepared by mixing SA-Tb in PPI detection buffer (Revvity), 125 nM FAM peptide; ASSGEEG-pY-KPFQDLI-K(FAM), and test 10 compounds in assay buffer consisting of 50 mM HEPES-Na pH 7.5, 100 mM NaCl, 1 mM EDTA, 2 mM DTT, 0.1% Tween-20 with a final volume of 20 uL. Compound stocks were dissolved at 10 mM in 100% DMSO and 11 point titration with 3 fold serial dilution was performed in white, opaque 384 well microplates. Reaction plates were incubated at room temperature for 30 minutes. Plates were centrifuged at low rpm for 5 mins, and the ratio of fluorescence intensities were measured at emission 15 wavelengths for fluorescein acceptor (520 nm) and terbium donor (495 nm) on Envision Plate reader. % Inhibition was calculated from the 520 / 495 ratio generated by using positive control peptide (ASSGEEG-pY-KPFQDLI ) for 100% inhibition and DMSO only reactions for 0% inhibition. Data 93 IPTS / 200079038.1Attorney Docket No.: KME-300WO was processed and dose response curves were generated using GraphPad Prism to determine the concentration required for inhibiting 50% of the HTRF signal (IC50).

[0279] The letter codes for IC50 (nM) include: AA (<50 nM); BB (50 – 100 nM); CC (>100 nM – 1,000 nM); DD (> 1,000 nM – 10,000 nM); and EE (>10,000 nM). 5

[0280] The STAT6 HTRF IC50results are shown in Table 5. Table 5. STAT6 HTRF Results94 IPTS / 200079038.1Attorney Docket No.: KME-300WOINCORPORATION BY REFERENCE

[0281] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and 5 individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

[0282] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will 10 become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0283] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. 15 Such equivalents are intended to be within the scope of the following claims. 95 IPTS / 200079038.1

Claims

Attorney Docket No.: KME-300WO CLAIMS What is claimed:

1. An inhibitor compound of Formula I:5 Formula I, or a pharmaceutically acceptable salt thereof, 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; 10 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, 15 oxygen, and sulfur; Ringoptionally substituted 5- to 6- membered heterocyclyl with1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 96 IPTS / 200079038.1Attorney Docket No.: KME-300WO 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)- 5 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 optionally substituted phenyl; RE3is hydrogen, halogen, optionally substituted C1-C6 alkyl or optionally substituted phenyl; or RE2and RE3are taken together with the atoms to which they are attached to form 10 optionally substituted phenyl; each of YE1and YE2is, independently, N or CRE7; YE3is N or CRE2; YE4is N or CRE3; YE5is CRE1or N; 15 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; 20 each RE4is, independently, hydrogen, or optionally substituted C1-C6alkyl; 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; 25 GSis –NRNL–, –(CRC7RC8)1-2–, or absent; each RC7is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy; each RC8is independently hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6alkyl, –C(O)-C1-C6alkyl, C3-C530 carbocyclyl, and 3- to 5-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RCGindependently is hydrogen, halogen, cyano, or optionally substituted C1-C6alkyl and C1-C6alkoxy; RNGis hydrogen or optionally substituted C1-C6 alkyl; 97 IPTS / 200079038.1Attorney Docket No.: KME-300WO RNLis hydrogen or optionally substituted C1-C6 alkyl; 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, 5 oxygen, and sulfur, phenyl, and 5- to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RE7is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, phenyl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and 10 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, 15 oxygen, and sulfur, or RN1and RN2on the same nitrogen atom are taken together with the nitrogen atom to which RN1and RN2are attached to form an optionally substituted 3- to 10- membered heterocyclyl with 1-4 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 20 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, 25 oxygen, and sulfur; each RC4, RC5, and RC6is, independently, hydrogen, halogen, cyano, or an optionally substituted group selected from C1-C6 alkyl and C1-C6 alkoxy, or RC4and RC5on the same carbon atom are taken together with the carbon atom to which RC4and RC5are attached to form an optionally substituted group selected from C3-C630 carbocyclyl and 3- to 7-membered heterocyclyl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 98 IPTS / 200079038.1Attorney Docket No.: KME-300WO RD2aRC4and RC5are optionally taken together to form, wherein each RD2aand RD2bis, independently, hydrogen or optionally substituted C1-C6 alkyl; m is 0 or 1; and p is 0 or 1. 5 2. The inhibitor compound of claim 1, wherein the compound is of Formula II:Formula II, or a pharmaceutically acceptable salt thereof.

3. The inhibitor compound of claim 1, wherein the compound is of Formula III:10Formula III, or a pharmaceutically acceptable salt thereof. 99 IPTS / 200079038.1Attorney Docket No.: KME-300WO 4. The inhibitor compound of claim 1, wherein the compound is of Formula IV:Formula IV, or a pharmaceutically acceptable salt thereof. * 5 5.selected from: ,100 IPTS / 200079038.1Attorney Docket No.: KME-300WO * wherein indicates bond to LE. * 6. The inhibitor compound of claim 4 or 5, wherein, indicates bond to LE.

7. The inhibitor compound of claim5101 IPTS / 200079038.1Attorney Docket No.: KME-300WO * 8. The inhibitor compound of claim 4 or 5, wherein, indicates bond to LE.

9. The inhibitor compound of claim 8, whereinfrom:

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

11. The inhibitor compound of claim 10, wherein Ring E1 is , 102 IPTS / 200079038.1Attorney Docket No.: KME-300WO wherein: each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – 5 NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4. The inhibitor compound of claim 11, wherein Ring E1 is.10 13. The inhibitor compound of claim 10, wherein Ring E1 is , wherein: RE8is –C(O)NRE9RE10or –NRE11C(O)RE12; each of RE9, RE10, and RE11is, independently, hydrogen or C1-C6alkyl; RE12is C1-C6 alkyl or C1-C6 haloalkyl; 15 each RE13is, independently, halogen, –OH, cyano, –NRN1RN2, –S(O)2NRN1RN2, – NRN3S(O)2RC2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, –C1- C6 alkyl-C1-C3 alkoxy, –C(O)-C1-C6 alkyl, –C1-C6 alkyl-NRN1RN2, –C(O)-NRN4RN5, – NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – 20 C(O)-C1-C6alkyl; and e1 is 0, 1, 2, 3, or 4. 103 IPTS / 200079038.1Attorney Docket No.: KME-300WO 14. The inhibitor compound of claim 13, wherein Ring15. The inhibitor compound of any one of claims 1-9, wherein Ring E1 is optionally substituted 8- to 10- membered bicyclic heteroaryl with 1-4 heteroatoms independently 5 selected from nitrogen, oxygen, and sulfur.

16. The inhibitor compound of claim 15, wherein Ring E1 is optionally substituted 9- membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

17. The inhibitor compound of claim 16, wherein Ring10 wherein: RE14is hydrogen, C1-C6 alkyl, –C(O)-C1-C6 alkyl, or C3-C6 cycloalkyl; each RE15is, 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, – 15 NRN3C(O)RC3, imidazolyl, or thiazolyl; each RN1, RN2, RN3, RN4, RN5, RC1, RC2, and RC3is, independently, hydrogen, C1-C6alkyl, or – C(O)-C1-C6alkyl; and e2 is 0, 1, 2, 3, or 4. 104 IPTS / 200079038.1Attorney Docket No.: KME-300WO19. The inhibitor compound of any one of claims 1-9, wherein Ring E1 is optionally substituted 5- to 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently 5 selected from nitrogen, oxygen, and sulfur.

20. The inhibitor compound of claim 19, wherein Ring E1 is optionally substituted 5- membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

21. The inhibitor compound of claim 19 or 20, wherein Ring E1 is. O 10 22. The inhibitor compound of any one of claims 1-21, wherein RE1,105 IPTS / 200079038.1Attorney Docket No.: KME-300WO23. The inhibitor compound of any one of claims 1-22, wherein524. The inhibitor compound of any one of claims 1-23, wherein RE2is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, phenyl, or phenyl substituted with 1-4 substituents selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

25. The inhibitor compound of any one of claims 1-24, wherein RE3is hydrogen, halogen, 10 C1-C6alkyl, C1-C6haloalkyl, phenyl, or phenyl substituted with 1-4 substituents selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl.

26. The inhibitor compound of any one of claims 1-23, wherein RE2and RE3are taken together with the atoms to which they are attached to form phenyl or phenyl substituted with 1-4 substituents selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. 15 27. The inhibitor compound of any one of claims 1-26, wherein each RE4is, independently, hydrogen, C1-C6alkyl, or –C1-C6alkyl-C3-C6cycloalkyl. 106 IPTS / 200079038.1Attorney Docket No.: KME-300WO29. An inhibitor compound selected from any one of the compounds of Table 1, or a 5 pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising an inhibitor compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

31. A method of modulating STAT6 in a subject or a biological sample, wherein the 10 method comprises administering to the subject or the biological sample an inhibitor compound of any one of claims 1-29, or a pharmaceutical composition of claim 30.

32. 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 1-29, or a pharmaceutical composition of claim 30. 15 33. The method of claim 32, 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 20 associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder. 107 IPTS / 200079038.1

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