STAT6 inhibitors and uses thereof

Abstract

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

Description

STAT6 INHIBITORS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 617.310, filed January 3, 2024, and U.S. Provisional Application No. 63 / 649,869. filed May 20, 2024.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to inhibitor compounds and methods useful for the inhibition of signal transducer and activator of transcription 6 (“STAT6”). The invention also provides pharmaceutically acceptable compositions comprising inhibitor compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

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

[0004] STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4 / IL-13- mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells (Hebenstreit et al. "Signaling mechanisms, interaction partners, and target genes of STAT6." Cytokine & growth factor reviews 17.3 (2006): 173-188: Chapoval et al. "Regulation of the T helper cell type 2 (Th2) / T regulatory cell (Treg) balance by IL-4 and STAT6." Journal of leukocyte biology 87.6 (2010): 101 1-1018). 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 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 (Glosson et al. "Wheezing and itching: The requirement for STAT proteins in allergic inflammation." Jak-Stat 1.1 (2012): 3-15; Loh et al. "Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication." Frontiers in oncology 9 (2019): 48). Accordingly, there remains a need to find STAT6inhibitors useful as therapeutic agents.SUMMARY OF THE INVENTION

[0005] It has now been found that compounds described herein, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of STAT6 protein.

[0006] In some embodiments, the present invention provides inhibitor compounds of formula I’:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0007] Inhibitor compounds described herein, and pharmacally acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0008] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0009] Inhibitor compounds described herein are also useful for the study of STAT6 protein in biological and pathological phenomena: the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new STAT6 inhibitors or other regulators of cell cycling, metastasis, angiogenesis, and immune cell evasion, in vitro or in vivo.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Invention:

[0010] Inhibitor compounds described herein, and compositions thereof, are useful as inhibitors of STAT6 protein which includes phosphorylated or activated STAT6 protein, e.g.. pSTAT6. In some embodiments, a provided inhibitor compound inhibits and / or modulates STAT6. pSTAT6, or STAT6 and pSTAT6.2. Compounds and Definitions:

[0011] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0012] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl )alkenyl.

[0013] 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. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionallyor alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0014] The term “lower alkyl” refers to a C1-4straight or branched alkyl group. Exemplar) lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0015] The term “haloalkyl” refers to a C1-6straight or branched alkyl group that is substituted with one or more halogen atoms and “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0016] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized fonn of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3.4-dihydro-2H-pyrrolyl). NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl)).

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

[0018] As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0019] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylenegroup, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0020] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

[0022] The term “halogen” means F, Cl, Br, or I.

[0023] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “and” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

[0024] The tenns “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 7t electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl. pyrrolyl, imidazolyl, pyrazolyl, triazolyl. tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroary l” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizmyl. carbazolyl. acridinyl. phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term “heteroaryl” maybe used interchangeably with the terms “heteroaryl ring,” '‘heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl. wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0025] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical.” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-2H pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in / V substituted pyrrolidinyl).

[0026] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl. thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring.” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3E7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. In some embodiments, a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl. wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0027] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The tenn “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties. as herein defined.

[0028] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisionedby this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable.” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery , purification, and use for one or more of the purposes disclosed herein.

[0029] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -0(CH2)0-4R°, -O-(CH2)0-4C(O)OR°; - (CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph. which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°: -C(S)R°; - (CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4S R°; - (CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)0-4OC (O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°: -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -(CH2)0-4P(O)2R°; -(CH2)0-4P(O)R°2; -(CH2)0-4OP(O)R°2; - (CH2)0-4OP(O)(OR°)2; SiR°3; — (C1-4straight or branched alkylene)O-N(R°)2; or — (C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atorn(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0030] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0-2R●, - (haloR●), -(CH2)0-2OH, -(CH2)0-2OR●, -(CH2)0-2CH(OR●)2; -O(haloR●), -CN. -N3, -(CH2)0-2C(O)R●, - (CH2)0-2C(O)OH, -(CH2)0-2C(O)OR●, -(CH2)0-2SR●, -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR●, - (CH2)0-2NR●2. — NO2, -SiR●3, -OSiR●3. -C(O)SR●-(C1-4straight or branched alkylene)C(O)OR●, or - SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0031] Suitable divalent substituents on a saturated carbon atom of an '‘optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, - O(C(R*2))2-3O- , or-S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable substituents on the aliphatic group of R* include halogen, -R●. -(haloR●). -OH, -OR●, -OfhaloR●). -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -wherein each R1is independently hydrogen, C1-6aliphatic which may besubstituted 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 R1, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or ary l mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group of R1are independently halogen, -R●. -(haloR●), - OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH:, -NHR●, -NR●2, or -NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] As used herein, the term "pharmacally acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmacally acceptable salts are well known in the art. For example, S. M. Berge ct al., describe pharmaceutically acceptable salts in detail in J. Phannaccutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmacally acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmacally acceptable salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate. methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0036] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmacally acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations fonned using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and ary l sulfonate. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds fomred during chromatographic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

[0037] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric. and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric fonns of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention

[0038] As used herein, the term ‘'provided compound” refers to any genus, subgenus, and / or species set forth herein.

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

[0040] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. In some embodiments, a “reference” sample or subject is one that is sufficiently similar to a particular sample or subject of interest to permit a relevant compari son. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control

[0041] As used herein, an “inhibitor compound” is a compound that binds a protein of interest. In some embodiments, an inhibitor compound binds a protein of interest and decreases its activity. In some embodiments, binding of an inhibitor compound to a protein of interest does not result in degradation of the protein of interest. In another embodiment, an inhibitor compound does not bind an E3 ligase in a manner that results in degradation of the protein of interest. In some embodiments, an inhibitor compound binds STAT6. In some embodiments, an inhibitor compound binds STAT6 and decreases its activity. In some embodiments, binding of an inhibitor compound to STAT6 does not result in degradation of STAT6. In another embodiment, an inhibitor compound does not bind an E3 ligase in a manner that results in degradation of the STAT6. In some embodiments, an inhibitor compound binds a protein of interest (e.g., STAT6) but does not bind an E3 ligase. In some embodiments, an E3 ligase is selected from a cereblon E3 ubiquitin ligase, a VHL E3 ubiquitin ligase, a DCAF E3 ubiquitin ligase, (e.g., a DCAF1 E3 ubiquitin ligase, a DCAF15 E3 ubiquitin ligase, or a DCAF16 E3 ubiquitin ligase), an IAP E3 ubiquitin ligase, an MDM2 E3 ligase, or a DC2 E3 ubiquitin ligase. It will be understood that, throughout this disclosure, reference to a “compound” or a “provided compound” refers to an inhibitor compound as defined above.

[0042] In some embodiments, an E3 ligase is a cereblon E3 ubiquitin ligase. In some embodiments, the inhibitor compound docs not comprise a structure of formula I-aa':or a pharmaceutically acceptable salt thereof, wherein:X1and X5are independently a covalent bond, -CR2-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, orX2is N, C-RB, Si-RB, or P=O;X3and X4are independently a covalent bond, -CR2-, -CF2-, -O-, -S-. or X3-X4is -CR=CR-; each R1is independently -H, RA, halogen, -CN, -NO2, -OR, -SR, -NR2,SiR3, -S(O)2R, -S(O)2NR2, -S(O)R -C(O)R, -C(O)OR -C(O)NR2, -C(O)N(R)OR -C(R)2N(R)C(O)R -C(R)2N(R)C(O)NR2, -OC(O)R -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)(NR2). -OP(O)(NR2)2. -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S(O)2R - NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2. -N(R)S(O)2R; or: two R1groups of Ring A are taken together with their intervening atoms to form an optionally substituted ring selected from a 3-10 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; benzo; or a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each RBis independently, hydrogen, halogen, -CN, -OR, -SR -S(O)R -S(O)2R -NR2, -P(O)(OR)2, - P(O)(NR2)OR, -P(O)(NR2)2, -Si(OH)2R -Si(OH)R2, -SiR3, or an optionally substituted C1.4 aliphatic;L1is a covalent bond or a C1-3bivalent hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR2-, -CF2-, -NR-, -O-, -S-, or -S(O)2;Ring A is phenylenyl, naphthalenyl, pyridinylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur,an 8-15 membered saturated or partially unsaturated tricyclic heterocyclylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-15 membered tricyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-10 membered saturated or partially unsaturated carbocyclic ring, a 3-10 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same or adjacent atoms or RBand an R group are taken together with their intervening atoms to fomr an optionally substituted 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0043] In some embodiments, the inhibitor compound does not compriseor

[0044] In some embodiments, an E3 ligase is a VHL E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not comprise a structure of formula I-ccc-3':or a pharmaceutically acceptable salt thereof, wherein: each of X4aand X5ais independently a bivalent moiety selected from -CH2-, -C(O)-, -C(S)-, oreach R4ais independently hydrogen, -Rb, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; or:R5ais hydrogen or C1-6aliphatic; each R6is independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-15 membered saturated or partially unsaturated tricyclic heterocyclylenyl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-15 membered tricyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring Cais a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; q is 0, 1, 2, 3 or 4; and each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0045] In some embodiments, the inhibitor compound does not comprise

[0046] In some embodiments, an E3 ligase is an MDM2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not comprise a structure of I-aaa-1, 1-aaa-2, 1-aaa-3, 1-aaa-4, 1-aaa-5, 1-aaa-6, 1-aaa-7, 1-aaa-8, 1-aaa-9, 1-aaa-10, 1-aaa-11, 1-aaa-12, 1-aaa-13, 1-aaa-14, 1-aaa-15, 1-aaa-16, 1-aaa-17, or I-aaa-18 respectively:or a pharmaceutically acceptable salt thereof, wherein:X is selected from -CR2-, -O-, -S-. -S(O)-, -S(O)2-, and -NR-; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom from which they are attached, independently selected from nitrogen, oxygen, and sulfur.Y and Z are independently selected from -CR= and -N=;Ring W is fused ring selected from benzo and a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1and R2are independently an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3and R4are independently selected from hydrogen and C1-6alkyl;R5is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered and, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R6is selected from hydrogen, -C(O)R. -C(O)OR, and -C(O)NR2;R7is selected from hydrogen and RA; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R8is selected from -C(O)R and RA;R9is a mono-, bis-, or tri-substituent on Ring W, wherein each of the substituents are independently selected from halogen and an optionally substituted C1-6aliphatic;R10is selected from an optionally substituted monocyclic or bicyclic ring selected from phenyl, a 5-10 membered and, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R11is -C(O)OR or -C(O)NR2;R13and R13are independently selected from hydrogen and RA. or:R12and R13are optionally taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated, partially unsaturated, carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R14is RA;R15is -CN;R16is selected from RA, -OR, -(CR2)0-6-C(O)R, -(CR2)0-6-C(O)OR. -(CR2)0-6-C(O)NR2, -(CR2)0-6-S(O)2R, - (CR2)0-6-N(R)S(O)2R, -(CR2)0-6-S(O)2NR2;R17is selected from -(CR2)0-6-C(O)NR2;R18and R19are independently selected from hydrogen and RA;R20and R21are independently selected from hydrogen. RA. halogen, and -OR, or:R20and R21are optionally taken together with their intervening atoms to form a fused 5-7 membered partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R22, R23.R25. and R27are independently selected from hydrogen, RA, halogen. -C(O)R, -C(O)OR, -C(O)NR2, -NR2, -OR, -S(O)R, -S(O)2R, -S(O)2NR2;R24R2band R28are independently selected from hydrogen, RA, -C(O)R, -C(O)OR, - C(O)NR2, -S(O)R, -S(O)2R, and -S(O)2NR2;R1and R2are independently selected from halogen, -C≡CR, -CN, -CF;. and -NO2;R3is -OR;R4', R5, R6' are independently selected from hydrogen, halogen. RA. -CN. -CF3, -NR2, -OR, -SR, and - S(O)2R;R7' is a mono-, bis-, or tri-substituent, wherein each of the substituents are independently selected from halogen;R8is a mono-, bis-, or tri-substituent, wherein each of the substituents are independently selected from hydrogen, halogen, RA, -CN, -C=CR, -NO2, and -OR;R9' is RA;Z1is selected from hydrogen, halogen, and -OR;R10' and R11' are independently selected from hydrogen and RA;R12is selected from -C(O)R, -C(O)OR, -C(O)NR2, -OR, -S(O)2R, -S(O)2NR2,and -S(O)R; andR1” is selected from hydrogen and RA.

[0047] In some embodiments, an E3 ligase is a DCAF E3 ubiquitin ligase (e.g., DCAF1 E3 ubiquitin ligase). In some embodiments, the inhibitor compound does not comprise a structure of formula 1-b-a orI-b-b:or a pharmaceutically acceptable salt thereof, wherein:Ring E1is phenyl, naphthyl, a 4-9 membered partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-9 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Ring F1is a 5 -membered monocyclic heteroarylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.Y1is a C1-3hydrocarbon chain wherein each methylene is optionally replaced with -CR2-, -CR(OR)-, -C(O)- , -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-; or -C(OR)= in formula I-b-a where Rdis absent;Rais hydrogen, an optionally substituted C1-6aliphatic, or;Ring G is phenyl, a 5-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rbis hydrogen, an optionally substituted C1-6aliphatic, phenyl, or a 5-6 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:Raand Rbare taken together with their intervening atoms to form an optionally substituted 9-10 membered saturated or partially unsaturated bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: when Y1is -C(NR)-, Rbis taken together with R of -C(NR)- with their intervening atoms to fonn a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur;Rcis -CO2R, -CONR2, -CR2CF2R, -CR2CONR2, -CR2C(O)R, -CR2CO2R, -CR2NR2, -CR2OR, - CR2SO2NR2, -CR2S(O)R, -CR2SO2R, -CR2S(O)(NR)R, -CR2CN, -CR2CR2NR2, -CR2CR2OR, - CR2CR=NOR, -CR2CR(OR)CR2OR, or an optionally substituted group selected from phenyl; a 4- 7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: -(CR2)1-2-Xa, wherein Xais halogen or an optionally substituted ring selected from phenyl; a 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or:Rband Rcare taken together with their intervening atoms to form an optionally substituted 4-6 membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or:Rais absent and Rband Rcare taken together with their intervening atoms to fomi an optionally substituted phenyl; or: when Y1is -C(OR)=, Rcis taken together with R of -C(OR)= with their intervening atoms to form a 5-7 membered partially unsaturated heterocyclyl with 0-1 heteroatoms, in addition to the 2 heteroatoms within the heterocyclyl, independently selected from nitrogen, oxygen, and sulfur;Rdis hydrogen or an optionally substituted C1-6aliphatic, or: when Rcis -CR2CONR2, Rdis taken together with a single R of -CR2CONR2with their intervening atoms to form a 5-7 membered saturated or partially unsaturated heterocyclyl with 0-3 heteroatoms, in addition to the nitrogen atom to which Rdis attached, independently selected from nitrogen, oxygen, and sulfur;Re, Rf, and Rgare each independently selected from hydrogen, oxo, RA, halogen, -CN, -NO2, -OR, - SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2. -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, - NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R. -NP(O)R2. -NRP(O)(OR)2, - NRP(O)(OR)NR2, -NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2, -P(O)(OR)NR2, and -P(O)(NR2)2; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, naphthyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of c, f, and g are independently 0, 1, 2, 3, or 4.

[0048] In some embodiments, the inhibitor compound does not comprise a structure of formula I-b-c:or a pharmaceutically acceptable salt thereof, wherein:Ring H is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring I is phenylenyl or a 5-10 membered monocyclic or bicyclic heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Ring J is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring K is phenyl, naphthyl, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroarylenyl with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rh, R1, Rj, and Rkare each independently selected from hydrogen, oxo, RA, halogen, -CN, -NO2, -OR, - SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, -NRP(O)(OR)NR2, - NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2. -P(O)(OR)NR2, and -P(O)(NR2)2, or: an R1group on Ring I and an RJgroup or Ring J are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aromatic ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: each of X1and X2are independently a covalent bond, spiro-fusion between the two rings that X1or X2connect, or a bivalent, saturated or unsaturated, straight or branched C1-6hydrocarbon chain, wherein 0-4 methylene units of X1and X2are independently replaced by -CR2-. -CR(OR)-, -CRF- , -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-; s” is 0 or 1; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0049] In some embodiments, an E3 ligase is a DC2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not comprise a structure of fonnula I-c-a-1 or I-c-a-2:or a pharmaceutically acceptable salt thereof, wherein:SBM and L are as defined and described above and herein;R1Zis hydrogen or optionally substituted C1-6aliphatic; each RaZ, Rbz, and RcZare independently hydrogen, R^, halogen, -CN, -NO2, -ORZ-SRZ-NRZ2, -S(O)2RZ, -S(O)2NRZ2, -S(O)RZ-S(O)(NRZ)RZ, -P(O)(ORZ)2, -P(O)(NRZ2)2, -CFRZ2, -CRZF2, -CF3, - CRZ2(ORZ), -CRZ2(NRZ2), -C(O)RZ, -C(O)ORZ, or -C(O)NRZ2; each RAZis independently an optionally substituted group selected from C1-10 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Rzis independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two Rzgroups on the same atom are optionally taken together with their intervening atom to form an optionally substituted 4-11 membered saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spirocyclic, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; each Ring Azis independently a bivalent ring selected from phenylenyl, naphthylenyl, a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10membered monocyclic or bicyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each Ring Bzis independently a bivalent ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-10 membered monocyclic or bicyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;LaZis absent, a covalent bond, or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units of the chain are independently and optionally replaced with - O-, -C(O)-, -C(S)-, -C(RZ)2-, -CH(RZ)-, -CF(RZ)-, -C(F)2, -N(RZ)-, -S-, -S(O)2- or -CRZ=CRZ-; z1, z2. and z3 are each independently 0, 1, 2, 3 or 4; each of z4 and z5 is independently 0 or 1.

[0050] In some embodiments, an inhibitor compound binds to and / or inhibits STAT6 protein with measurable affinity. In certain embodiments, an inhibitor compound has an IC50and / or binding constant of less than about 50 pM. 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.3a. Description of Exemplary Embodiments Related to Methods of Use:

[0051] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituentseach of X1, X4, X5and X6is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, X5and X6is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(RK)2, NH, NRw, N, 0, or S, wherein at least one ofY2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2;eachrepresents a single bond or a double bond;Ring X and its Rxsubstituentswherein represents a bond to Ring W, andrepresents a bond to Lx;Ring Y is a ring selected from phenyl, naphthyl, 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;represents a bond to Ring Y; Rwis selected from hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3. -S(O)R, -S(O)2R, - S(O)(NR)R -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, NR2, -SiR3, - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2. -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R;Rzis RA, -OR, or NR2; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-. -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2-, -S(O)(NR)-, or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0052] It will be understood that formula I cannot extend beyond the formulae described within this section (3a) below and herein. It will be understood that all references to “defined and described herein” solely refer to this section (3a) of the application. Additionally, all chemical formulae and embodimentswithin section 3a can only apply to and be combined with formulae and embodiments from this section(3a).

[0053] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I, wherein the inhibitor compound is of fonnula I’ :or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituentseach of X1, X4, and X5is independently CH. CRw. or N: each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4. and X5is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, 0, or S, wherein at least one of Y2and Y3is CH. CRw, CH2, CH(Rw), or C(Rw)2; each represents a single bond or a double bond:Ring X and its Rxsubstituentswherein represents a bond to Ring W, andrepresents a bond to the rest of the molecule;Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rwis selected from hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3. -S(O)R, -S(O)2R, - S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC (O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, - S(O)R, -S(O)2R -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R3, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-. -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0054] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I, wherein the inhibitor compound is of formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituents iseach of X1, X4, and X5is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH. CRw. CH2, CH(Rw), or C(Rwj2; each represents a single bond or a double bond;Ring X and its Rxsubstituents iswherein represents a bond to Ring W, andrepresents a bond to the rest of the molecule;Ring Y is a ring selected from naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rwis selected from hydrogen, RA, RB, halogen, -CN, -NCh, -OR, -SR, -NR2, -SiR2, -S(O)R, -S(O)2R, - S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, - S(O)R, -S(O)2R -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R3, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-. -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0055] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I, wherein the inhibitor compound is of formula III:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituentseach of X1, X4, and X5is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, 0, or S, wherein at least one of Y2and Y3is CH. CRw. CH2, CH(Rw), or C(Rwj2; each represents a single bond or a double bond;Ring X and its Rxsubstituentswherein represents a bond to Ring W, andrepresents a bond to Lx;Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;represents a bond to Ring Y;Rwis selected from hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2. and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R;Rzis RA, -OR. or NR2; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phcnylcnyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturatedmonocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0056] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I, wherein the inhibitor compound is of formula IV :or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituentseach of X1, X4, X5and X6is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, X5and X6is N; each of Y1and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S;eachrepresents a single bond or a double bond;Ring X and its Rxsubstituentswherein represents a bond to Ring W, andrepresents a bond to the rest of the molecule;Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rwis selected from hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR2, -S(O)R, -S(O)2R, - S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR. -SR, -NR2. -SiR2. - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR. -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R;Rzis RA, -OR, or NR2; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-. -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroary lenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturatedmonocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to fonn a 3-7 membered saturated or partially unsaturated ring having0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0057] In some embodiments, the present invention provides methods of use related to an inhibitor compound of formula I’, wherein:(i) when Ring X and its Rxsubstituents is X1is N, and Y1is NH. NRw. or N, thenY2and Y3are not NH, NRw, or N;(ii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH or CRw, each of X2and X3is C, and each ofY2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2, then Y1is not CH, CRw, CH2, CH(Rw), or C(Rw)2;(iii) when Ring X and its Rxsubstituents isX1is N, and Y1is S, then Ring Y is not phenyl or 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;(iv) when Ring X and its Rxsubstituents is , X1is N. and Y1is NH. NRw. or N. then Y3is not S;(v) when Ring X and its Rxsubstituents isX1is N, and Y1is 0, then Y2is not NH,NRw, or N;(vi) when Ring X and its Rxsubstituents is X1is N, Y1is NH, NRw, or N, and Y2and Y3are CH, CRw, CH2, CH(Rw), or C(Rw)2, then z is not 0 or 1;(vii) when Ring X and its Rxsubstituents is , each of X1. X4, and X5is CH or CRw, each of X2and X3is C, and Y2is CH. CRw, CH2, CH(Rw), or C(Rw)2, then only one of Y2andY3is 0;(viii) when Ring X and its Rxsubstituents is each of X1, X4, and X5is CH or CRw,each of X2and X3is C, Y1is O, NH, NRw, or N, and Y2and Y3are CH, CRw, CH2, CH(Rw), orC(Rw)2, then z is not 0 or 1; and(ix) when Ring X and its Rxsubstituents is , X5is N, and Y1is NH, NRw, or N, thenY2is not NH, NRw, or N.

[0058] In some embodiments, the inhibitor compound of formula I, I’, II, III, or IV is not a compound of structure A-B-C defined by the combination of the building blocks A, B, and C within the table below:

[0059] In some embodiments, the inhibitor compound of formula I, I’, II, III, or IV is not any of compounds 1-1 through 1-1548, or pharmaceutically acceptable salts thereof, described in PCT / US2024 / 044544. In some embodiments, the inhibitor compound of formula 1. 1’, II. Ill, or IV is not a compound of Table 1, or a pharmaceutically acceptable salt thereof, of International Application No. PCT / US2024 / 044544.

[0060] In some embodiments, the inhibitor compound of formula I, I’, II, III, or IV is not a compound selected from Table A.Table A:or a salt or free base / acid thereof.

[0061] As described above and defined herein. Ring W and its Rwsubstituents iswherein each of X1, X4, X5and X6is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, X5and X6is N; each ofY1, Y2. and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2. NH, NRw,N, 0, or S, wherein at least one of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2; and eachrepresents a single bond or a double bond.

[0062] In some embodiments, Ring W and its Rwsubstituents iswherein each of X1, X4, and X5is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each of Y1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2; and eachrepresents a single bond or a double bond.

[0063] In some embodiments, Ring W and its Rwsubstituentswherein each ofX1, X4, X5and X6is independently CH, CRw. or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, X5and X6is N; each of Y1, Y2, and Y3is independently CH,CRw, CH2, CH(Rw). C(Rw)2, NH, NRw. N, O, or S. wherein at least one of Y2and Y3is CH, CRw, CH2,CH(Rw), or C(Rw)2; and eachrepresents a single bond or a double bond.

[0064] In some embodiments, the ring containing X2, X3, Y1, Y2, and Y3is aromatic or heteroaromatic, i.e., the definitions ofY1, Y2, Y3, andare selected to satisfy valency of an aromatic or heteroaromatic ring. In some embodiments, the ring containing X2, X3, Y1, Y2, and Y3is not aromatic or heteroaromatic, i.e., the definitions ofY1, Y2, Y3, andare selected to satisfy valency of a partially unsaturated ring.

[0065] In some embodiments, Ring W and its Rwsubstituents is:

[0067] As defined above and described herein, each of X1, X4, X5, and X6is independently CH, CRw, or N. In some embodiments, each of X1, X4, X5and X6is CH or CRw. In some embodiments, each of X1,X4, and X5is CH or CRw. In some embodiments, X1is CH. In some embodiments, X1is CRw. In some embodiments, X1is N. In some embodiments, X4is CH. In some embodiments, X4is CRw. In some embodiments, X4is N. In some embodiments, X5is CH. In some embodiments, X5is CRw. In some embodiments, X5is N. In some embodiments, X6is CH. In some embodiments, X6is CRw. In some embodiments, X6is N.

[0068] As defined above and described herein, each of X2and X3is independently C or N. In some embodiments, both of X2and X3are C. In some embodiments, X2is C. In some embodiments, X2is N. In some embodiments, X3is C. In some embodiments, X3is N.

[0069] In some embodiments, X1, X4, and X5are CH or CRw, and X2and X3are C. In some embodiments, X1is N, X2and X3are C, and X4and X5are CH or CRw. In some embodiments, X1, X4, and X5are CH or CRw, X2is N, and X3are C. In some embodiments, X1, X4, and X5are CH or CRw, X2is C, and X3are N. In some embodiments. X1and X5are CH or CRw. X2and X3are C. and X4is N. In some embodiments, X1and X4are CH or CRw, X2and X3are C, and X5is N.

[0070] In some embodiments, X1, X4, X5, and X6are CH or CRw, and X2and X3are C. In some embodiments, X1is N, X2and X3are C, and X4, X5, and X6are CH or CRw. In some embodiments, X1, X4, X5, and X6are CH or CRw, X2is N, and X3are C. In some embodiments, X1, X4, X5, and Xbare CH or CRw, X2is C, and X3are N. In some embodiments, X1, X5, and X6are CH or CRw, X2and X3are C, and X4is N. In some embodiments. X1. X4. and X6are CH or CRw, X2and X3are C, and X3is N. In some embodiments, X1, X4, and X5are CH or CRw, X2and X3are C, and X6is N.

[0071] As defined above and described herein, each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2. In some embodiments, both of Y2and Y3are CH, CRw, CH2, CH(Rw), or C(Rw)2. In some embodiments, each ofY1, Y2, and Y3is independently CH. CRw. NH, NRw, N, O, or S. wherein at least one of Y2and Y3is CH or CRw. In some embodiments. Y1is CH. In some embodiments, Y1is CRw. In some embodiments, Y1is CH2. In some embodiments, Y1is CH(Rw). In some embodiments, Y1is C(Rw)2. In some embodiments, Y1is NH. In some embodiments, Y1is NRw. In some embodiments, Y1is N. In some embodiments, Y1is O. In some embodiments, Y1is S. In some embodiments, Y2is CH. In some embodiments, Y2is CRw. In some embodiments, Y2is CH2. In some embodiments, Y2is CH(Rw). In some embodiments, Y2is C(Rw)2. In some embodiments, Y2is NH. In some embodiments. Y2is NRw. In some embodiments. Y2is N. In some embodiments. Y2is O. In some embodiments. Y2is S. In some embodiments, Y3is CH. In some embodiments, Y3is CRw. In some embodiments, Y3is CH2. In some embodiments, Y3is CH(Rw). In some embodiments, Y3is C(Rw)2. In some embodiments, Y3is NH. In some embodiments, Y3is NRw. In some embodiments, Y3is N. In some embodiments, Y3is 0. In some embodiments, Y3is S.

[0072] In some embodiments, Y1is NH or NRw, and Y2and Y3are CH or CRw. In some embodiments,Y1is O, and Y2and Y3are CH or CRw. In some embodiments, Y1is S, and Y2and Y3are CH or CRw.

[0073] In some embodiments, Ring W and its Rwsubstituents is. In some

[0074] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments Ring W and its Rwsubstituents is

[0079] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments, Ring W and its Rwsubstituents is

[0080] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments, Ring W and its Rwsubstituents is

[0081] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments, Ring W and its Rwsubstituents is

[0082] In some embodiments, Ring W and its Rwsubstituents is

[0083] In some embodiments, Ring W and its Rwsubstituents

[0084] In some embodiments, Ring W and its RwsubstituentsIn some embodiments, Ring W and its Rwsubstituents i

[0085] In some embodiments. Ring W and its Rwsubstituents is

[0086] In some embodiments, Ring W and its Rwsubstituents is

[0087] In some embodiment, Ring W is as depicted in the compounds of Table 1 A, below.

[0088] In some embodiments, Ring W and its Rwsubstituents are

[0093] As described above and defined herein, Ring X and its Rxsubstituents isorrepresents a bond to Ring W, andrepresents a bond to Lxor to the rest of the molecule.

[0094] In some embodiments. Ring X and its Rxsubstituents isIn some embodiments. Ring X and its Rxsubstituents isIn some embodiments, Ring X and its Rxsubstituents isIn some embodiments, Ring X and its Rxsubstituents is

[0095] In some embodiment, Ring X is as depicted in the compounds of Table 1 A, below.

[0099] As described above and defined herein, Ring Y is a ring selected from phenyl, naphthyl, 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0100] In some embodiments, Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0101] In some embodiments. Ring Y is a ring selected from naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic hetcroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0102] In some embodiments, Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0103] In some embodiments, Ring Y is phenyl. In some embodiments, Ring Y is naphthyl. In some embodiments, Ring Y is a 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl. In some embodiments, Ring Y is a 5-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, Ring Y is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is cyclopropyl. In some embodiments, Ring Y is cyclobutyl. In some embodiments, Ring Y is cyclopentyl. In some embodiments. Ring Y is hexyl.

[0105] In some embodiments, Ring Y is a 5-6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 6-7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 3 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 4 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 5 membered saturated or partially unsaturatedmonocyclic carbocyclyl. In some embodiments. Ring Y is a 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0106] In some embodiments, Ring Y is a 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl.

[0107] In some embodiments. Ring Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring Y is a 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0108] In some embodiments, Ring Y is a 5 -membered monocyclic heteroary l ring with 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 5 -membered monocyclic heteroaryl ring with 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5 -membered monocyclic heteroaiy 1 ring with 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered monocyclic heteroaryl ring with 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered monocyclic heteroaryl ring with 2-3 nitrogen heteroatoms.

[0109] In some embodiments, Ring Y is a 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 6-membered monocyclic heteroaryl with 1-4 nitrogen heteroatoms. In some embodiments, Ring Y is pyridinyl, pyrimidinyl, pyridazinyl, ortriazinyl.

[0110] In some embodiments, Ring Y is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] In some embodiments, Ring Y is an 8-11 membered saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 8-11 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 9-10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected form nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 9 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 10 membered saturated or partially unsaturated bicyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is tetrahydroisoquinolinyl ortetrahydroquinolinyl .

[0112] In some embodiments, Ring Y is a 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring Y is a 9-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 9 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 9 membered bicyclic heteroaryl with 1-4 nitrogen heteroatoms.

[0116] In some embodiment, Ring Y is

[0117] In some embodiment. Ring Y is as depicted in the compounds of Table 1A. below.

[0118] In some embodiments. Ring Y and its Rysubstituents are

[0119] In some embodiments, Ring Y and its Rysubstituents are

[0120] In some embodiments, Ring Y is

[0121] In some embodiments, Ring Y and its Rysubstituents are

[0122] As described above and defined herein. Rxand Ryare independently selected from hydrogen,RA, halogen, -CN. -NO2. -OR -SR -NR2.SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2,-C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0123] In some embodiments, Rxand Ryare independently selected from RA, halogen, -CN, -NO2, - OR -SR -NR2, -SiR3. -S(O)R -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R. -C(O)OR - C(O)NR2. -C(O)NR0R, -OC(O)R -OC(O)NR2, -P(O)R2. -P(O)(OR)2. -OP(O)R2. -OP(O)(OR)2. - NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0124] As described above and defined herein, each Rwis independently selected from hydrogen, RA,RB, halogen, -CN, -NO2, -OR -SR -NR2,SiR3, -S(O)R, -S(O)2R -S(O)(NR)R, -S(O)2NR2, -C(O)R -C(O)OR,C(O)NR2, -C(O)NR0R, -OC(O)R -OC(O)NR2, -P(O)R2. -P(O)(OR)2. -OP(O)R2. -OP(O)(OR)2. -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0125] In some embodiments, each Rwis independently selected from hydrogen, RA, halogen, -CN, - NO2, -OR, -SR, -NR2, -SIR3, -S(O)R, -S(O)2R -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, - NRC(O)OR -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0126] In some embodiments, each Rwis independently selected from RA, RB, halogen, -CN, -NO2, - OR, -SR, -NR2, -SIR3, -S(O)R -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, - C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, - NRC(O)OR -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0127] In some embodiments, one or more of Rw. Rx, and Ryis hydrogen. In some embodiments, one or more of Rw. Rx, and Ryis RA. In some embodiments, one or more of Rw, Rx, and Ryis halogen. In some embodiments, one or more of Rw, Rx, and Ryis -CN. In some embodiments, one or more of Rw, Rx, and Ryis -NO2. In some embodiments, one or more of Rw, Rx, and Ryis -OR. In some embodiments, one or more of Rw, Rx, and Ryis -SR. In some embodiments, one or more of Rw, Rx, and Ryis -NR2. In some embodiments, one or more of Rw, Rx, and Ryis -SiR3. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)2R. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)2NR2. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)(NR)R. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)OR. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)NR2. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)NROR. In some embodiments, one or more of Rw, Rx, and Ryis -OC(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -OC(O)NR2. In some embodiments, one or more of Rw, Rx, and Ryis -OP(O)R2. In some embodiments, one or more of Rw, Rx, and Ryis -OP(O)(OR)2. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)OR. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)N(R)2. In some embodiments, one or more of Rw, Rx, and Ryis -NRS(O)2R.

[0128] In some embodiments, Rw-C(O)OR. In some embodiments, Rwis -C(O)NR2. In some embodiments, Rwis an optionally substituted phenyl. In some embodiments, Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0129] In some embodiments, Rwis RB. In some embodiments, Rwis RA.

[0130] In some embodiments, Rwis fluoro, chloro, or bromo.

[0131] In some embodiments, Rwis -C(O)NHR. In some embodiments, Rwis -C(O)NHR, wherein R of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NHR, wherein R of RwisC1-6aliphatic, optionally substituted with -CN.

[0132] In some embodiments, Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic, optionally substituted with -C(O)N(R°)2. In some embodiments, Rwis C1-6aliphatic, optionally substituted with -NR°(O)N(R°)2. In some embodiments, Rwis. In some such embodiments, R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, Rwis -CH2F, -CHF2, or -CF3.

[0133] In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, Rwis. In some embodiments. Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) or -NR°2. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) and -NR°2. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) or -NR°2, wherein each R° is independently hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) and -NR°2, wherein eachR° is independently hydrogen or C1-6aliphatic. In some embodiments, Rwis

[0134] In some embodiments, Rwis an optionally substituted phenyl.

[0135] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments. R” is an optionally substituted cyclopropyl. In some embodiments, Rwis an optionally substituted cyclobutyl. In some embodiments, Rwis an optionally substituted cyclopentyl. In some embodiments, Rwis an optionally substituted cyclohexyl. In some embodiments, Rwis an optionally substituted cyclopropenyl. In some embodiments, Rwis an optionally substituted cyclobutenyl. In some embodiments, Rwis an optionally substituted cyclopentenyl. In some embodiments, Rwis an optionally substituted cyclohexenyl.

[0136] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, Rwis an optionally substituted 4 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted azetidinyl, oxetanyl, or thietanyl.

[0138] In some embodiments, Rwis an optionally substituted 5 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis an optionally substituted pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl. or imidazolinyl. In some embodiments, Rwis an optionally substituted dihydropyridinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, or tetrahydrothiophenyl .

[0139] In some embodiments, Rwis an optionally substituted 6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyl. 4H-pyranyl, 1,4-dioxanyl, 1,4-dioxinyl. thianyl. 2H-thiopyranyl, 4H-thiopyranyl, 1.3-dithanyl, 1,4-dithanyl, morpholinyl, or thiomorpholinyl. In some embodiments, Rwis an optionally substituted dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, or tetrahydrothiopyranyl .

[0140] In some embodiments, Rwis an optionally substitutedIn some embodiments, RwisRwis. In some embodiments, Wmis 0. In some embodiments. Wmis S. In some embodiments,Wmis C(O). In some embodiments, Wmis NR°. In some embodiments, Wmis NR°, wherein R° is hydrogen or C1-6aliphatic.

[0141] In some embodiments, Rwis an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Rwis an optionally substituted imidazolyl, optionally substituted with -C(O)N(R°)2. In some embodiments, Rwis an optionally substituted furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, Rwis furanyl, optionally substituted with -C(O)N(R°)2.

[0142] In some embodiments Rwis an optionally substituted 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted 6 membered heteroaryl having 1-4 nitrogen heteroatoms. In some embodiments, Rwis optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, Rwis an optionally substituted pyridinonyl, pyrazinonyl, or pyrimidinoyl.

[0143] In some embodiments, Rwis -NHR, wherein R is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis -NHR. wherein R is an optionally substituted 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments, Rwis -S(O)2NH2. In some embodiments, Rwis -S(O)2NHR, wherein R is an optionally substituted C1-6aliphatic. In embodiments, Rwis S(O)2NHR, wherein R is an optionally substituted phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0145] In embodiments, Rwis -S(O)2(NH)R. In some embodiments, Rwis -S(O)2(NH)H. In some embodiments, Rwis -S(O)2(NH)R, wherein R is an optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)2(NH)R, wherein R is an optionally substituted phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0146] In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2.-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, - OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R. In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR,-C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2. or - NRS(O)2R. In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, or -NRS(O)2R. In some embodiments. Rwis -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, or -NRC(O)N(R)2. In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, or -C(O)NROR. In some embodiments, Rwis -C(O)R, -C(O)OR, or -C(O)NR2.

[0147] In some embodiments, Rwis -C(O)H. In some embodiments, Rwis -C(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)R. wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0148] In some embodiments, Rwis -C(O)R, wherein Ris of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0149] In some embodiments, Rwis -C(O)OH. In some embodiments. Rwis -C(O)OR, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0150] In some embodiments, Rwis -C(O)NH2. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0151] In some embodiments, Rwis -C(O)NHR, wherein R is an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NHR, wherein R is C1-6aliphatic. In some embodiments. Rwis - C(O)NHR, wherein R is methyl, ethyl, or cyclopropyl. In some embodiments, Rwis -C(O)NR2, wherein the two R groups of Rware taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected form nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NR2, wherein the two R groups of Rware taken together with their intervening atoms to fonn a 3-7 membered saturated or partially unsaturated monocyclic ring having 0 heteroatoms, in addition to the atom or adjacent atoms to which they are attached. In some embodiments, Rwis -C(O)NR2, wherein the two R groups of Rware taken together with their intervening atoms to form an aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, or piperidinyl.

[0152] In some embodiments, Rwis -C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments. Rwis - C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0153] In some embodiments, Rwis -OC(O)H. In some embodiments. Rwis -OC(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0154] In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0155] In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis - NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0156] In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis -NRC(O)R. wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0157] In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRC(O)N(R)2. wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0158] In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments. Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogenor an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0159] In some embodiments, Rwis -S(O)H. In some embodiments, Rwis -S(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -S(O)R, wherein R is of Rwis an optionally substituted 4- 7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0160] In some embodiments, Rwis -S(O)2H. In some embodiments, Rwis -S(O)2R. wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)2R, wherein R is of Rwis optionally substituted phenyl. In some embodiments. Rwis -S(O)2R. wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)2R, wherein R is of Rwis an optionally substituted 5-6 membered heteroary l ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0161] In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)(NR)R. wherein each R is of Rwis independently hydrogen or optionally substituted phenyl. In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)(NR)R. wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0162] In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis -S(O)2NR2. wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0163] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, Rwis an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, Rwis an optionally substituted:

[0164] In some embodiments, Rwis:In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0165] In some embodiments, Rwis:

[0166] In some embodiments, Rwis an optionally substituted:

[0167] In some embodiments, Rwis:wherein Ring W1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] As defined above and described herein. Ring W1is an optionally substituted 3-7 memberedsaturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring W1is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 5 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0169] In some embodiments, Rwis:

[0170] In some embodiments, Rwis:wherein Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring, or a 5- 6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0171] As defined above and described herein, Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring. In some embodiments, Ring W2is an optionally substituted 5-6 membered partially unsaturated heterocyclic ring. In some embodiments, Ring W2is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W2is a 5 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W2is an optionally substitutedoxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, 2-imidazolinyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl.

[0172] In some embodiments, Rwis an optionally substituted ring selected from:

[0173] In some embodiments, Rwis:wherein each Rº is a defined above and described herein (e.g.. hydrogen or C1-6aliphatic).

[0174] In some embodiments, Rwis:

[0175] In some embodiments Rwis an optionally substituted 7-11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted 9-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted benzo[d][l,3]dioxolyL In some embodiments Rwis an optionally substituted an 11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0176] In some embodiments Rwis an optionally substituted 8-11 membered bicyclic arx l or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rwis an optionally substituted naphthal enyl. In some embodiments, Rwis an optionally substituted dihydrobenzodioxepinyl. In some embodiments, Rwis an optionally substituted indenyl or dihydroindenyl.

[0177] In some embodiments, Rwis an optionally substituted 9-10 membered bicyclic heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0178] In some embodiments Rwis an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments Rwis an optionally substituted indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, thienopyridinyl, pyrrolo[3,2-d]pyridinyl, pyrrolo[2,3,-b?]pyridinyl, pyrazolyl[ 1,5-a]pyridinyl, or imidazo[l,2-a]pyridinyl, azaindazolyl (e.g., 4-, 5-, 6-, or 7-azaindazolyl). pyrrolol[2.3-c]pyridinyl or indolizinyl.

[0179] In some embodiments Rwis an optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments Rwis an optionally substituted quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl. quinazolinyl, cinnolinyl, or 1,8-naphthyridinyl.

[0180] In some embodiments. Rwis fluoro, chloro, -CN, -OH, -OMe, -OCH2CO2Me. -CO2H, - C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, -C(O)NMe2, -C(O)N(Me)Et, - C(O)N(Me)nPr, -CH2NHMe,

[0181] In some embodiments, Rwis fluoro, chloro, -CN, methyl, -CF3, -CHF2, -OH, -OMe, - OCH2CO2Me, -CO2H, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, -C(O)NMe2, -C(O)N(Me)Et, -C(O)N(Me)nPr, -CH2NHMe,

[0182] In some embodiments, Rwis

[0183] In some embodiments, Rwis -S(O)2NH2, -S(O)2N(CH3)2, -S(O)(NH)CH3,

[0184] In some embodiments, Rwis

[0185] In some embodiments, Rwis

[0186] In some embodiments, Rwis -CH2CH2CH3,

[0188] In some embodiments, Rwis -C(O)NH2. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0190] In some embodiments, each Rxis independently selected from RA, halogen, -CN, -NO2, -OR, - SR, -NR2, -SIR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2,-C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0191] In some embodiments, Rxis -CO2Me. or -CH2OH.

[0192] In some embodiments, Rxis -C(O)R or -C(O)OR. In some embodiments, Rxis -C(O)R. In some embodiments, Rxis -C(O)R, wherein R of Rxis an optionally substituted C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic optionally substituted with -C(O)OR°, -OR°, halogen (e.g., fluoro), or =O. In some embodiments, Rxis -C(O)OR. In some embodiments, Rxis -C(O)OR, wherein R of Rxis an optionally substituted C1-6aliphatic.

[0194] In some embodiments, Rxis optionally substituted C1-6aliphatic. In some embodiments, RxisC1-6aliphatic optionally substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic.

[0195] In some embodiments, Rxis -CO2Me, -CH2OH, -C(O)Me, -C(O)Et. -C(O)iPr, -C(O)cyclopropyl, -C(O)oxetanyl, -C(O)tetrahydropyranyl, or pyridyl.

[0196] In some embodiments, Rxis fluoro. In some embodiments, Rxis -S(O)2CH3. In some embodiments, Rxis -C(O)N(CH3)2.

[0197] In some embodiments, Rxis -C(O)R, wherein R of Rxis optionally substituted C1-6aliphatic. In some embodiments. Rxis -C(O)R. wherein R of Rxis C1-6aliphatic. In some embodiments, Rxis -C(O)R,wherein R of Rxis methyl, ethyl, n-propyl, or isopropyl. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -OR° or -C(O)OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -C(O)OR°, wherein R° is hydrogen or C1-6aliphatic.

[0198] In some embodiments, Rxis

[0199] In some embodiments, each Ryis independently selected from RA, halogen, -CN, -NO2, -OR, - SR, -NR2, -SiR3. -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0200] In some embodiments, Ryis fluoro, chloro, bromo, iodo, methyl, ethyl, cyclopropyl, -CF3, - CN, CH2O, -CO2H, -CO2Me, -CO2tBu, -C(O)Me, -NH2, -NHMe, -NHAc, -NHC(O)Et, -OH, -OMe, - OCH2CH2NH2, -CH2OH, -CH2OMe, -CH2NHMe, -CH2NHAc, -CH2SO2Me, -SO2Me, -SO2NH2, -SO2NHMe,

[0201] In some embodiments, Ryis -C(O)H.

[0202] In some embodiment, Rw, Rx, and Ryare as depicted in the compounds of Table 1A, below.

[0203] As described above and defined herein, each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, RAis an optionally substituted C1-6aliphatic. In some embodiments, RAis an optionally substituted phenyl. In some embodiments, RAis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, RAis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RAis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

[0205] In some embodiments, RAis C1-6alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, RAis C1-6haloalkyl (e.g., -CF3, -CHF2).

[0206] In some embodiment, RAis as depicted in the compounds of Table 1 A, below.

[0207] As described above and defined herein, each RBis independently -LB-CyB1-H or -LB-CyB1- CyB2.

[0208] In some embodiments, RBis -LB-CyB1-H. In some embodiments, RBis -LB-CyB1-CyB2.

[0210] In some embodiments. RBisIn some embodiments, RBis

[0211] In some embodiments, RBis. In some embodiments, RBisembodiments, RBis

[0212] In some embodiments, RBis as depicted in the compounds of Table 1A, below.

[0216] As described above and defined herein, each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, - CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-.

[0217] In some embodiments, each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-.

[0218] In some embodiments, LBis a covalent bond. In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR- . -S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-. In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -NR-, -S-, -S(O)-, or -S(O)2-. In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, or -NR-. In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-, -C(O)-, -NR-, -S-. -S(O)-, or -S(O)2- . In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-, -C(O)-, or -NR-. In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1 methylene unit of the chain is replaced with -C(O)-. In some embodiments, LBis -C(O)-.

[0219] In some embodiments, LBis a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain. In some embodiments, LBis -CH2-.

[0220] In some embodiments, LBis -C(O)-. -C(S)-, -C(NR)R-, -S(O)-. -S(O)2- or -S(O)(NR)-. In some embodiments, LBis -C(O)-, -C(S)-, or -C(NR)R-. In some embodiments, LBis -C(O)-, — S(O)-, -S(O)2- or -S(O)(NR)-. In some embodiments, LBis -C(S)-. In some embodiments, LBis -C(NR)R-. In some embodiments, LBis -S(O)-. In some embodiments, LBis -S(O)2-. In some embodiments, LBis -S(O)(NR)-

[0221] As described above and defined herein, each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl. heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0222] In some embodiments, each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylcnyl or hcteroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0223] It will be appreciated that all embodiments to CyB1may refer to a terminal ring (or otherwise optionally substituted ring) in structures with -LB-CyB1(i.e., when RBis -LB-CyB1-H), or a ring further connected to CyB2as in structures -LB-CyB1-CyB2, regardless of how presented. By way of example, an embodiment to CyB1is phenylenyl, refers to phenylenyl in -LB-CyB1-CyB2, and phenyl in -LB-CyB1-H.Similarly, an embodiment to CyB1isrefers toin -LB-CyB1-CyB2, andin -LB-CyB1-H. Similarly, an embodiment to CyB1isin -LB-CyB1-CyB2, andin -LB-CyB1-H.

[0224] In some embodiments, each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0225] In some embodiments, CyB1is optionally substituted phenylenyl. In some embodiments, CyB1is phenylenyl.

[0226] In some embodiments, CyB1is optionally substituted 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is optionally substituted 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0227] In some embodiments, CyB1is optionally substituted 3-7 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is optionally substituted 6-membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is optionally substituted 6-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is optionally substituted 6-membered saturated or partially unsaturated heterocyclylenyl having 1-2 nitrogen heteroatoms. In some embodiments, CyB1is optionally substituted piperadinylenyl or piperazinylenyl.

[0228] In some embodiments, CyB1is a 3-7 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, CyB1is a 6-membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is a 6- membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is a 6-membered saturated or partially unsaturated heterocyclylenyl having 1-2 nitrogen heteroatoms. In some embodiments, CyB1is a piperadinylenyl or piperazinylenyl. In some embodiments, CyB1is

[0229] In some embodiments, CyB1is an optionally substituted piperidinonyl or piperazinonyl. In some embodiments, CyB1is an optionally substituted dihydropyridinyl. In some embodiments, CyB1is an optionally substituted thiomorpholinyl.

[0230] In some embodiments, CyB1is optionally substituted morpholinyl.

[0231] In some embodiments, CyB1is a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0232] In some embodiments, CyB1is an optionally substituted 8-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 8-membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 8-membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 8-membered saturated or partially unsaturated heterocyclylenyl having 1-2 nitrogen heteroatoms. In some embodiments, CyB1is optionally substitutedIn some embodiments, CyB1is an optionally substituted

[0233] In some embodiments, CyB1is optionally substituted indazolyl. In some embodiments, CyB1is optionally substituted pyrrolo[2,3-b]pyridine.

[0234] In some embodiments, CyB1is an optionally substituted 5-6 membered monocyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 6 membered monocyclic heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted pyridinonyl, pyrazinonyl, or pyrimidinoyl.

[0235] In some embodiments, CyB1is optionally substituted furanyl. In some embodiments, CyB1is optionally substituted isoxazolyl. In some embodiments, CyB1is optionally substituted pyrrolyl. In some embodiments, CyB1is optionally substituted pyridinonyl. In some embodiments, CyB1is optionally substituted pyridazinyl. In some embodiments, CyB1is an optionally substituted 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0236] In some embodiments, CyB1is an optionally substituted 10-15 membered saturated or partially saturated tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 10-15 membered saturated or partially saturated tricyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is an optionally substituted 10-15 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0237] In some embodiments, CyB1is a 13-membered saturated or partially saturated tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB1is a 15-membered saturated or partially saturated tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0238] As described above and defined herein, each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0239] In some embodiments, each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1 -4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0240] In some embodiments, each CyB2is independently an optionally ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0241] In some embodiments, CyB2is optionally substituted phenyl. In some embodiments, CyB2is phenyl. In some embodiments, CyB2is phenyl, optionally substituted with -CN, halogen, -R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic.

[0242] In some embodiments, CyB2is optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0243] In some embodiments, CyB2is optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, CyB2is optionally substituted cyclopropyl. In some embodiments, CyB2is cyclopropyl. In some embodiments, CyB2is optionally substituted cyclobutyl. In some embodiments, CyB2is cyclobutyl.

[0244] In some embodiments, CyB2is optionally substituted cyclopentyl. In some embodiments, CyB2is cyclopentyl. In some embodiments, CyB2is optionally substituted cyclohexyl. In some embodiments, CyB2is cyclohexyl.

[0245] In some embodiments, CyB2is optionally substituted 5-10 membered monocyclic or bicyclic and or heteroary l with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0246] In some embodiments, CyB2is optionally substituted 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted 5-6 membered monocyclic heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted pyridinyl. In some embodiments, CyB2is pyridinyl, optionally substituted with -CN, halogen, -R°, -OR°, -N(R°); - C(O)OR°, wherein each R° is independently hydrogen; C1-6aliphatic, which may be optionally substituted with halogen, -(CH2)0-2OH. or -(CH2)0-2OR●. where R●is C1-4aliphatic; or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur (e.g., phenyl or morpholinyl).

[0247] In some embodiments, CyB2is optionally substituted 6 membered monocyclic heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl.

[0248] In some embodiments. CyB2is optionally substituted optionally substituted pyridinonyl, pyrazinonyl, or pyrimidinoyl

[0249] In some embodiments, CyB2is optionally substituted 5 membered monocyclic heteroaryl with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted pyrazolyl, imidazolyl, or triazolyl.

[0250] In some embodiments, CyB2is optionally substituted 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0251] In some embodiments, CyB2is optionally substituted 9-membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted 9-membered bicyclic heteroaryl with 1-4 nitrogen heteroatoms. In some embodiments, CyB2is optionally substituted benzimidazolyl, indazolyl, or azaindolyl (e.g., pyrrolo[2,3- c]pyridinyl or pyrrolo]2,3-b]pyridinyl). In some embodiments, CyB2is benzimidazolyl indazolyl, or azaindolyl (e.g., pyrrolo[2.3-c]pyridinyl or pyrrolo]2.3-b]pyridinyl) optionally substituted with -CN, halogen or -R°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, CyB2is optionally substituted indolyl or azaindolyl.

[0252] In some embodiments, CyB2is optionally substituted [l,2,4]triazolo[4,3-a]pyridinyl.

[0253] In some embodiments, CyB2is optionally substituted 10-membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, CyB2is optionally substituted 10-membered bicyclic heteroaryl with 1-4 nitrogen heteroatoms. In some embodiments, CyB2is optionally substituted quinoxalinyl, isoquinolinyl, 2,6-naphthyridinyl, or 2,7- naphthyridinyl. hr some embodiments, CyB2is quinoxalinyl, isoquinolinyl, 2,6-naphthyridinyl, or 2,7- naphthyridinyl, optionally substituted with -R°, wherein R° is hydrogen or C1-6aliphatic.

[0254] In some embodiments, CyB2is optionally substituted naphthalenyl. In some embodiments, CyB2is naphthalenyl, optionally substituted with -R° or -OR°, wherein R° is hydrogen or C1-6aliphatic.

[0255] In some embodiments, CyB2is optionally substituted benzo[d][l,3]dioxolyl.

[0256] In some embodiments, CyB2is

[0257] In some embodiments, CyB2is an optionally substituted 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0258] In some embodiments, CyB2is an optionally substituted 10-15 membered saturated or partially saturated tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB2is an optionally substituted 10-15 membered saturated or partially saturated tricyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB2is an optionally substituted 10-15 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0259] In some embodiments. CyB2is a 13 membered saturated or partially saturated tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, CyB2is a 15 membered saturated or partially saturated tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0260] As described above and defined herein, each R is independently hydrogen, or an optionallysubstituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0261] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-6aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur.

[0262] In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3 membered saturated or partially unsaturated carbocyclic ring.

[0263] In some embodiments, R is as depicted in the compounds of Table 1 A, below.

[0264] As decided above and defined herein, Lxiswhereinrepresents a bond to Ring Y.

[0265] In some embodiments, Lxiswhereinrepresents a bond to Ring Y.

[0266] In some embodiments, Lxis -C(O)(CH2)1-3-represents a bond to Ring Y.

[0268] In some embodiments, Lxis -C(O)-, -C(O)CH2-, -S(O)2CH2-, -C(O)CH2CH2-, -C(O)OCH2-, -

[0269] In some embodiments, Lxis

[0270] In some embodiments, Lxis -C(O)CH2CH2-.

[0271] In some embodiments, Lxis -S(O)2CH2CH2-.

[0272] In some embodiment, Lxis as depicted in the compounds of Table 1A, below.

[0273] As described above and defined herein. Rzis RA. -OR, or -NR2. In some embodiments, RzisRA. In some embodiments, Rzis -OR. In some embodiments, Rzis -NR2.

[0274] As described above and defined herein, each of w, x, y, and z are independently 0, 1, 2, 3, or 4.

[0275] In some embodiments, one or more of w, x, and y is 0. In some embodiments, one or more of w, x, and y is 1. In some embodiments, one or more of w, x, and y is 2. In some embodiments, one or more of w, x, and y is 3. In some embodiments, one or more of w, x, and y is 4.

[0276] In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4.

[0277] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0278] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4.

[0279] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 1, 2, or 3. In some embodiments, z is 2, 3, or 4.

[0280] In some embodiment, w, x, y, and z are as depicted in the compounds of Table 1 A, below.

[0281] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula I-a-1 or La-2:or a pharmaceutically acceptable salt thereof, wherein Ring X, Ring Y, Rw. Rx. Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0282] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula La-3 or La-4:or a pharmaceutically acceptable salt thereof, wherein Ring X, Ring Y, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0283] In certain embodiments, the present invention provides methods of use related to a compound of fonnula I, wherein the compound is of formula La-5 or La-6:or a pharmaceutically acceptable salt thereof, wherein Ring X, Ring Y, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0284] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula La-7 :or a pharmaceutically acceptable salt thereof, wherein Ring W, Ring X, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0285] In certain embodiments, the present invention provides methods of use related to a compound of fonnula I, wherein the compound is of fonnula La-8:or a pharmaceutically acceptable salt thereof, wherein Ring W, Ring X, Ring Y, Rw, Rx, Ry, w, x, and y are as defined above and described herein both individually and in combination.

[0286] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula I-a-9 or I-a-10:or a pharmaceutically acceptable salt thereof, wherein Ring Y, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0287] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula La-11 or La-12:or a pharmaceutically acceptable salt thereof, wherein Ring Y, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0288] In certain embodiments, the present invention provides methods of use related to a compound of fonnula I, wherein the compound is of formula La-13 or La-14:or a pharmaceutically acceptable salt thereof, wherein Ring Y, Rw, Rx, Ry, Lx, w, x, and y are as defined above and described herein both individually and in combination.

[0289] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula I-a-15:or a pharmaceutically acceptable salt thereof, wherein Ring W. Ring Y. Rw. Rx, Ry, w. x, and y are as defined above and described herein both individually and in combination.

[0290] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of formula I-a-16:or a pharmaceutically acceptable salt thereof, wherein Ring W, Rw, Rx, Ry, w, x, and y are as defined above and described herein both individually and in combination.

[0291] In certain embodiments, the present invention provides methods of use related to a compound of fonnula I, wherein the compound is of one of formula I-a-la, I-a-2a, I-a-lb, or I-a-2b:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described herein both individually and in combination, and wherein:Rwis Rw, wherein Rwis as defined above and described herein both individually and in combination.

[0292] In some embodiments, Rwis an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0293] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Rwis an optionally substituted cyclopropyl. In some embodiments. Rvvis an optionally substituted cyclobutyl. In some embodiments, Rwis an optionally substituted cyclopentyl. In some embodiments, Rwis an optionally substituted cyclohexyl. In some embodiments, Rwis an optionally substituted cyclopropenyl. In some embodiments, Rwis an optionally substituted cyclobutenyl. In some embodiments, Rwis an optionally substituted cyclopentenyl. In some embodiments, Rwis an optionally substituted cyclohexenyl.

[0294] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0295] In some embodiments, Rwis an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis an optionally substituted azetidinyl, oxetanyl, or thietanyl.

[0296] In some embodiments, Rwis an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, or imidazolinyl. In some embodiments. Rwis an optionally substituted dihydropyridinyl, pyrrolidinyl. dihydrofuranyl. tetrahydrofuranyl, dihydrothiophenyl. or tetrahydrothiophenyl .

[0297] In some embodiments, Rwis an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,4-dioxinyl, thianyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,3-dithanyl, 1,4-dithanyl, morpholinyl, or thiomorpholinyl. In some embodiments, Rwis an optionally substituted dihydropyridinyl, tetrahydropyridinyl. dihydropyranyl, tetrahydropyranyl. dihydrothiopyranyl. or tetrahydrothiopyranyl .

[0298] In some embodiments, Rwis an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5 -membered heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Rwis an optionally substituted imidazolyl, optionally substituted with -C(O)N(R°)2. In some embodiments, Rwis an optionally substituted furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, Rwis furanyl, optionally substituted with -C(O)N(R°)2.

[0299] In some embodiments, Rwis an optionally substituted 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 6 membered hcteroaryl having 1-4 nitrogen heteroatoms. In some embodiments, Rwis optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, Rwis an optionally substituted pyridinonyl, pyrazinonyl, or pyrimidinoyl.

[0300] In some embodiments, Rwis an optionally substituted 7-11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 9-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted benzo[d][l,3]dioxolyl. In some embodiments, Rwis an optionally substituted an 11- membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0301] In some embodiments. Rwis an optionally substituted 8-11 membered bicyclic and or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rwis an optionally substituted naphthalenyl. In some embodiments, Rwis an optionally substituted dihydrobenzodioxepinyl. In some embodiments, Rwis an optionally substituted indenyl or dihydroindenyl.

[0302] In some embodiments, Rwis an optionally substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0303] In some embodiments, Rwis an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rwis an optionally substituted indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, thienopyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[2,3,-b]pyridinyl, pyrazolyl[l,5-a]pyridinyl, or imidazo[l,2-a]pyridinyl, azaindazolyl (e.g., 4-, 5-, 6-, or 7-azaindazolyl), pyrrolol[2.3-c]pyridinyl or indolizinyl.

[0304] In some embodiments, Rwis an optionally substituted 10-membered bicyclic hcteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rwis an optionally substituted quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, or 1,8-naphthyridinyl.

[0308] In some embodiments, Rwis an optionally substituted phenyl. In some embodiments, Rwis phenyl, optionally substituted with halogen (e.g., fluoro or chloro). -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°. wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis phenyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic.

[0309] In some embodiments, Rwis an optionally substituted 5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted pyrrolidinyl. In some embodiments, Rwis pyrrolidinyl. optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°. or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyrrolidinyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted 6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis an optionally substituted piperadinyl. In some embodiments, Rwis piperadinyl. optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°. or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis piperadinyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted piperazinyl. In some embodiments, Rwis piperazinyl, optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments. Rwis piperazinyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic.

[0310] In some embodiments, Rwis an optionally substituted 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, Rwis an optionally substituted pyrrolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments, Rwis pyrrolyl, pyrazolyl, imidazolyl, or triazolyl, optionally substituted with halogen (e.g., fluoro or chloro), -CN. C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro). -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyrrolyl, pyrazolyl, imidazolyl, or triazolyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted pyrazolyl. In some embodiments, Rwis pyrazolyl, optionally substituted withhalogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyrazolyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted imidazolyl. In some embodiments, Rwis imidazolyl, optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), or -OR°. wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis imidazolyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic.

[0311] In some embodiments, Rwis an optionally substituted 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, Rwis an optionally substituted pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some embodiments, Rwis pyridinyl, pyridazinyl. pyrimidinyl, pyrazinyl, or triazinyl. optionally substituted with halogen (e.g., fluoro or chloro). -CN. C1-6aliphatic optionally further substituted with halogen (e.g.. fluoro or chloro). -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted pyridinyl. In some embodiments, Rwis pyridinyl, optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°. wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyridinyl, optionally substituted with halogen (e.g.. fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted pyridazinyl. In some embodiments, Rwis pyridazinyl, optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyridazinyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted pyridinonyl, pyridazinonyl, pyrimidinonyl, pyrazinonyl, or triazinonyl. In some embodiments. Rwis pyridinonyl, pyridazinonyl, pyrimidinonyl, pyrazinonyl, or triazinonyl, optionally substituted with halogen (e.g., fluoro or chloro), - CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyridinonyl, pyridazinonyl, pyrimidinonyl, pyrazinonyl, or triazinonyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic. In some embodiments, Rwis an optionally substituted pyridinonyl. In some embodiments, Rwis pyridinonyl. optionally substituted with halogen (e.g., fluoro or chloro), -CN, C1-6aliphatic optionally further substituted with halogen (e.g., fluoro or chloro), -S(O)2R°, or -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis pyridinonyl, optionally substituted with halogen (e.g., fluoro or chloro) or C1-6aliphatic.

[0312] In some embodiments, Rwis an optionally substituted cyclopropyl. In some embodiments, Rwis an optionally substituted 5 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Rwis an optionally substituted cyclopentanyl or cyclopentenyl. In some embodiments, Rwis an optionally substituted 6 membered saturated or partially unsaturated carbocyclyl. In some embodiments, Rwis an optionally substituted cyclohexanyl or cyclohexenyl. In some embodiments, Rwis an optionally substituted naphthalenyl.

[0313] In some embodiments, Rwis an optionally substituted 9 membered bicyclic hcteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted indolyl, azaindolyl, isoindolyl, azaisoindolyl, indazolyl, azaindazolyl, benzimidazolyl, or azabenzimidazolyl. In some embodiments, Rwis an optionally substituted indolyl. In some embodiments. Rwis an optionally substituted benzothiophenyl, benzofuranyl, isobenzofuranyl, benzoisooxazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl, or benzothiadiazolyl.

[0314] In some embodiments, Rwis an optionally substituted 8-11 membered saturated or partially unsaturated spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 9-11 membered saturated or partially unsaturated spiro heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 9 membered saturated or partially unsaturated spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis an optionally substituted 9 membered saturated or partially unsaturated spiro heterocyclyl having 1-3 nitrogen heteroatoms. In some embodiments, Rwis an optionally substituted 4,6- spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0315] In some embodiments, Rwis an optionally substituted 10 membered saturated or partially unsaturated spiro heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 10 membered saturated or partially unsaturated spiro heterocyclyl having 1-3 nitrogen heteroatoms. In some embodiments, Rwis an optionally substituted 5,6-spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0316] In some embodiments, Rwis an optionally substituted 11 membered saturated or partially unsaturated spiro heterocyclyl having 1 -3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 11 membered saturated or partially unsaturated spiro heterocyclyl having 1-3 nitrogen heteroatoms. In some embodiments, Rwis an optionally substituted 6,6-spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0317] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of one of formula I-b-1 through I-b-6:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described herein both individually and in combination.

[0318] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of one of fonnula I-c-1 through I-c-6:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described herein both individually and in combination.

[0319] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of one of formula I-d-1 through I-d-6:or a pharmacally acceptable salt thereof, wherein each variable is as defined above and described herein both individually and in combination.

[0320] In certain embodiments, the present invention provides methods of use related to a compound of formula I, wherein the compound is of one of fonnula I-e-1 through I-e-6:or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described herein both individually and in combination.

[0321] Exemplary compounds for use in provided methods of the invention are set forth in Table 1A and Table 2A, below.Table 1A. Exemplary CompoundsTable 2A. Exemplary Compounds

[0322] In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound set forth in Table 1A, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound set forth in Table 1A, above.

[0323] In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound set forth in Table 1A, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound set forth in Table 1A, above.

[0324] In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound set forth in Table 2A, above, or a pharmacally acceptable salt thereof. In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound set forth in Table 2 A, above.

[0325] In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound set forth in Table 2A, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound set forth in Table 2 A, above.

[0326] In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound described herein (e.g., a compound of formula I, I’, II, III, or IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods of inhibiting STAT6, or a mutant thereof, comprising administering a compound described herein (e.g., a compound of fonnula I, I’, II, III, or IV).

[0327] In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound described herein (e.g., a compound of formula I, I’, II, III, or IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides methods of treating a STAT6-mediated disease, disorder, or condition described herein, comprising administering a compound described herein (e.g., a compound of formula I, I’, II. III. or IV).

[0328] In some embodiments, the present invention provides a compound described herein (such as a compound of formula 1, 1’, II, III, or IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (such as a compound of fonnula I, I’, II, III, or IV), or a pharmaceutically acceptable salt thereof, and a pharmacally acceptable carrier, adjuvant, or vehicle for use as a medicament for inhibiting STAT6, or a mutant thereof. In some embodiments, the presentinvention provides a compound described herein (such as a compound of formula I, I’, II, III, or IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein (such as a compound of formula I, I’, II, III, or IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament for treating a STAT6-mediated disease, disorder, or condition described herein.

[0329] In some embodiments, the invention also provides a compound described herein (such as a compound of formula I, I’, II, III, or IV), or pharmaceutical compositions described herein, for use in a method for modulating (e.g., inhibiting) STAT6 as described herein. In some embodiments, the invention also provides a compound described herein (such as a compound of formula I, I’, II, III, or IV), or pharmaceutical compositions described herein, for use in a method for treating a STAT6-mediated disorder as described herein.Uses o f Compounds and Pharmaceutically Acceptable Compositions

[0330] Compounds and compositions described herein are generally useful for the modulation of STAT6 protein activity including phosphorylated or activated STAT6 protein (e.g., pSTAT6) activity.

[0331] According to one embodiment, the invention relates to a method of modulating (e.g., inhibiting) STAT6 or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[0332] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, the STAT6 is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0333] Inhibition of STAT6, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0334] According to another embodiment, the invention relates to a method of modulating (e.g., inhibiting) STAT6, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by STAT6 or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0335] The activity of a compound utilized in this invention as a modulator (e.g., inhibitor) of STAT6 or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays thatdetermine inhibition of either the activity and / or the subsequent functional consequences of activated STAT6 protein or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to STAT6 protein. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / STAT6 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be detennined by running a competition experiment where new inhibitors are incubated with STAT6 protein bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as a modulator (e.g., inhibitor) of STAT proteins, or a mutant thereof, are set forth in the Examples below.

[0336] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a histon 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.

[0337] Provided compounds are modulators (e.g., inhibitors) of STAT6 protein and are therefore useful for treating one or more disorders associated with activity of STAT6 protein. Tirus, in certain embodiments, the present invention provides a method for treating a STAT6-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

[0338] 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 invention 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.

[0339] STAT6 functions as a transcription factor to induce gene expression and plays an important role in the IL-4 / IL-13 signaling pathway and thus is critical in IL-4 / IL-13 mediated biological responses including in human malignancies (e.g., Patel, B.K.R., et al. "Localization of the human stat6 gene to chromosome 12q 13. 3-ql4. 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 (Th 2) cells and Th2 immune response and plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma (e.g., Walford, H. H. and Doherty, T. A. “STAT6 and lung inflammation.” Jak-stat 2.4 (2013): e25301). It has been found that STAT6 induces the expression of BCL2L1 / BCL-X(L), which is responsible for the anti-apoptotic activity of IL-4 and is shown to play a prominent role in adaptive immunity such as providing innate immunesignaling in response to virus infection (e.g., Chen, II , et al, '‘Activation of STAT6 by STING is critical for antiviral innate immunity,” Cell 147.2 (2011): 436-446). Knockout studies in mice have suggested the role STAT6 in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins. STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation. STAT6 is also required for the development of IL-9-secreting T cells.

[0340] 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.

[0341] In some embodiments, treatment with a provided compound results in lesser IL-4 induced TARC release compared to a reference or standard level. In some embodiments, treatment with a provided compound results in lesser IL- 13 induced CD23 expression compared to a reference or standard level. In some embodiments, treatment with a provided compound results in lesser IL-13 induced periostin release compared to a reference or standard level.

[0342] In some embodiments, treatment with a provided compound inhibits IL-4 induced TARC release. In some embodiments, treatment with a provided compound inhibits IL- 13 induced CD23 expression. ISE, treatment with a provided compound inhibits IL-13 induced periostin release.

[0343] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and / or conditions wherein the disorder, disease, or condition is a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, conditions associated with organ transplantation, immunodeficiency disorders, an infectious disease, thrombin-induced platelet aggregation, liver disease, or pathologic immune conditions involving T cell activation.

[0344] Diseases and conditions treatable according to the methods of this invention include, but are not limited to, viral disease, autoimmune diseases, autoinflammatory syndromes, atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological disorders, immunodeficiency disorders such as AIDS and HIV, osteoarthritis, infectious diseases, and pathologic immune conditions involving T cell activation in a patient. In one embodiment, a human patient is treated with a compound of the current invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably modulate (e.g., inhibit) STAT6 or a mutant thereof

[0345] Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseasesto which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma exacerbated or induced following bacterial or viral infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early -phase asthmatics.

[0346] Another aspect of the present invention relates to 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 invention to the subject. The disease may be a lung disease such as, e.g., asthma, airway hyperresponsiveness (AHR), an allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD). reactive airway disease, chronic rhinosinusitis, or essentially any other disease of the upper or lower airways that produces airflow obstruction.

[0347] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4 to 6 am, i.e., at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[0348] In some embodiments, STAT6, via its Src homology 2 (SH2) domain, is recruited to the phosphotyrosine residues and is phosphorylated on Tyr641. In some embodiments. STAT6 then dimerizes via reciprocal SH2 domain-pTyr641 interactions, translocates to the nucleus, and participates in the expression of genes leading to asthma and airway hyperresponsiveness (AHR).

[0349] In some embodiments, the present invention provides a method of treating asthma in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the present invention provides a method of treating airway hyperresponsiveness (AHR) in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the present invention provides a method of treating allergic rhinitis in a patient in need thereof, comprising administering a compound of the present invention, or apharmaceutically acceptable salt thereof.

[0352] In some embodiments, the present invention provides a method of treating allergic asthma in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the present invention provides a method of treating emphysema in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the present invention provides a method of treating chronic rhinosinusitis in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the present invention provides a method of treating COPD in a patient in need thereof, comprising administering a compound of the present invention, or a pharmacally acceptable salt thereof.

[0356] Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention 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 invention 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.

[0357] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds of the invention are also usefid in the treatment of eosinophil related disorders, e.g.. eosinophilia, in particular eosinophil related disorders of the airways (e.g., involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and / or lungs as well as. for example, eosinophil- related disorders of the airways consequential or concomitant to LofHer's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and cosinophil-rclatcd disorders affecting the airways occasioned by drug-reaction.

[0358] Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin. In some embodiments, the present invention provides a method of treating inflammatory or allergic conditions of the skin in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments the inflammatory disease of the skin is selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multifonna, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0360] Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis. dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, 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 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 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, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0361] In some embodiments, the present invention provides a method of treating an autoimmune disease selected from encephalomyelitis, systemic sclerosis, idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, graft versus host disease (acute and chronic), and other tissue fibrosis diseases.

[0362] In some embodiments, the present invention provides 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, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis. Juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA). cryopyrin associated periodic syndrome (CAPS), and osteoarthritis.

[0364] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease or TH17-associated disease. In some embodiments the TH17 mediated disease or TH17-associated disease is selected from psoriasis, psoriatric arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis), or graft- versus-host disease.

[0365] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0366] In some embodiments, the present invention provides a method of treating an autoimmunedisease or inflammatory disorder is selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic autoimmune hepatitis, progressive 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.

[0367] In some embodiments, the present invention provides a method of treating STAT6 gain of function (GOF) mutations in a patient in need thereof, comprising administering a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT6 GOF mutation is STAT6VT.

[0368] In some embodiments, the cardiovascular disease which can be treated according to the methods of the present invention include, but are not limited to. restenosis, cardiomegaly, 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.

[0369] In some embodiments, the neurodegenerative disease which can be treated according to the methods of the present invention 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.

[0370] In some embodiments the invention provides 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.

[0371] In some embodiments the invention provides a method of treating a disease or condition commonly occurring in connection with transplantation. In some embodiments, the disease or condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease.

[0372] In some embodiments the invention provides 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.

[0373] In some embodiments the invention provides a method of treating a viral disease. In some embodiments, the viral infection is HIV or COVID19 infection.

[0374] In some embodiments, the present invention provides a method of treating a JAK-associatcd disease other than cancer.

[0375] Furthermore, the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of an inflammatory disease, an obstructive respiratory disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation.Combination Therapies

[0376] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0377] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. It will be appreciated that the present disclosure contemplates use of the combination therapies described herein only for treating the diseases, disorders, and conditions described herein.

[0378] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0379] Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), glatiramer acetate (Copaxone®), and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants. ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e g., ketokenozole and ritonavir), pirfenidone (Esbriet®), nintedanib (Ofev®), intravenous immunoglobulins, bosentan (Tracleer®), nifedipine (Procardia XL®), sildenafil (Revatio®), losartan (Cozaar®), iloprost (Ventavis*), topical nitroglycerin, N-acctylcystcine. antiacid therapy, and agents for treating immunodeficiency disorders such as gamma globulin.

[0380] In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.

[0381] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another nonnally within five hours from one another.

[0382] As used herein, the tenn “combination.” “combined.” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0383] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0384] One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more othertherapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.

[0385] In one embodiment, the present invention provides a composition comprising a provided compound and one or more additional therapeutic agents. The therapeutic agent may be administered together with a provided compound, or may be administered prior to or following administration of a provided compound. Suitable therapeutic agents are described in further detail below. In certain embodiments, a provided compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours. 12 hours. 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0386] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a provided compound and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D- penicillamine (Depen® or Cuprimine®). azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune ®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab. anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Corrcctol® and Scnokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin®HFA, Proventil ® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®). and flunisolide (Aerobid®). Afviar®, Symbicort®, Dulera®. cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®). and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.

[0387] In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib. colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol and febuxostat (Uloric®).

[0388] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D- pcnicillaminc (Depcn® or Cupriminc®), azathioprinc (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), '‘anti -IL- 1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T-cell" agents such as abatacept (Orencia®) and ‘‘anti -IL-6” agents such as tocilizumab (Actemra®).

[0389] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (N SAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[0390] In some embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (N SAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0391] In some embodiments, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®. Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0392] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®). inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulcra®, cromolyn sodium (Intal®), methylxanthincs such as theophylline (Thco-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab(Xolair®).

[0393] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®). pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and fonnoterol (Foradil®). anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®). Afviar®, Symbicort®, and Dulera®.

[0394] In some embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfmavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.

[0395] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0396] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0397] In some embodiments, the present invention provides a method of treating Alzheimer’s disease comprising administering to a patient in need thereof a provided compound and one or more additionaltherapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0398] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®. Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®. Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept. also known as VEGF Trap (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafmlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®. Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®. Novartis); nilotinib (Tasigna®. Novartis); dasatinib (Sprycel®. BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®. Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bmton’s tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacy clics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0399] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmacals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0400] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft vs. host disease comprising administering to a patient in need thereof a provided compound and one or more additional therapeutic agents selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0401] In another embodiment, the present invention provides a method of treating or lessening theseverity of a disease comprising administering to a patient in need thereof a provided compound and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis. Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune thyroiditis. Sjogren's syndrome, multiple sclerosis, systemic sclerosis. Lyme neuroborreliosis. Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, diseases of the bone and joints leading to joint inflammation and pain, cartilage and / or bone destruction, as well as bone regrowth and fusion, including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, osteoporosis, a thromboembolic disorder, (e.g.. myocardial infarct, 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, deep venous thrombosis), inflammatory pelvic disease, urethritis, skin sunbum, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, idiopathicautoimmune hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitus, agammaglobulinemia, psoriasis, allergy, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, Sjogren’s disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, atherosclerosis, Addison’s disease, Parkinson’s disease, Alzheimer’s disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism. Guillain-Barre syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves’ disease.

[0402] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a provided compound and a PI3K inhibitor, wherein the disease is selected from a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, conditions associated with organ transplantation, immunodeficiency disorders, an infectious disease, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, and a cardiovascular disorder.

[0403] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a provided compound and a PI3K inhibitor, wherein the disease is selected from psoriasis or diseases in which the PI3K / PKB pathway is aberrantly activated, 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 induced or exacerbated following bacterial or viral infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to. acute, arachidic. catarrhal, croupus. chronic or phthinoid bronchitis, 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, sidcrosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan)infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidennolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis and glomerulonephritis (with and w ithout nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis. Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

[0404] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer): duvelisib (formerly IPI-145. Infinity Pharmaceuticals): PQR309 (Piqur Therapeutics. Switzerland); and TGR1202 (formerly RP5230. TG Therapeutics).

[0405] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "‘appropriate for the disease, or condition, being treated.”

[0406] The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formcstanc and, in particular, non-stcroids, especially aminoglutethimidc, roglethimidc, pyridoglutethimide, trilostane. testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™

[0407] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (Afmitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0408] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[0409] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™.

[0410] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The temr "gonadorelin agonist" as used herein includes, but is not limited to abarelix. goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0411] The term "compounds targeting / decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factorreceptors (PDGFR). such as compounds which target, decrease or inhibit the activity of PDGFR. especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit / SCFR receptor tyrosine kinase, suchas imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N- phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family, and / or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin: examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl] amino (-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), fressa, Tarceva, OSI-774, Cl-1033, EKB- 569, GW-2016, El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met. especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momclotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but notlimited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF- 4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0412] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0413] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®. Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®1, AstraZeneca).

[0414] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027. SF-1126. DS-7423, PBI-05204, GSK-2126458, ZSTK- 474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0415] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[0416] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib

[0417] Further anti -angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

[0418] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[0419] Compounds which induce cell differentiation processes include, but are not limited to. retinoic acid, α- γ- or δ- tocopherol or a- y- or 8-tocotrienol.

[0420] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5 -alkyl substituted 2-arylaminophcnylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, suchas 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[0421] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™ Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™.

[0422] The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0423] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[0424] The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[0425] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0426] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB- 2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.

[0427] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[0428] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDGbinders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.

[0429] The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5- fluorouracil. cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-l ,3 -dione derivatives.

[0430] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[0431] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α- hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0432] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[0433] The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or afterthe other drag substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drag substance, said compound of the invention and said drag substance being in the same or different pharmaceutical composition.

[0434] Suitable anti-inflammatory drags include steroids, in particular glucocorticosteroids such as budesonide. beclamethasone dipropionate, fluticasone propionate, ciclesonide ormometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer). SCH-351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554 / UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, fomioterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0435] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine. astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0436] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1 , CCR-2, CCR-3, CCR-4. CCR-5. CCR-6, CCR- 7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8- yl]carbonyl]aniino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0437] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[0438] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.

[0439] Those additional agents may be administered separately from an inventive compoundcontaining composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0440] As used herein, the term “combination.” “combined.” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0441] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of an inventive compound can be administered.

[0442] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg / kg body weight / day of the additional therapeutic agent can be administered.

[0443] The amount of one or more other therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent is administered at a dosage of about 50%, about 55%. about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered forthat agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is provided for dosing per the FDA label insert.

[0444] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.3b. Description of Exemplary Compound and Composition Embodiments

[0445] In certain embodiments, the present invention provides an inhibitor compound of formula I’:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituents iseach of X1, X4, and X5is independently CH. CRw. or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, 0, or S, wherein at least one ofY2and Y3is CH. CRK, CH2, CH(RK), or C(Rw)2; eachrepresents a single bond or a double bond;Ring X and its Rxsubstituentswherein represents a bond to Ring W. andrepresents a bond to the rest of the molecule;Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rwis selected from hydrogen. RA. RB. halogen, -CN, -NO2, -OR, -SR. -NR2. -SiR,. -S(O)R. -S(O)2R, - S(O)(NR)R, -S(O)2NR2. -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3. - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R,-OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur: each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-. -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl, arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur: or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w, x, y, and z are independently 0, 1, 2, 3, or 4, and wherein:(i) when Ring X and its Rxsubstituents isX1is N, and Y1is NH, NRw, or N, then Y2and Y3are not NH, NRw, or N;(ii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH or CRw, each of X2and X3is C, and each of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2, then Y1is not CH. CRw. CH2. CH(Rw), or C(Rw)2:(iii) when Ring X and its Rxsubstituents isX1is N, and Y1is S, then Ring Y is not phenyl or 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;(iv) when Ring X and its Rxsubstituents isthen Y3is not S:(v) when Ring X and its Rxsubstituents isNH, NRw, or N;(vi) when Ring X and its Rxsubstituents isX1is N, Y1is NH, NRw, or N, and Y2and Y3are CH, CRw, CH2, CH(Rw), or C( Rw)2, then z is not 0 or 1;(vii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH or CRw, each of X2and X3is C, and Y2is CH, CRw, CH2, CH(Rw), or C(Rw)2, then only one ofY2and Y3is O;(viii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH orCRw, each of X2and X3is C, Y1is 0, NH, NRw, or N, and Y2and Y3are CH, CRw, CH2,CH(Rw), or C(Rw)2, then z is not 0 or 1 ; and(ix) when Ring X and its Rxsubstituents is X5is N. and Y1is NH. NRw. or N. thenY2is not NH, N Rw, or N, and wherein the inhibitor compound is not a compound of structure A-B-C defined by the combination of the building blocks A, B, and C, within the table below:

[0446] In some embodiments, the inhibitor compound of formula I’ specifically affects, as its primary mechanism of action, the inhibition of STAT6.

[0447] It will be understood that formula I’ cannot extend beyond the formulae described within this section (3b) below and herein. It will be understood that all references to “defined and described herein" solely refer to this section (3b) of the application. Additionally, all chemical formulae and embodiments within section 3b can only apply to and can be combined with formulae and embodiments from this section (3b).

[0448] In some embodiments, the inhibitor compound of formula I’ is not any of compounds 1-1 through 1-1548, or pharmaceutically acceptable salts thereof, described in PCT / US2024 / 044544. In some embodiments, the inhibitor compound of formula I, I’, II, III, or IV is not a compound of Table 1, or a pharmacally acceptable salt thereof, of International Application No. PCT / US2024 / 044544.

[0449] In some embodiments, the inhibitor compound of formula I’ is not a compound selected from Table BTable B:Bocor a salt or free base / acid thereof.

[0450] As described above and defined herein. Ring W and its Rwsubstituents is, wherein each of X1, X4, and X5is independently CH, CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each of Y1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH. CRw, CH2, CH(Rw), or C(Rw)2; and eachrepresents a single bond or a double bond.

[0451] In some embodiments, the ring containing X2, X3, Y1, Y2, and Y3is aromatic or heteroaromatic, i.e., the definitions of Y1, Y2, Y3, andare selected to satisfy valency of an aromatic or heteroaromatic ring. In some embodiments, the ring containing X2, X3, Y1, Y2, and Y3is not aromatic or heteroaromatic, i.e., the definitions of Y1, Y2, Y3, andare selected to satisfy valency of a partially unsaturated ring.

[0452] In some embodiments, Ring W and its Rwsubstituents is:

[0453] As defined above and described herein, each of X1, X4, and X5is independently CH, CRw, orN. In some embodiments, each of X1, X4, and X3is CH or CRw. In some embodiments, X1is CH. In some embodiments, X1is CRw. In some embodiments, X1is N. In some embodiments, X4is CH. In some embodiments, X4is CRw. In some embodiments, X4is N. In some embodiments, X5is CH. In some embodiments, X5is CRw. In some embodiments, X5is N.

[0454] As defined above and described herein, each of X2and X3is independently C or N. In some embodiments, both of X2and X3are C. In some embodiments, X2is C. In some embodiments, X2is N. In some embodiments, X3is C. In some embodiments, X3is N.

[0455] In some embodiments, X1, X4, and X5are CH or CRw, and X2and X3are C. In some embodiments, X1is N, X2and X3are C, and X4and X5are CH or CRw. In some embodiments, X1, X4, and X5are CH or CRw, X2is N, and X3are C. In some embodiments, X1, X4, and X5are CH or CRw, X2is C, and X3are N. In some embodiments, X1and X5are CH or CRw, X2and X3are C. and X4is N. In some embodiments. X1and X4are CH or CRw, X2and X3are C. and X5is N.

[0456] As defined above and described herein, each of Y1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2. In some embodiments, both of Y2and Y3are CH, CRw, CH2, CH(Rw), or C(Rw)2. In some embodiments, each ofY1, Y2, and Y3is independently CH. CRw, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH or CRw. In some embodiments. Y1is CH. In some embodiments, Y1is CRw. In some embodiments. Y1is CH2. In some embodiments. Y1is CH(Rw). In some embodiments, Y1is C(Rw)2. In some embodiments, Y1is NH. In some embodiments, Y1is NRw. In some embodiments, Y1is N. In some embodiments, Y1is O. In some embodiments, Y1is S. In some embodiments, Y2is CH. In some embodiments, Y2is CRw. In some embodiments, Y2is CH2. In some embodiments, Y2is CH(Rw). In some embodiments, Y2is C(Rw)2. In some embodiments, Y2is NH. In some embodiments, Y2is NRw. In some embodiments, Y2is N. In some embodiments. Y2is O. In some embodiments, Y2is S. In some embodiments. Y3is CH. In some embodiments, Y3is CRw. In some embodiments. Y3is CH2. In some embodiments, Y3is CH(Rw). In some embodiments, Y3is C(Rw)2. In some embodiments, Y3is NH. In some embodiments, Y3is NRw. In some embodiments, Y3is N. In some embodiments, Y3is 0. In some embodiments, Y3is S.

[0457] In some embodiments, Y1is NH or NRw, and Y2and Y3are CH or CRw. In some embodiments,Y1is 0, and Y2and Y3are CH or CRw. In some embodiments. Y1is S, and Y2and Y3are CH or CRw.

[0458] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments. Ring W and its Rwsubstituents isIn some embodiments. Ring W

[0459] In some embodiments, Ring W and its Rwsubstituents is

[0461] In some embodiments, Ring W and its Rwsubstituents is522

[0462] In some embodiments, Ring W and its Rwsubstituents is

[0463] In some embodiments, Ring W and its w substituents isIn some embodiments Ring W and itsRw substituents isIn some embodiments Ring W and its Rwsubstituents is

[0464] In some embodiments, Ring W and its Rwsubstituents isIn some embodiments, Ring W and its Rwsubstituents is523

[0465] In some embodiments, Ring W and its Rwsubstituents isome embodiments, Ring W and its Rwsubstituents is

[0466] In some embodiments, Ring W and

[0467] In some embodiments. Ring W and itsIn some embodiments, Ring W and its Rwsubstituents

[0468] In some embodiments. Ring W and its Rwsubstituents

[0469] In some embodiments, Ring W and its Rwsubstituents is

[0470] In some embodiment, Ring W is as depicted in the compounds of Table 1B, below.

[0471] In some embodiments, Ring W and its Rwsubstituents are

[0472] In some embodiments. Ring W and its Rwsubstituents are

[0473] In some embodiments, Ring W and its Rwsubstituents are525

[0474] In some embodiments, Ring W and its Rwsubstituents are

[0475] In some embodiments, Ring W and its Rwsubstituents are535

[0476] As described above and defined herein, Ring X and its Rxsubstituents iswhereinrepresents a bond to Ring W, andrepresents a bond to the rest of the molecule.

[0477] In some embodiments, Ring X and its Rxsubstituents is In some embodiments, Ring X and its Rxsubstituents isIn some embodiments, Ring X and its Rxsubstituents isIn some embodiments, Ring X and its Rxsubstituents is

[0478] In some embodiment. Ring X is as depicted in the compounds of Table 1B. below.

[0481] In some embodiments, Ring X and its Rxsubstituents are

[0482] As described above and defined herein, Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0483] In some embodiments, Ring Y is phenyl.

[0484] In some embodiments, Ring Y is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 3-6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is cyclopropyl. In some embodiments, Ring Y is cyclobutyl. In some embodiments, Ring Y is cyclopentyl. In some embodiments. Ring Y is hexyl.

[0485] In some embodiments. Ring Y is a 5-6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 6-7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is a 3 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 4 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 5 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments. Ring Y is a 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, Ring Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0486] In some embodiments, Ring Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0487] In some embodiments, Ring Y is a 5-membered monocyclic hctcroaryl ring with 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered monocyclic heteroaryl ring with 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5 -membered monocyclic hctcroaryl ring with 3 hctcroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring Y is a 5 -membered monocyclicheteroaryl ring with 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 5-membered monocyclic heteroaryl ring with 2-3 nitrogen heteroatoms.

[0488] In some embodiments, Ring Y is a 6-membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Y is a 6-membered monocyclic heteroaryl with 1-4 nitrogen heteroatoms. In some embodiments, Ring Y is pyridinyl, pyrimidinyl. pyridazinyl, ortriazinyl.

[0489] In some embodiments. Ring Y is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0491] In some embodiments. Ring Y is

[0492]

[0493] In some embodiment, Ring Y is

[0494] In some embodiment, Ring Y is as depicted in the compounds of Table 1B, below.

[0495] In some embodiments, Ring Y and its Rysubstituents are

[0496] In some embodiments, Ring Y and its Rysubstituents are

[0497] In some embodiments, Ring Y is

[0498] In some embodiments, Ring Y and its Rysubstituents are

[0499] As described above and defined herein. Rxand Ryare independently selected from hydrogen,RA, halogen, -CN, -NO2, -OR, -SR, -NR2,SiR3, -S(O)R -S(O)2R -S(O)(NR)R -S(O)2NR2, -C(O)R -C(O)OR -C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0500] In some embodiments, Rxand Ryare independently selected from RA, halogen, -CN, -NO2, - OR -SR -NR2, -SIR, -S(O)R -S(O)2R, -S(O)(NR)R -S(O)2NR2. -C(O)R, -C(O)OR - C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, - NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0501] As described above and defined herein, each Rwis independently selected from hydrogen, RA,RB, halogen, -CN, -NO2, -OR -SR -NR2,SiR3, -S(O)R, -S(O)2R -S(O)(NR)R. -S(O)2NR2-C(O)R -C(O)OR,C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, - NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0502] In some embodiments, each Rwis independently selected from hydrogen, RA, halogen, -CN, - NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R -S(O)(NR)R, -S(O)2NR2, -C(O)R -C(O)OR - C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2. -OP(O)(OR)2, - NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0503] In some embodiments, each Rwis independently selected from RA, RB, halogen, -CN, -NO2, - OR -SR -NR2, -SiR3, -S(O)R -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR - C(O)NR2, -C(O)NROR, -OC(O)R -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, - NRC(O)OR -NRC(O)R -NRC(O)N(R)2, and -NRS(O)2R.

[0504] In some embodiments, one or more of Rw. Rx, and Ryis hydrogen. In some embodiments, one or more of Rw. Rx. and Ryis RA. In some embodiments, one or more of Rw, Rx, and Ryis halogen. In some embodiments, one or more of Rw, Rx, and Ryis -CN. In some embodiments, one or more of Rw, Rx, and Ryis -NO2. In some embodiments, one or more of Rw, Rx, and Ryis -OR. In some embodiments, one or more of Rw, Rx, and Ryis -SR. In some embodiments, one or more of Rw, Rx, and Ryis -NR2. In some embodiments, one or more of Rw, Rx, and Ryis -SiR3. In some embodiments, one or more of Rw, Rx. andRyis -S(O)2R. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)2NR2. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)(NR)R. In some embodiments, one or more of Rw, Rx, and Ryis -S(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)OR. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)NR2. In some embodiments, one or more of Rw, Rx, and Ryis -C(O)NROR. In some embodiments, one or more ofRw, Rx, and Ryis -OC(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -OC(O)NR2. In some embodiments, one or more of Rw, Rx, and Ryis -OP(O)R2. In some embodiments, one or more of Rw, Rx, and Ryis -OP(O)(OR)2. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)OR. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)R. In some embodiments, one or more of Rw, Rx, and Ryis -NRC(O)N(R)2. In some embodiments, one or more of Rw, Rx, and Ryis -NRS(O)2R.

[0505] In some embodiments, Rw-C(O)OR. In some embodiments, Rwis -C(O)NR2. In some embodiments. Rwis an optionally substituted phenyl. In some embodiments. Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0506] In some embodiments, Rwis RB. In some embodiments, Rwis RA.

[0507] In some embodiments, Rwis fluoro, chloro, or bromo.

[0508] In some embodiments, Rwis -C(O)NHR. In some embodiments, Rwis -C(O)NHR, wherein R of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NHR, wherein R of RwisC1-6aliphatic, optionally substituted with -CN.

[0509] In some embodiments, Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic, optionally substituted with -C(O)N(R°)2. In some embodiments, Rwis C1-6aliphatic, optionally substituted with -NR°(O)N(R°)2. In some embodiments, RwisIn some such embodiments, R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments, Rwis -CH2F, -CHF2, or -CF3.

[0510] In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro). In some embodiments. RwisIn some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) or -NR°2. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) and -NR°2. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) or -NR°2, wherein each R° is independently hydrogen or C1-6aliphatic. In some embodiments, Rwis C1-6aliphatic optionally substituted with halogen (e.g., fluoro) and -NR°2, wherein eachR° is independently hydrogen or C1-6aliphatic. In some embodiments, Rwis

[0511] In some embodiments, Rwis an optionally substituted phenyl.

[0512] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments. Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, Rwis an optionally substituted cyclopropyl. In some embodiments, Rwis an optionally substituted cyclobutyl. In some embodiments, Rwis an optionally substituted cyclopentyl. In some embodiments, Rwis an optionally substituted cyclohexyl. In some embodiments, Rwis an optionally substituted cyclopropenyl. In some embodiments, Rwis an optionally substituted cyclobutenyl. In some embodiments, Rwis an optionally substituted cyclopentenyl. In some embodiments. Rwis an optionally substituted cyclohexenyl.

[0513] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0514] In some embodiments, Rwis an optionally substituted 4 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted azetidinyl, oxetanyl, or thietanyl.

[0515] In some embodiments, Rwis an optionally substituted 5 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis an optionally substituted pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, or imidazolinyl. In some embodiments, Rwis an optionally substituted dihydropyridinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, or tetrahydrothiophenyl .

[0516] In some embodiments, Rwis an optionally substituted 6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyL 4H-pyranyl, 1,4-dioxanyl, 1,4-dioxinyl, thianyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,3-dithanyl, 1,4-dithanyl, morpholinyl, or thiomorpholinyl. In some embodiments, Rwis an optionally substituted dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, or tetrahydrothiopyranyl .

[0517] In some embodiments, Rwis an optionally substitutedIn some embodiments, Rwembodiments, Rwis. In some embodiments, Wmis 0. In some embodiments, Wmis S. In some embodiments, Wmis C(O). In some embodiments, Wmis NR°. In some embodiments, Wmis NR°, wherein R° is hydrogen or C1-6aliphatic.

[0518] In some embodiments, Rwis an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Rwis an optionally substituted imidazolyl, optionally substituted with -C(O)N(R°)2. In some embodiments, Rwis an optionally substituted furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments. Rwis furanyl, optionally substituted with -C(O)N(R°)2.

[0519] In some embodiments Rwis an optionally substituted 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis anoptionally substituted 6 membered heteroaryl having 1-4 nitrogen heteroatoms. In some embodiments, Rwis optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, Rwis an optionally substituted pyridinonyl, pyrazinonyl, or pyrimidinoyl.

[0520] In some embodiments, Rwis -NHR, wherein R is an optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis -NHR. wherein R is an optionally substituted 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0521] In some embodiments, Rwis -S(O)2NH2. In some embodiments, Rwis -S(O)2NHR, wherein R is an optionally substituted C1-6aliphatic. In embodiments, Rwis S(O)2NHR, wherein R is an optionally substituted phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0522] In embodiments, Rwis -S(O)2(NH)R. In some embodiments, Rwis -S(O)2(NH)H. In some embodiments, Rwis -S(O)2(NH)R, wherein R is an optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)2(NH)R, wherein R is an optionally substituted phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0523] In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2.-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, - OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R. In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR,-C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2. -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2. or - NRS(O)2R. In some embodiments. Rwis -S(O)R, -S(O)2R, -S(O)(NR)R. -S(O)2NR2, or -NRS(O)2R. In some embodiments, Rwis -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -NRC(O)OR, -NRC(O)R, or -NRC(O)N(R)2. In some embodiments, Rwis -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, or -C(O)NROR. In some embodiments, Rwis -C(O)R, -C(O)OR, or -C(O)NR2.

[0524] In some embodiments, Rwis -C(O)H. In some embodiments, Rwis -C(O)R. wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments. Rwis -C(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

[0525] In some embodiments, Rwis -C(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Rwis -C(O)R. wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0526] In some embodiments, Rwis -C(O)OH. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments. Rwis -C(O)OR, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)OR, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0527] In some embodiments, Rwis -C(O)NH2. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0528] In some embodiments, Rwis -C(O)NHR, wherein R is an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NHR, wherein R is Ci.e aliphatic. In some embodiments, Rwis - C(O)NHR, wherein R is methyl, ethyl, or cyclopropyl. In some embodiments, Rwis -C(O)NR2, wherein the two R groups of Rware taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected fonn nitrogen, oxygen, and sulfur. In some embodiments. Rwis -C(O)NR2. wherein the two R groups of Rware taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic ring having 0 heteroatoms, in addition to the atom or adjacent atoms to which they are attached. In some embodiments, Rwis -C(O)NR2, wherein the two R groups of Rware taken together with their intervening atoms to form an aziridinyl, azetidinyl. diazetidinyl, pyrrolidinyl, or piperidinyl.

[0529] In some embodiments, Rwis -C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NROR, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis - C(O)NROR wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NROR wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0530] In some embodiments, Rwis -OC(O)H. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments. Rwis -OC(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -OC(O)R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0531] In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments. Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -OC(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0532] In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis - NRC(O)OR wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRC(O)OR, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0533] In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRC(O)R,wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRC(O)R, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0534] In some embodiments. Rwis -NRC(O)N(R)2. wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRC(O)N(R)2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0535] In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -NRS(O)2R, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0536] In some embodiments, Rwis -S(O)H. In some embodiments, Rwis -S(O)R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -S(O)R, wherein R is of Rwis an optionally substituted 4- 7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, hr some embodiments, Rwis -S(O)R, wherein R is of Rwis an optionally substituted 5-6 membered hcteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0537] In some embodiments, Rwis -S(O)2H. In some embodiments, Rwis -S(O)2R, wherein R is of Rwis optionally substituted C1-6aliphatic. In some embodiments. Rwis -S(O)2R, wherein R is of Rwis optionally substituted phenyl. In some embodiments, Rwis -S(O)2R, wherein R is of Rwis an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)2R, wherein R is of Rwis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

[0538] In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or optionally substituted phenyl. In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)(NR)R, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0539] In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -S(O)2NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0540] In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, Rwis an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, Rwis an optionally substituted:

[0541] In some embodiments, Rwis:In some such embodiments, R° is hydrogen or C1-6aliphatic.

[0542] In some embodiments, Rwis:

[0543] In some embodiments, Rwis an optionally substituted:

[0544] In some embodiments, Rwis:wherein Ring W1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0545] As defined above and described herein, Ring W1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1 additional heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring W1is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 5 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W1is an optionally substituted 6 membered monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0546] In some embodiments, Rwis:

[0547] In some embodiments, Rwis:wherein Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring, or a 5- 6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0548] As defined above and described herein. Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring, or a 5-6 membered monocyclic heteroaryl ring having 1 -2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W2is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring. In some embodiments, Ring W2is an optionally substituted 5-6 membered partially unsaturated heterocyclic ring. In some embodiments. Ring W2is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments. Ring W2is a 5 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring W2is an optionally substituted oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, 2-imidazolinyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl.

[0549] In some embodiments, Rwis an optionally substituted ring selected from:

[0550] In some embodiments, Rwis:wherein each Rº is a defined above and described herein (e.g., hydrogen or C1-6aliphatic).

[0551] In some embodiments, Rwis:

[0552] In some embodiments Rwis an optionally substituted 7-11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted 9-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments Rwis an optionally substituted benzo[d][l,3]dioxolyl. In some embodiments Rwis an optionally substituted an 11 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0553] In some embodiments Rwis an optionally substituted 8- 11 membered bicyclic aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Rwis an optionally substituted naphthalenyl. In some embodiments, Rwis an optionally substituted dihydrobenzodioxepinyl. In some embodiments, Rwis an optionally substituted indenyl or dihydroindenyl.

[0554] In some embodiments, Rwis an optionally substituted 9-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0555] In some embodiments Rwis an optionally substituted 9-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments Rwis an optionally substituted indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, thienopyridinyl, pyrrolo[3,2-Z>]pyridinyl, pyrrolo[2,3,-i]pyridinyl, pyrazolyl[l,5-o]pyridinyl, or imidazo[l,2-a]pyridinyl, azaindazolyl (e g., 4-, 5-, 6-, or 7-azaindazolyl), pyrrolol[2,3-c]pyridinyl or indolizinyl.

[0556] In some embodiments Rwis an optionally substituted 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments Rwis an optionally substituted quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, or 1,8-naphthyridinyl.

[0557] In some embodiments, Rwis fluoro, chloro, -CN, -OH, -OMe, -OCH2CO2Me, -CO2H, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, -C(O)NMe2, -C(O)N(Me)Et, - C(O)N(Me)nPr, -CH2NHMe,

[0558] In some embodiments, Rwis fluoro, chloro, -CN, methyl, -CF3, -CHF2, -OH, -OMe, -OCH2CO2Me, -CO2H, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, - C(O)NMe2, -C(O)N(Me)Et,-C(O)N(Me)nPr, -CH2NHMe,

[0560] In some embodiments, Rwis -S(O)2NH2, -S(O)2N(CH3)2, -S(O)(NH)CH3,

[0562] In some embodiments, Rwis

[0563] In some embodiments, Rwis -CH2CH2CH3,

[0565] In some embodiments, Rwis -C(O)NH2. In some embodiments. Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted C1-6aliphatic. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted phenyl. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rwis -C(O)NR2, wherein each R is of Rwis independently hydrogen or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0567] In some embodiments, each Rxis independently selected from RA, halogen, -CN, -NO2, -OR, - SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0568] In some embodiments, Rxis -CO2Me. or -CH2OH.

[0569] In some embodiments, Rxis -C(O)R or -C(O)OR. In some embodiments, Rxis -C(O)R. In some embodiments, Rxis -C(O)R, wherein R of Rxis an optionally substituted C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic optionally substituted with -C(O)OR°, -OR°, halogen (e.g., fluoro), or =O. In some embodiments, Rxis -C(O)OR. In some embodiments, Rxis -C(O)OR, wherein R of Rxis an optionally substituted C1-6aliphatic.

[0571] In some embodiments, Rxis optionally substituted C1-6aliphatic. In some embodiments, Rxis C1-6aliphatic optionally substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic.

[0572] In some embodiments, Rxis -CO2Me, -CH2OH, -C(O)Me, -C(O)Et, -C(O)iPr, - C(O)cyclopropyl, -C(O)oxetanyl, -C(O)tetrahydropyranyl, or pyridyl.

[0573] In some embodiments, Rxis fluoro. In some embodiments, Rxis -S(O)2CH3. In some embodiments, Rxis -C(O)N(CH3)2.

[0574] In some embodiments, Rxis -C(O)R, wherein R of Rxis optionally substituted C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic. In some embodiments, Rxis -C(O)R,wherein R of Rxis methyl, ethyl, n-propyl, or isopropyl. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -OR° or -C(O)OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -OR°, wherein R° is hydrogen or C1-6aliphatic. In some embodiments, Rxis -C(O)R, wherein R of Rxis C1-6aliphatic substituted with -C(O)OR°, wherein R° is hydrogen or C1-6aliphatic.

[0575] In some embodiments, Rxis

[0576] In some embodiments, each Ryis independently selected from RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2,-C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

[0577] In some embodiments, Ryis fluoro, chloro, bromo, iodo, methyl, ethyl, cyclopropyl, -CFs, - CN, CH2O, -CO2H, -CO2Me, -CO2tBu, -C(O)Me, -NH2, -NHMe, -NHAc, -NHC(O)Et, -OH, -OMe, - OCH2CH2NH2, -CH2OH, -CH2OMe, -CH2NHMe, -CH2NHAc, -CH2SO2Me, -SO2Me, -SO2NH2, -

[0578] In some embodiments, Ryis -C(O)H.

[0579] In some embodiment, Rw, Rx, and Ryare as depicted in the compounds of Table IB, below.

[0580] As described above and defined herein, each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0581] In some embodiments, R ' is an optionally substituted C1-6aliphatic. In some embodiments, RAis an optionally substituted phenyl. In some embodiments, RAis an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic. In some embodiments, RAis an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RAis an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

[0582] In some embodiments, RAis C...

Claims

CLAIMS1. An compound of formula I’ :or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituentseach of X1, X4, and X5is independently CH. CRw, or N; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4, and X5is N; each of Y1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, O, or S, wherein at least one of Y2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2; eachrepresents a single bond or a double bond;Ring X and its Rxsubstituentswhereinrepresents a bond to Ring W, andrepresents a bond to the rest of the molecule;Ring Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;Rwis selected from hydrogen, RA, RB, halogen, -CN, -N02, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, - S(O)(NR)R -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC (O)NR2, - P(O)R2. -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2. -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2. and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN, -N02, -OR, -SR, -NR2, -Si R3, - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R,-OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, - NRC(O)N(R)2, and -NRS(O)2R; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur: each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or hetcroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl. arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclyl. heterocyclyl. aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; andeach of w, x, y, and z are independently 0, 1, 2, 3, or 4, and wherein:(i) when Ring X and its Rxsubstituents isX1is N, and Y1is NH, NRw, or N, thenY2and Y3are not NH, NRw, or N;(ii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH or CRw, each of X2and X3is C, and each ofY2and Y3is CH, CRw, CH2, CH(Rw), or C(Rw)2, then Y1is not CH, CRw, CH2, CH(Rw), or C(Rw)2;(iii) when Ring X and its Rxsubstituents isX1is N, and Y1is S, then Ring Y is not phenyl or 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;(iv) when Ring X and its Rxsubstituents isX1is N, and Y1is NH, NRw, or N, then Y3is not S;(v) when Ring X and its Rxsubstituents isX1is N, and Y1is 0, then Y2is not NH,NRw, or N;(vi) when Ring X and its Rxsubstituents isand Y3are CH, CRw, CH2, CH(Rw), or C(Rw)2, then z is not 0 or 1;(vii) when Ring X and its Rxsubstituents iseach of X1, X4, and X5is CH or CRw, each of X2and X’ is C, and Y2is CH, CRw, CH2, CH(Rw), or C(Rw)2, then only one of Y2and Y3is 0;(viii) when Ring X and its Rxsubstituents is, each of X1, X4, and X5is CH or CRw, each of X2and X3is C, Y1is 0, NH, NRw, or N, and Y2and Y3are CH, CRw, CH2, CH(Rw), orC(Rw)2, then z is not 0 or 1; and(ix) when Ring X and its Rxsubstituents is , X5is N, and Y1is NH, NRw, or N, then Y2is not NH, NRw, or N, and wherein the compound is not of structure A-B-C defined by the combination of the building blocks A, B,2. The compound of claim 1, wherein Ring W and its Rwsubstituents is:

3. The compound of claim 1, wherein Ring W and its Rwsubstituents is:

4. The compound of any one of claims 1 -3, wherein Ring Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

5. The compound of claim 4, wherein Ring Y is6. The compound of any one of claims 1-5. wherein an occurrence of Rwis -S(O)R, -S(O)2R, - S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or - NRS(O)2R.

7. The compound of any one of claims 1-6, wherein an occurrence of Rwis RB.

8. The compound of any one of claims 1-7, wherein an occurrence of Rwis halogen (e.g., fluoro).

9. The compound of any one of claims 1-8, wherein the compound is of formula I-a-lb or I-a-2b:or a pharmaceutically acceptable salt thereof, wherein: Rwis hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, - S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2. -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2. - P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R_ -NRC(O)N(R)2, or -NRS(O)2R.

10. The compound of claim 9, wherein Rwis an optionally substituted ring selected from phenyl, a 3- 7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

11. The compound of any one of claims 1-10, wherein the compound is of formula I-b-5, 1-b-6, 1-c-5,I-c-6, 1-d-5, 1-d-6, 1-e-5, or I-e-6:or a pharmaceutically acceptable salt thereof, wherein:Rwis hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, - S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2. -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2. - P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

12. The compound of any one of claims 1-11, wherein RBis -LB-CyB1-H.

13. The compound of any one of claims 1-11, wherein RBis -LB-CyB1-CyB2.

14. The compound of any one of claims 1-13, wherein CyB1is an optionally substituted 8-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

15. The compound of any one of claims 1-13. wherein CyB1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

16. The compound of any one of claims 1-11, wherein RBis17. The compound of any one of claims 1-16, wherein CyB2is optionally substituted 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

18. The compound of claim 1 , wherein:(i) Ring W and its Rwsubstituents isRing Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1 -4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or(ii) Ring W and its Rwsubstituents isRing Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2: each LBis independently a covalent bond or a Cns bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or(in) Ring W and its Rwsubstituents isRing Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur:z is 2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic ary l or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

19. The compound of any one of claims 1-18, wherein the compound is not a compound selected from Table B20. The compound of claim 1, wherein the compound is selected from Table 1B, or a pharmaceutically acceptable salt thereof.

21. A compound selected from Table 2B, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

23. A method of inhibiting STAT6, the method comprising contacting STAT6 with a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

24. The method of claim 23, wherein the contacting occurs in a patient or a biological sample.

25. A method of inhibiting STAT6, the method comprising contacting STAT6 with a compound of fonnula I:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituents iseach ofX1, X4, X5and X6is independently CH, CRw, orN; each of X2and X3is independently C or N, wherein at most one of X1, X2, X3, X4. X5and X6is N; each ofY1, Y2, and Y3is independently CH, CRw, CH2, CH(Rw), C(Rw)2, NH, NRw, N, 0, or S, wherein at least one of Y2and Y3is CH. CRw. CH2, CH(Rw), or C(Rw)2; eachrepresents a single bond or a double bond;Ring X and its Rxsubstituents iswherein represents a bond to Ring W, andrepresents a bond to Lx;Ring Y is a ring selected from phenyl, naphthyl, 3-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Lxisrepresents a bond to Ring Y;Rwis selected from hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3. -S(O)R, -S(O)2R, - S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R;Rxand Ryare independently selected from hydrogen, RA, halogen, -CN. -NO2, -OR, -SR. NR2, -SiR3, - S(O)R, -S(O)2R, -S(O)(NR)R -S(O)2NR2-C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2. -OP(O)R2. -OP(O)(OR)2, -NRC(O)OR. -NRC(O)R. - NRC(O)N(R)2, and -NRS(O)2R;Rzis RA, -OR, or NR2; each RAis independently an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur: each RBis independently -LB-CyB1-H or -LB-CyB1-CyB2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-. -C(O)-. -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, - S(O)2-, -S(O)(NR)-. or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclylenyl or heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylcnyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclylenyl, heterocyclylenyl. arylenyl, or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each CyB2is independently an optionally substituted ring selected from phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-10 membered monocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 5-15 membered saturated or partially saturated monocyclic,bicyclic, or tricyclic carbocyclyl, heterocyclyl, aryl, or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same atom or adjacent atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms, in addition to the atom or adjacent atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and each of w. x, y, and z are independently 0. 1, 2, 3, or 4.

26. The method of claim 25, wherein the compound is of formula I’:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its RwsubstituentsRing Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

27. The method of claim 25, wherein the compound is of formula II:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its Rwsubstituents iRing Y is a ring selected from naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

28. The method of claim 25, wherein the compound is of formula III:or a pharmaceutically acceptable salt thereof, wherein:Ring W and its RwsubstituentsRing Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 8-10 membered bicyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; andrepresents a bond to Ring Y.

29. The method of anv one of claims 25-28, wherein Ring W and its Rwsubstituents is:

30. The method of any one of claims 25-28, wherein Ring W and its Rwsubstituents is:

31. The method of claim 25, wherein the compound is of formula IV :or a pharmaceutically acceptable salt thereof, wherein:Ring W and its RwsubstituentsRing Y is a ring selected from phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

32. The method of claim 25 or 31, wherein Ring W and its Rwsubstituents is:

33. The method of claim 25 or 31, wherein Ring W and its Rwsubstituents is:

34. The method of any one of claims 25, 26, or 28-33, wherein Ring Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

35. The method of claim 34, wherein Ring Y is36. The method of any one of claims 25-35, wherein an occurrence of Rwis -S(O)R, -S(O)2R, - S(O)(NR)R -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, - P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and - NRS(O)2R.

37. The method of any one of claims 25-36, wherein an occurrence of Rwis RB.

38. The method of any one of claims 25-37, wherein an occurrence of Rwis halogen (e.g., fluoro).

39. The method of any one of claims 25-38, wherein the compound is of formula I-a-lb. I-a-2a, I-a- lb, or I-a-2b:or a pharmaceutically acceptable salt thereof, wherein:Rwis hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, - S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, - P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

40. The method of claim 39, wherein Rwis an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

41. The method of any one of claims 25-40, wherein the compound is of formula I-b-1 through I-b-6,I-c-1 through I-c-6, formula I-d-1 through I-d-6, or formula I-e-1 through I-e-6or a pharmaceutically acceptable salt thereof, wherein:Rwis hydrogen, RA, RB, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, - S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, - P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R.

42. The method of any one of claims 25-41. wherein RBis -LB-CyB1-H.

43. The method of any one of claims 25-41, wherein RBis -LB-CyB1-CyB2.

44. The method of any one of claims 25-43. wherein CyB1is an optionally substituted 8-10 membered saturated or partially unsaturated bicyclic heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

45. The method of any one of claims 25-43, wherein CyB1is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

46. The method of any one of claims 25-41, wherein RBis47. The method of any one of claims 25-46, wherein CyB2is optionally substituted 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

48. The method of claim 26, wherein:(i) Ring W and its RwsubstituentsRing Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur: z is 2;each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic ary l or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or(ii) Ring W and its Rwsubstituents isRing Y is a 5-6 membered monocyclic heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur: z is 2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 memberedmonocyclic or bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or(iii) Ring W and its RwsubstituentsRing Y is a 5-6 membered monocyclic he teroary I with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur: z is 2; each LBis independently a covalent bond or a C1-3bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, - S-, -S(O)-, -S(O)2- -S(O)(NR)- or -CR=CR-; each CyB1is independently an optionally substituted ring selected from phenylenyl, a 3-7 membered saturated or partially unsaturated carbocyclylenyl or heterocyclylenyl having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic arylenyl or heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each CyB2is independently an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic ary l or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

49. The method of claim 25, wherein the compound is selected from Table 1A or Table 1B, or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 25-49, wherein the contacting occurs in a patient or a biological sample.

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