STAT6 inhibitors and their uses

Abstract

The present invention provides a compound, a composition, and a method of using the same as a STAT6 inhibitor.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] 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.

[0003] Technical field of invention

[0004] The present invention relates to a compound and a method useful for inhibiting signal transducer and activator of transcription 6 ("STAT6"). Furthermore, the present invention provides a pharmaceutically acceptable composition comprising a compound of the present invention, and a method of using said composition in the treatment of various disorders. Background Technology

[0005] Signal transduction and transcription activator 6 (STAT6 or interleukin-4-Stat / IL4-STAT) is an undruggable transcription factor belonging to the structurally conserved signal transduction and transcription activator (STAT) protein family (STAT1 to STAT6). Like other STAT proteins, the activation of STAT6 is triggered when hormones, immunomodulatory cytokines, or growth factors bind to specific receptors on the cell surface. Once activated, phosphorylation of the C-terminal tyrosine residue occurs, inducing the translocation and transmission of the signal from the cytosol to the nucleus, which consequently leads to the activation of gene expression.

[0006] STAT6 is involved in type 2 immunity and the induction of allergies. It may participate in IL-4 / IL-13-mediated allergic responses and may play an important role in the differentiation of type 2 T-helper (Th2) cells (Hebenstreit et al. "Signaling mechanisms, interaction partners, and target genes of STAT6."). Cytokine & growth factor reviews 17.3 (2006): 173-188; Chapoval et al. “Regulation of the T helper cell type 2 (Th2) / T regulatory cell (Treg) balance by IL-4 and STAT6.” Journal of leukocyte biology 87.6 (2010): 1011-1018). STAT6 is a key node in the Janus kinase (JAK) pathway primarily activated by interleukin-4 (IL4) and interleukin-13 (IL13), inflammatory cytokines produced by Th2 cells, mast cells, and basophils, and their cognate receptors. 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.). For example, there is a need to discover and develop STAT6 drugs to treat allergic / inflammatory diseases and cancer (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 implications.” Frontiers in oncology 9 (2019): 48). Therefore, there is still a need to find STAT6 inhibitors that are useful as therapeutic agents.

[0007] Now, it has been revealed that the compound of the present invention and the pharmaceutically acceptable composition thereof are effective as STAT6 protein inhibitors.

[0008] In some embodiments, the present disclosure provides an inhibitor compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0009] [Chemical Formula Ia]

[0010]

[0011] (In the above chemical formulas, each variable is as defined and described in this specification).

[0012] In some embodiments, the present disclosure provides an inhibitor compound of formula Ib or a pharmaceutically acceptable salt thereof:

[0013] [Chemical Formula Ib]

[0014]

[0015] (In the above chemical formulas, each variable is as defined and described in this specification).

[0016] The inhibitor compounds and pharmaceutically acceptable compositions thereof described herein are useful for treating various diseases, disorders, or conditions associated with the regulation of signaling pathways involving the STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0017] The inhibitor compounds described herein are also useful for the study of STAT6 proteins in biological and pathological phenomena; the study of intracellular signaling pathways occurring in body tissues; and for in vitro or in vivo comparative evaluation of novel STAT6 inhibitors, or other regulators of the cell cycle, metastasis, angiogenesis, and immune cell evasion. Specific details for implementing the invention

[0018] 1. General description of specific embodiments of the present invention:

[0019] The inhibitor compounds and compositions thereof described herein are useful as inhibitors of phosphorylated or activated STAT6 proteins, including, for example, pSTAT6. In some embodiments, the provided inhibitor compounds inhibit and / or regulate STAT6, pSTAT6, or both STAT6 and pSTAT6.

[0020] 2. Compounds and Definitions:

[0021] The compounds of the present invention generally include those described herein and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are CAS versions (Handbook of Chemistry and Physics, 75 th It is identified according to the periodic table of elements of Ed. In addition, the general principles of organic chemistry are referenced in the literature ["Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999], and the literature ["March's Advanced Organic Chemistry", 5 th [Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001] is described, the full contents of which are incorporated herein by reference.

[0022] As used herein, the terms “aliphatic” or “aliphatic group” mean a substituted or unsubstituted hydrocarbon chain of straight (i.e., unbranched) or branched chain containing one or more fully saturated or unsaturated units, or a monocyclic or bicyclic hydrocarbon having a single attachment site to the rest of the molecule, containing one or more fully saturated or unsaturated units and not mono-aromatic (which is also referred to herein as “carbocyclic,” “aliphatic,” or “cycloalkyl”). Unless otherwise specified, the aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms. In yet another embodiment, the aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet another embodiment, the aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon having a single attachment site to the rest of the molecule, which is fully saturated or contains one or more unsaturated units and is not monoaromatic. In some embodiments, the carbocyclic ring may be a 5 to 12-membered bicyclic, cross-linked bicyclic, or spirocyclic ring. The carbocyclic ring may include one or more oxo (=O) or thioxo (=S) substituents. 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.

[0023] As used herein, the term “crosslinked bicyclic” refers to any saturated or partially unsaturated bicyclic ring system having at least one crosslink, i.e., carbocyclic or heterocyclic. As defined by IUPAC, a “crosslink” is an valence bond connecting an unbranched chain of atoms, or atoms, or two bridgeheads, where a “bridgehead” is any skeletal atom bonded to three or more skeletal atoms (excluding hydrogen) in the ring system. In some embodiments, the crosslinked bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such crosslinked bicyclic groups are well known in the art and comprise the groups presented below, each of which is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the crosslinked bicyclic group is optionally substituted with one or more substituents as presented for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the cross-linked bicyclic group is optionally substituted. Exemplary cross-linked bicyclics include the following:

[0024] .

[0025] The term "lower alkyl" is C 1-4 It refers to straight-chain or branched-chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0026] The term "haloalkyl" refers to C substituted with one or more halogen atoms. 1-6 It refers to a straight-chain or branched-chain alkyl group, and the term "lower haloalkyl" refers to a C group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched-chain alkyl group.

[0027] The term "heteroatom" refers to one or more oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of a basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, e.g., (3,4-dihydro-2 H - As in pyrrolyl) N, (as in pyrrolidinyl) NH or (as in N-substituted pyrrolidinyl) NR + It means (including ).

[0028] As used herein, the term "unsaturated" means that the moiety has one or more unsaturated units.

[0029] As used herein, the term "2 is C 1-8 (or C 1-6 ) Saturated or unsaturated, straight or branched hydrocarbon chains refer to straight or branched dialkylene, alkenylene, and alkynylene chains as defined in this specification.

[0030] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" refers to a polymethylene group, i.e., -(CH2) n - and, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for the substituted aliphatic group.

[0031] The term "alkenylene" refers to a divalent 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 by substituents. Suitable substituents include those described below for the substituted aliphatic group.

[0032] As used herein, the term "cyclopropylenyl" has the following structure: The divalent cyclopropyl group of refers to the cyclopropyl group.

[0033] The term "halogen" means F, Cl, Br, or I.

[0034] The term "aryl," used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In specific embodiments of the present invention, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracyl, etc. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc. The term "arylenyl" refers to a divalent aryl group (e.g., phenylenyl).

[0035] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl” or “heteroaralkoxy,” refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, 6, 10, or 14 π electrons shared within a cyclic alignment, and having 1 to 5 heteroatoms in addition to carbon atoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. The heteroaryl group comprises, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinil, pyrimidinil, pyrazinil, indolizinil, furinyl, naphthiridinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroar-” also comprise a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclil rings. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranil, dibenzofuranil, indazollyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinil, phthalazinil, quinazolinil, quinoxalinil, 4 HIncludes quinolidinyl, carbazolyl, acrridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. The heteroaryl group may be monocyclic, bicyclic, cross-linked bicyclic, or spirocyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and includes a ring optionally substituted with any of these terms. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are optionally substituted independently. The term "heteroarylenyl" refers to a divalent heteroaryl group (e.g., pyridylenyl).

[0036] As used herein, the terms “heterocycle,” “heterocyclile,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5 to 7-membered monocyclic or 7 to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and, as defined above, has one or more, preferably 1 to 4, heteroatoms in addition to the carbon atom. When used in relation to the ring atoms of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen is (3,4-dihydro-2 H - As in pyrrolyl) N, (as in pyrrolidinyl) NH, or ( N - As in substituted pyrrolidinyl) + It could be NR.

[0037] The heterocyclic ring can form a stable structure by attaching to its pendant group at any heteroatom or carbon atom, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazefinyl, oxazefinyl, thiazefinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclile," "heterocyclile ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein, and refer to a group in which a heterocyclile ring is fused to one or more aryl, heteroaryl, or alicyclic rings, e.g., indolinyl, 3 H- Indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl are also included. In some embodiments, the heterocyclic ring may be a 5 to 12-membered bicyclic, cross-linked bicyclic, or spirocyclic ring. The heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently and optionally substituted.

[0038] As used herein, the term “partially unsaturated” refers to a ring moiety comprising at least one double or triple bond. The term “partially unsaturated” comprises a ring having multiple unsaturated sites, but is not intended to comprise an aryl or heteroaryl moiety as defined herein.

[0039] As described herein, the compounds of the present disclosure may contain "substituted" moiety. Generally, the term "substituted" means that one or more hydrogens of a specified moiety are replaced with suitable substituents. Unless otherwise indicated, "optionally substituted" groups may have suitable substituents at each substitutable position of the group, and where more than one position within any given structure may be substituted with more than one substituent selected from the specified group, the substituents may be the same or different at all positions. The combinations of substituents conceived by the present invention are preferably those that form a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that remains substantially unchanged when exposed to conditions that enable generation, detection, and, in certain embodiments, recovery, purification, and use for one or more purposes disclosed herein.

[0040] Suitable monovalent substituents on the substitutable carbon atom of the "selectively substituted" group are independently halogens; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°; -(CH2) 0-4 CH(OR°)2; -(CH2) 0-4 -(CH2) that can be substituted with SR°; R° 0-4 -(CH2) that can be replaced by Ph; R° 0-4 O(CH2) 0-1 Ph; -CH=CHPh that can be replaced by R°; -(CH2) that can be replaced by R° 0-4 O(CH2) 0-1 -Piridil; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2; -(CH2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2) 0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2) 0-4 N(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) 0-4 C(O)R°; -C(S)R°; -(CH2) 0-4 C(O)OR°; -(CH2) 0-4 C(O)SR°; -(CH2) 0-4 C(O)OSiR°3; -(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR°; -(CH2) 0-4 SC(O)R°; -(CH2) 0-4 C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; - (CH2) 0-4 S(O)2R°; -(CH2) 0-4 S(O)2OR°; -(CH2) 0-4 OS(O)2R°; -S(O)2NR°2; -(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -(CH2) 0-4 P(O)2R°; -(CH2) 0-4 P(O)R°2; -(CH2) 0-4 OP(O)R°2; -(CH2) 0-4 OP(O)(OR°)2; SiR°3; -(C 1-4 Straight-chain or branched-chain alkylene)ON(R°)2; or -(C 1-4 (Straight-chain or branched-chain alkylene)C(O)ON(R°)2, where each R° can be substituted as defined below and independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2)0-1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent cases of R° are taken together with an atom interposed between them to form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0041] A suitable monovalent substituent on R° (or a ring formed by taking two independent cases of R° together with an atom interposed between them) is independently a halogen, -(CH2) 0-2 R ● , -(HalloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2; -O(HalloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C 1-4 Straight-chain or branched-chain alkylene)C(O)OR ● or -SSR● and, where each R ● is unsubstituted, or if preceded by "halo", is substituted with only one or more halogens, and C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0042] Suitable divalent substituents on the saturated carbon atom of the "selectively substituted" group are as follows: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 Includes S-, where R in each independent case * C, which can be substituted for hydrogen as defined below. 1-6 It is selected from aliphatic, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A suitable divalent substituent bonded to an adjacent substitutable carbon of the "optionally substituted" group is -O(CR * 2) 2-3 Includes O-, where R in each independent case * C, which can be substituted for hydrogen as defined below. 1-6 It is selected from aliphatic, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] R * Suitable substituents on the aliphatic group are halogens, -R ● , -(HalloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● Includes 2, or -NO2, where each R ● is unsubstituted, or, when preceded by "halo", is substituted with only one or more halogens, and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur.

[0044] The suitable substituent on the substitutable nitrogen of the "selectively substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † Includes, where each R † C, which can be independently substituted for hydrogen as defined below. 1-6 It is an aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, R in two independent cases †It is taken together with atoms interposed between them to form an unsubstituted ternary to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] R † Suitable substituents on the aliphatic group of are independently halogens, -R ● , -(HalloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted, or, when preceded by "halo", is substituted with only one or more halogens, and independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from pH, or nitrogen, oxygen, or sulfur.

[0046] As used herein, the term “pharmaceuticalally acceptable salt” refers to a salt that, within the scope of reasonable medical judgment, is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and corresponds to a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in the literature incorporated herein by reference [J. Pharmaceutical Sciences, 1977, 66, 1-19]. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed from inorganic acids such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed using other methods used in the art, such as ion exchange.Other pharmaceutically accepted salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, Includes pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc.

[0047] Salts derived from appropriate bases are alkali metals, alkaline earth metals, ammonium, and N + (C 1-4 It includes alkyl)tetrasalts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, for example, using an acidic or basic mobile phase during chromatography. Salt forms of the provided compounds formed during chromatographic purification (e.g., diammonium salts) are also considered herein and are readily apparent to those skilled in the art.

[0048] Unless otherwise noted, the structures depicted herein are also intended to include all isomer forms of the structure (e.g., enantiomers, diastereomers, and geometric isomers (or form isomers)); for example, R and S arrangements for each asymmetric center, Z and E double bond isomers, and Z and E form isomers. Thus, not only single stereochemical isomers of the compounds of the present invention but also mixtures of enantiomers, diastereomers, and geometric isomers (or form isomers) are within the scope of the present invention. Unless otherwise noted, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Additionally, unless otherwise noted, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention, including those replaced with C-rich carbons, are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological analysis methods, or as therapeutic agents according to the present invention.

[0049] As used herein, the term “provided compound” refers to any genus, subgenus, and / or species described herein.

[0050] As used herein, the terms “measurable affinity” and “measurably inhibiting” mean a measurable change in STAT6 protein activity between a sample containing STAT6 protein with the compound or composition thereof of the present invention and an equivalent sample containing STAT6 protein without said compound or composition thereof.

[0051] As used herein, the term “reference” describes a standard or control that serves as a reference when performing a comparison. In some embodiments, the “reference” sample or object is sufficiently similar to the specific sample or object of interest to enable an appropriate comparison. For example, in some embodiments, a formulation, animal, individual, population, sample, sequence, or value of interest is compared with a reference or control formulation, animal, individual, population, sample, sequence, or value. In some embodiments, the reference or control is tested and / or determined substantially simultaneously with the test or determination of interest. In some embodiments, the reference or control is a past reference or control, which is optionally embodied in a tangible medium. Typically, as will be understood by those skilled in the art, the reference or control is determined or characterized under conditions or circumstances similar to the conditions or circumstances being evaluated. Those skilled in the art will understand where there is sufficient similarity to make it reasonable to rely on and / or compare a specific possible reference or control.

[0052] As used herein, "inhibitor compound" is a compound that binds to a protein of interest. In some embodiments, the inhibitor compound binds to the protein of interest and reduces its activity. In some embodiments, binding of the inhibitor compound to the protein of interest does not result in degradation of the protein of interest. In another embodiment, the inhibitor compound does not bind to E3 ligase in a manner that results in degradation of the protein of interest. In some embodiments, the inhibitor compound binds to STAT6. In some embodiments, the inhibitor compound binds to STAT6 and reduces its activity. In some embodiments, binding of the inhibitor compound to STAT6 does not result in degradation of STAT6. In another embodiment, the inhibitor compound does not bind to E3 ligase in a manner that results in degradation of STAT6. In some embodiments, the inhibitor compound binds to the protein of interest (e.g., STAT6) but does not bind to E3 ligase. In some embodiments, the E3 ligase is selected from cereblon E3 ubiquitin ligase, VHL E3 ubiquitin ligase, DCAF E3 ubiquitin ligase (e.g., DCAF1 E3 ubiquitin ligase, DCAF15 E3 ubiquitin ligase, or DCAF16 E3 ubiquitin ligase), IAP E3 ubiquitin ligase, MDM2 E3 ligase, or DC2 E3 ubiquitin ligase. Throughout the entire disclosure, references to "compound" or "provided compound" will be understood to refer to the inhibitor compound defined above.

[0053] In some embodiments, the E3 ligase is cereblon E3 ubiquitin ligase. In some embodiments, the inhibitor compound is the chemical formula I-aa' Does not contain the structure of or pharmaceutically acceptable salts thereof:

[0054] [Chemical formula I-aa']

[0055]

[0056] In the above chemical formula,

[0057] X 1 and X 5 are independently covalent bonds, -CR2-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)-, or And;

[0058] X 2 is N, CR B , Si-R B , or P=O and;

[0059] X 3 and X 4 is independently a covalent bond, -CR2-, -CF2-, -O-, -S- or;

[0060] X 3 -X 4 is -CR=CR- and;

[0061] Each R 1 is independently -H, R A , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR 2, -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;

[0062] The two Rs of ring A 1The group is taken together with an atom interposed between them to form a selectively substituted ring selected from a 3 to 10-membered saturated or partially unsaturated carbocyclile or heterocyclile having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; benzo; or a 5 to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0063] Each R B is 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 optionally substituted C 1-4 aliphatic;

[0064] L 1 covalent bond or C 1-3 It is a divalent hydrocarbon chain, wherein one or two methylene units of the chain are independently and optionally replaced with -C(O)-, -C(S)-, -CR2-, -CF2-, -NR-, -O-, -S-, or -S(O)2;

[0065] Ring A is phenylenyl, naphthalenyl, pyridinyllenyl, 4 to 7-membered saturated or partially unsaturated carbocyclilenyl, 4 to 7-membered saturated or partially unsaturated heterocyclilenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8 to 10-membered bicyclic saturated or partially unsaturated heterocyclilenyl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 6-membered heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8 to 10-membered bicyclic heteroarynyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8 to 15-membered saturated or partially unsaturated tricyclic heterocyclilenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or nitrogen, oxygen, and It is an 8 to 15-membered tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from sulfur;

[0066] Each R A C independently 1-6 An optionally substituted group selected from an aliphatic, phenyl, 3 to 10-membered saturated or partially unsaturated carbocyclic ring, a 3 to 10-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0067] Each R is independently hydrogen or C 1-6 A selectively substituted group selected from a 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0068] Two R groups or R on the same or adjacent atoms B and R groups are taken together with atoms interposed between them to form optionally substituted 3 to 11-membered saturated or partially unsaturated monocyclic, bicyclic, cross-linked bicyclic, or spirocyclic carbocyclic or heterocyclic rings having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0069] In some embodiments, the inhibitor compound is or It does not include.

[0070] In some embodiments, the E3 ligase is VHL E3 ubiquitin ligase. In some embodiments, the inhibitor compound is the chemical formula I-ccc-3' Does not contain the structure of or pharmaceutically acceptable salts thereof:

[0071] [Chemical formula I-ccc-3']

[0072]

[0073] In the above chemical formula,

[0074] Each X 4a and X 5a is independently -CH2-, -C(O)-, -C(S)-, or The 2 selected from are moiety;

[0075] Each R 4a is independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR 2, -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;

[0076] R 5ais hydrogen or C 1-6 aliphatic;

[0077] Each R 6 C independently 1-6 A selectively substituted group selected from a 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur; a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8 to 15-membered saturated or partially unsaturated tricyclic heterocyclylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8 to 15-membered tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0078] ring C a is selected from a hexavalent aryl comprising 0 to 2 nitrogen atoms or a pentogeneous heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0079] q is 0, 1, 2, 3, or 4;

[0080] Each R is independently hydrogen or C 1-6 A selectively substituted group selected from a 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0081] Two R groups on the same nitrogen phase are optionally taken together with an atom interposed between them to form a 4 to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to nitrogen.

[0082] In some embodiments, the inhibitor compound is It does not include.

[0083] In some embodiments, the E3 ligase is MDM2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound is each I-aaa-1 , I-aaa-2 , I-aaa-3 , I-aaa-4 , I-aaa-5 , I-aaa-6 , I-aaa-7 , I-aaa-8 , I-aaa-9 , I-aaa-10 , I-aaa-11 , I-aaa-12 , I-aaa-13 , I-aaa-14 , I-aaa-15 , I-aaa-16 , I-aaa-17 , or I-aaa-18 Includes the structure of or pharmaceutically acceptable salts thereof:

[0084] [Chemical Formula I-aaa-1]

[0085]

[0086] [Chemical Formula I-aaa-2]

[0087]

[0088] [Chemical Formula I-aaa-3]

[0089]

[0090] [Chemical Formula I-aaa-4]

[0091]

[0092] [Chemical Formula I-aaa-5]

[0093]

[0094] [Chemical Formula I-aaa-6]

[0095]

[0096] [Chemical Formula I-aaa-7]

[0097]

[0098] [Chemical Formula I-aaa-8]

[0099]

[0100] [Chemical Formula I-aaa-9]

[0101]

[0102] [Chemical Formula I-aaa-10]

[0103]

[0104] [Chemical Formula I-aaa-11]

[0105]

[0106] [Chemical Formula I-aaa-12]

[0107]

[0108] [Chemical Formula I-aaa-13]

[0109]

[0110] [Chemical Formula I-aaa-14]

[0111]

[0112] [Chemical Formula I-aaa-15]

[0113]

[0114] [Chemical Formula I-aaa-16]

[0115]

[0116] [Chemical Formula I-aaa-17]

[0117]

[0118] [Chemical Formula I-aaa-18]

[0119]

[0120] In the above chemical formula,

[0121] X is selected from -CR2-, -O-, -S-, -S(O)-, -S(O)2-, and -NR-, and

[0122] Each R is independently hydrogen or C 1-6 A selectively substituted group selected from a 4 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0123] Two R groups on the same atom are optionally taken together with an atom interposed between them to form a 4 to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the atoms to which they are attached, and

[0124] Y and Z are independently selected from -CR= and -N=;

[0125] Ring W is a fused ring selected from benzo, and 5- to 6-membered heteroaryls having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0126] R 1 and R 2 is an optionally substituted monocyclic or bicyclic ring selected from 5 to 10-membered heteroaryls comprising phenyl, 5 to 10-membered aryls, and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0127] R 3 and R 4 is hydrogen and C 1-6 Independently selected from alkyls;

[0128] R 5is selected from an optionally substituted monocyclic or bicyclic ring selected from 5 to 10-membered heteroaryls comprising phenyl, 5 to 10-membered aryls, and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0129] R 6 is selected from hydrogen, -C(O)R, -C(O)OR, and -C(O)NR2;

[0130] R 7 Silver, hydrogen, and R A Selected from;

[0131] Each R A C independently 1-6 A selectively substituted group selected from a 3 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0132] R 8 -C(O)R and R A Selected from;

[0133] R 9 is a single, double, or triple substituent on ring W, where each substituent is a halogen and an optionally substituted C 1-6 Independently selected from aliphatic groups;

[0134] R 10 Selected from an optionally substituted monocyclic or bicyclic ring selected from 5 to 10-membered heteroaryls comprising phenyl, 5 to 10-membered aryls, and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0135] R 11 is -C(O)OR or -C(O)NR2 and;

[0136] R12 　 and R 13 Silver, hydrogen, and R A Selected independently from;

[0137] R 12 and R 13 The silver is optionally taken together with an atom interposed between them to form an optionally substituted 3 to 8-membered saturated, partially unsaturated, carbocyclic, or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0138] R 14 is R A And;

[0139] R 15 is -CN and;

[0140] R 16 is R A , -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 Selected from -S(O)2NR2;

[0141] R 17 -(CR2) 0-6 Selected from -C(O)NR2;

[0142] R 18 and R 19 is hydrogen and R A Selected independently from;

[0143] R 20 　 and R 21 Silver is hydrogen, R A , halogen, and -OR are independently selected or;

[0144] R 20 and R 21The atom is optionally taken together with an interposed atom between them to form a fused 5 to 7-membered partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a fused 5 to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0145] R 22 , R 23 , R 25 , and R 27 Silver is hydrogen, R A Independently selected from , halogen, -C(O)R, -C(O)OR, -C(O)NR2, -NR2, -OR, -S(O)R, -S(O)2R, -S(O)2NR2;

[0146] R 24 , R 26 , and R 28 Silver is hydrogen, R A , -C(O)R, -C(O)OR, -C(O)NR2, Independently selected from -S(O)R, -S(O)2R, and -S(O)2NR2;

[0147] R 1' and R 2' is a halogen, -C≡CN, -CF3, 　 and independently selected from -NO2;

[0148] R 3' is -OR and;

[0149] R 4' , R 5' , R 6' is hydrogen, halogen, R A Independently selected from , -CN, -CF3, -NR2, -OR, -SR, and -S(O)2R;

[0150] R 7' is a single-, double-, or triple-substituent, where each substituent is independently selected from halogens;

[0151] R 8' is a single-, double-, or triple-substituent, where each substituent is hydrogen, halogen, R A Independently selected from , -CN, -C≡CR, -NO2, and -OR;

[0152] R 9' is R A And;

[0153] Z 1 It is selected from hydrogen, halogen, and -OR;

[0154] R 10' and R 11' is hydrogen and R A Selected independently from;

[0155] R 12' -C(O)R, -C(O)OR, -C(O)NR2, -OR, -S(O)2R, -S(O)2NR 2, Selected from and -S(O)R;

[0156] R 1" is hydrogen and R A Selected from.

[0157] In some embodiments, the E3 ligase is DCAF E3 ubiquitin ligase (e.g., DCAF1 E3 ubiquitin ligase). In some embodiments, the inhibitor compound is of the chemical formula Iba or Ibb It does not contain the structure of or pharmaceutically acceptable salts thereof.

[0158] [Chemical formula Iba]

[0159]

[0160] [Chemical Formula Ibb]

[0161]

[0162] In the above chemical formula,

[0163] Ring E 1is a 4 to 9-membered partially unsaturated monocyclic, bicyclic, or cross-linked bicyclic carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from phenyl, naphthyl, nitrogen, oxygen, and sulfur, or a 5 to 9-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0164] Ring F 1 It is a pentatonic monocyclic heteroarylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0165] Y 1 C 1-3 Hydrocarbon chain (wherein each methylene is optionally replaced with -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-); or R d Chemical formula in which is absent Iba -C(OR)=at;

[0166] R a is hydrogen, optionally substituted C 1-6 Aliphatic, or And;

[0167] Ring G is a 5 to 7-membered saturated or partially unsaturated carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, or a 5 to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0168] R b is hydrogen, optionally substituted C 1-6 It is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, and sulfur, or

[0169] R a and R bIt is taken together with atoms interposed between them to form an optionally substituted 9 to 10-membered saturated or partially unsaturated bicyclic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0170] Y 1 If this is -C(NR)-, R b is taken together with the R of -C(NR)- and the atoms interposed between them to form a 5 to 7-membered partially unsaturated heterocyclile having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur in addition to the two heteroatoms in the heterocyclile;

[0171] R c -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 phenyl; a 4 to 7-membered saturated or partially unsaturated carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted group selected from a 5 to 9-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or

[0172] -(CR2) 1-2 -X a (Here, X ais a halogen, or a selectively substituted ring selected from phenyl; a 4 to 7-membered saturated or partially unsaturated carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5 to 9-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or;

[0173] R b and R c ...is taken together with atoms interposed between these to form an optionally substituted 4 to 6-membered saturated or partially unsaturated carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0174] R a is absent and R b and R c is taken together with an atom interposed between them to form a selectively substituted phenyl, or;

[0175] Y 1 If this -C(OR)=, R c is taken together with the R of -C(NR)- and the atoms interposed between them to form a 5 to 7-membered partially unsaturated heterocyclile having 0 to 1 heteroatom independently selected from nitrogen, oxygen, and sulfur in addition to the two heteroatoms in the heterocyclile, and

[0176] R d is hydrogen or optionally substituted C 1-6 aliphatic, or

[0177] R c If a is -CR2CONR2, R d is taken together with a single R of -CR2CONR2 and an atom interposed between them, so R dIn addition to the attached nitrogen atom, it forms a 5 to 7-membered saturated or partially unsaturated heterocyclile having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0178] R e , R f , and R g are independently hydrogen, iodine, and R A , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR 2, -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;

[0179] Each R A C independently 1-6 A selectively substituted group selected from a 3 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0180] Each R is independently hydrogen or C 1-6A selectively substituted group selected from a 3 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, naphthyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0181] Two R groups on the same atom are taken together with an atom interposed between them to form an optionally substituted 3 to 7-membered saturated or partially unsaturated ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the atoms to which they are attached;

[0182] e, f, and g are each independently 0, 1, 2, 3, or 4.

[0183] In some embodiments, the inhibitor compound has the chemical formula Ibc The structure of or does not contain pharmaceutically acceptable salts thereof:

[0184] [Chemical Formula Ibc]

[0185]

[0186] In the above chemical formula,

[0187] Ring H is a 3 to 11-membered saturated or partially unsaturated monocyclic, bicyclic, cross-linked bicyclic, or spirocyclic carbocyclile or heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0188] Ring I is phenylenyl, or a 5 to 10-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0189] Ring J is a 3 to 11-membered saturated or partially unsaturated monocyclic, bicyclic, cross-linked bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0190] Ring K is a 5 to 13-membered monocyclic, bicyclic, or tricyclic heteroarylenyl having 1 to 5 heteroatoms independently selected from phenyl, naphthyl, or nitrogen, oxygen, and sulfur;

[0191] R h , R i , R j , and R k are independently hydrogen, iodine, and R A , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR 2, -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, is selected from -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;

[0192] R on ring I i R on the ring J and the loop j The group is optionally taken together with an atom interposed between them to form a 5 to 8-membered saturated, partially unsaturated, or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0193] X 1 and X 2Each independently has a covalent bond, X 1 or X 2 Spiro-fusion between two connected rings, or divalent, saturated or unsaturated, straight or branched chain C 1-6 It is a hydrocarbon chain, and here X 1 and X 2 0 to 4 methylene units of are independently replaced with -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-;

[0194] s" is 0 or 1 and;

[0195] w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0196] In some embodiments, the E3 ligase is a DC2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound is a chemical formula Ica-1 or Ica-2 The structure of or It does not contain pharmaceutically acceptable salts:

[0197] [Chemical Formula Ica-1]

[0198]

[0199] [Chemical Formula Ica-2]

[0200]

[0201] In the above chemical formula,

[0202] SBM and L are as defined and described above and in this specification;

[0203] R 1Z is hydrogen or optionally substituted C 1-6 aliphatic;

[0204] Each R aZ , R bZ , and R cZ is independently hydrogen, R AZ, halogen, -CN, -NO2, -OR Z -SR Z -NR Z 2, -S(O)2R Z , -S(O)2NR Z 2, -S(O)R Z -S(O)(NR Z )R Z , -P(O)(OR Z )2, -P(O)(NR Z 2)2, -CFR Z 2, -CR Z F2, -CF3, -CR Z 2(OR Z ), -CR Z 2(NR Z 2), -C(O)R Z , -C(O)OR Z , or -C(O)NR Z 2 and;

[0205] Each R AZ C independently 1-10 A selectively substituted group selected from a 3 to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0206] Each R Z is independently hydrogen, or C 1-6 A selectively substituted group selected from a 4 to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0207] Two Rs on the same atom ZThe group is optionally taken together with an atom interposed between them, so as to have, in addition to the atom to which they are attached, an optionally substituted 4 to 11-membered saturated or partially unsaturated carbocyclic having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0208] Forming heterocyclic, monocyclic, bicyclic, cross-linked bicyclic, spirocyclic, or heteroaryl rings;

[0209] Each ring A Z is a divalent ring selected from a 4 to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclilenyl or heterocyclilenyl having 1 to 3 heteroatoms independently selected from phenylenyl, naphthylenyl, nitrogen, oxygen, and sulfur, or a 5 to 10-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0210] Each ring B Z is a divalent ring selected from 3 to 10-membered saturated or partially unsaturated monocyclic, bicyclic, cross-linked bicyclic, or spirocyclic carbocyclilenyl or heterocyclilenyl having 1 to 3 heteroatoms independently selected from phenylenyl, nitrogen, oxygen, and sulfur, or 5 to 10-membered monocyclic or bicyclic heteroarylenyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0211] L aZ is absence, covalent bond, or C 1-3 It is a divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1 to 3 methylene units of the chain are independently and optionally -O-, -C(O)-, -C(S)-, -C(R Z )2-, -CH(R Z )-, -CF(RZ )-, -C(F)2, -N(R Z )-, -S-, -S(O)2- or -CR Z =CR Z Replaced by -;

[0212] z1, z2, and z3 are each independently 0, l, 2, 3, or 4;

[0213] z4 and z5 are each independently 0 or 1.

[0214] In some embodiments, the inhibitor compound binds to the STAT6 protein with a measurable affinity and / or inhibits it. In certain embodiments, the inhibitor compound has an IC50 of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or has a combination constant.

[0215] 3. Description of exemplary embodiments:

[0216] In some embodiments, the present invention has a chemical formula Ia Provides an inhibitor compound of or a pharmaceutically acceptable salt thereof:

[0217] [Chemical Formula Ia]

[0218]

[0219] In the above chemical formula,

[0220] is a single or double bond;

[0221] Ring W is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur; a 9-membered bicyclic saturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from naphthyl, nitrogen, oxygen, or sulfur; or a 13-membered tricyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0222] Each R w is a halogen, -CN, -OR w1 , -N(R w1 )2, -(CH2) n C(O)NR2, -(CH2) n N(R)C(O)NR2, -(O) m -phenyl, C 1-4 A 6-membered monocyclic saturated or partially unsaturated heterocyclie having 1 to 3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 5-membered to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclie, or heteroaryl is a halogen, C 1-4 Optionally substituted with aliphatic, -OR, or -C(O)NR2;

[0223] Each R w1 Silver is hydrogen, C 1-4Independently selected from a six-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR;

[0224] Each R x C independently 1-4 Aliphatic, halogen, or -C(O)NR2;

[0225] Each R is independently hydrogen or C 1-4 aliphatic;

[0226] L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, where one methylene unit is optionally replaced with -NR-;

[0227] Ring Y is a pentagonal monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a decagonal bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0228] Each R y C independently 1-4 Aliphatic, halogen, -OR, or -C(O)NR2;

[0229] Each m is independently 0 or 1 and;

[0230] Each n is independently 0, 1, 2, or 3;

[0231] Each w, x, and y is independently 0, 1, 2, 3, or 4, and

[0232] Here, the chemical formula Ia The compounds are not compounds of structure ABC defined by combinations of building blocks A, B, and C in each of the following tables (i) to (ii):

[0233] (i)

[0234]

[0235] (ii)

[0236]

[0237] In some embodiments, the present invention has a chemical formula Ib Provides a compound of or a pharmaceutically acceptable salt thereof:

[0238] [Chemical Formula Ib]

[0239]

[0240] In the above chemical formula,

[0241] ring W' is or And;

[0242] W 1 is O, NH, or NR w And;

[0243] Ring X is a pentatonic monocyclic heteroarylenyl, phenylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a pentatonic or heptacyclic heterocycliclenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and is saturated or partially unsaturated monocyclic heterocycliclenyl;

[0244] Each R w is a halogen, -CN, -OR w1 , -N(R w1 )2, -(CH2) n C(O)NR2, -(CH2) n N(R)C(O)NR2, -(O) m -phenyl, C 1-4A six-membered saturated or partially unsaturated monocyclic heterocyclile having one to three heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a five-membered to six-membered monocyclic heteroaryl having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclile, or heteroaryl is a halogen, C 1-4 Optionally substituted with aliphatic, -OR, or -C(O)NR2;

[0245] Each R w1 Silver is hydrogen, C 1-4 Independently selected from a six-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR;

[0246] Each R x C independently 1-4 Aliphatic, halogen, or -C(O)NR2;

[0247] Each R is independently hydrogen or C 1-4 aliphatic;

[0248] G is hydrogen or And;

[0249] L XA is a covalent bond or a divalent straight chain or branched chain C 1-3 aliphatic;

[0250] L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, where one methylene unit is selectively substituted with -NR-;

[0251] Ring Y is a pentagonal monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a decagonal bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0252] Each R y C independently 1-4 Aliphatic, halogen, -OR, or -C(O)NR2;

[0253] Each m is independently 0 or 1 and;

[0254] Each n is independently 0, 1, 2, or 3;

[0255] Each w, x, and y is independently 0, 1, 2, 3, or 4.

[0256] In some embodiments, the chemical formula Ia or Ib Inhibitor compounds specifically affect the inhibition of STAT6 as a major mechanism of action.

[0257] As described above and defined in this specification, ring W is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur; a 9-membered bicyclic saturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from naphthyl, nitrogen, oxygen, or sulfur; or a 13-membered tricyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0258] In some embodiments, the ring W is phenyl or naphthyl. In some embodiments, the ring W is phenyl. In some embodiments, the ring W is naphthyl.

[0259] In some embodiments, ring W is a nine-membered bicyclic saturated heterocyclile having one to three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is a nine-membered bicyclic saturated heterocyclile having one to two heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0260] In some embodiments, ring W is a 10-membered saturated or partially unsaturated bicyclic heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is a 10-membered saturated or partially unsaturated bicyclic heterocyclile having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is chromanyl, chromenyl, isochromenyl, tetrahydroisoquinolinyl, tetrahydroquinolinilyl, 1,2-dihydroquinolinyl, or 1,2-dihydroisoquinolinyl.

[0261] In some embodiments, ring W is a pentagonal or hexagonal heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is a pentagonal heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl. In some embodiments, ring W is a hexagonal heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is pyridinyl, pyrimidinonyl, pyridazinyl, or triazinyl.

[0262] In some embodiments, ring W is a determinant bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is a determinant bicyclic heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W is a determinant bicyclic heteroaryl having 1 to 2 nitrogen heteroatoms. In some embodiments, ring W is quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, or 1,8-naphthiridinyl.

[0263] In some embodiments, ring W is a 13-membered tricyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring W is 3H-benzo[e]indolyl.

[0264] In some embodiments, ring W is is. In some embodiments, ring W is is. In some embodiments, ring W is is. In some embodiments, ring W is am.

[0265] In some embodiments, ring W is , or am.

[0266] In some embodiments, ring W is , or am.

[0267] In some embodiments, ring W is , or am.

[0268] In some embodiments, ring W is , or am.

[0269] In some embodiments, ring W is , , or am.

[0270] In some embodiments, ring W is , , or am.

[0271] In some embodiments, the ring W is as follows Table 1A or Table 1B As shown in the compound.

[0272] In some embodiments, ring W and its R w The substituent , or am.

[0273] .

[0274] In some embodiments, ring W and its R w The substituent or am.

[0275] As described above and defined in this specification, W 1 is O, NH, or NR w is. In some embodiments, W 1 is O. In some embodiments, W 1 is NH or NR w is. In some embodiments, W 1 is NH. In some embodiments, W 1 NR w am.

[0276] As described above and defined in this specification, ring W' is or and, here W 1 ...is as defined in this specification.

[0277] In some embodiments, ring W' is am.

[0278] In some embodiments, ring W' is am.

[0279] In some embodiments, ring W' and its R w The substituent or am.

[0280] In some embodiments, ring W' and its R w The substituent or am.

[0281] In some embodiments, ring W' and its R w The substituent or am.

[0282] In some embodiments, ring W' and its R w The substituent is. In some embodiments, ring W' and its R w The substituent am.

[0283] In some embodiments, ring W' and its R w The substituent am.

[0284] In some embodiments, ring W' and its R w The substituent , or am.

[0285] In some embodiments, ring W' and its R w The substituent , , or am.

[0286] In some embodiments, the ring W' is as follows Table 1A or Table 1B As shown in the compound.

[0287] In some embodiments, ring W' , or am.

[0288] As described above and defined in this specification, is a single or double bond. In some embodiments, is a single bond. In some embodiments, is a double bond.

[0289] As described above and defined in this specification, the compound of formula Ia is a moiety: Includes, where # represents the attachment point for G, and R x and x are as defined in this specification.

[0290] In some embodiments, moiety Is and, where # indicates the attachment point to G. In some embodiments, the moiety Is and, where # indicates the attachment point to G. In some embodiments, the moiety Is and, where # indicates the attachment point to G. In some embodiments, the moiety silver and here # represents the attachment point for G.

[0291] In some embodiments, moiety is doing Table 1A or Table 1B As shown in the compound.

[0292] In some embodiments, moiety Is or and, where # indicates the attachment point to G. In some embodiments, the moiety Is and, where # indicates the attachment point to G. In some embodiments, the moiety Is and here # represents the attachment point for G.

[0293] As described above and defined in this specification, ring X is a pentarylenyl monocyclic phenylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a pentary or heptacyclic heterocyclic saturated or partially unsaturated monocyclic heterocyclic phenylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0294] In some embodiments, ring X is a pentagonal heteroarylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is a thiazole ring.

[0295] In some embodiments, ring X is phenylenyl.

[0296] In some embodiments, ring X is a pentary or heptary saturated or partially unsaturated monocyclic heterocyclilenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is a pentary saturated or partially unsaturated monocyclic heterocyclilenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is a pentary saturated or partially unsaturated monocyclic heterocyclilenyl having 1 heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is a pyrrolidine ring. In some embodiments, ring X is a heptary saturated or partially unsaturated monocyclic heterocyclilenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is a heptarian saturated or partially unsaturated monocyclic heterocyclic renyl having one heteroatom selected from nitrogen, oxygen, or sulfur. In some embodiments, ring X is an azepan ring.

[0297] In some embodiments, ring X and its R x The substituent , or and here # represents the attachment point for G.

[0298] In some embodiments, ring X and its R x The substituent , or and here # represents the attachment point for G.

[0299] In some embodiments, ring X is as follows Table 1A or Table 1B As shown in the compound.

[0300] In some embodiments, ring X and its R X The substituent , or and here # represents the attachment point for G.

[0301] As described above and defined in this specification, G is hydrogen or am.

[0302] In some embodiments, G is hydrogen. In some embodiments, G is am.

[0303] In some embodiments, G is as follows Table 1A or Table 1B As shown in the compound.

[0304] As described above and defined in this specification, L XA is a covalent bond or a divalent straight chain or branched chain C 1-3 They are a regionalist.

[0305] In some embodiments, L XA is a covalent bond. In some embodiments, L XA is a divalent straight chain or branched chain C 1-3 It is aliphatic. In some embodiments, L XA is a straight or branched chain C 1-3 It is an alkylene. In some embodiments, L XA is a straight or branched chain C 1-2It is an alkylene. In some embodiments, L XA is -CH2-.

[0306] In some embodiments, L XA is doing Table 1A or Table 1B As shown in the compound.

[0307] As described above and defined in this specification, L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, where one methylene unit is optionally replaced with -NR-.

[0308] In some embodiments, L XB is a straight or branched chain C 1-3 It is an alkylene, wherein one methylene unit is optionally replaced with -NR-. In some embodiments, L XB is a straight or branched chain C 1-2 It is an alkylene, wherein one methylene unit is optionally replaced with -NR-. In some embodiments, L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic. In some embodiments, L XB is a straight or branched chain C 1-3 It is an alkylene. In some embodiments, L XB is a straight or branched chain C 1-2 It is an alkylene. In some embodiments, L XB is -CH2-. In some embodiments, L XB is -CH2CH2-. In some embodiments, L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, where one methylene unit is replaced by -NR-. In some embodiments, L XB is -NH-.

[0309] In some embodiments, L XB is doing Table 1A or Table 1B As shown in the compound.

[0310] As described above and defined in this specification, ring Y is a pentaryl monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a decaryl bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0311] In some embodiments, ring Y is a pentagonal monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Y is a pentagonal monocyclic heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a pentagonal monocyclic heteroaryl ring having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a pentagonal monocyclic heteroaryl ring having 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a pentagonal monocyclic heteroaryl ring having 2 to 3 nitrogen heteroatoms. In some embodiments, ring Y is a triazolyl.

[0312] In some embodiments, ring Y is phenyl.

[0313] In some embodiments, ring Y is a 10-membered bicyclic saturated or partially unsaturated heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring Y is 3,4-dihydro-2H-benzo[b][1,4]oxazinyl.

[0314] In some embodiments, ring Y is or am.

[0315] In some embodiments, ring Y is , or is. In some embodiments, ring Y is am.

[0316] In some embodiments, ring Y is , or am.

[0317] In some embodiments, ring Y is , or is. In some embodiments, ring Y is am.

[0318] In some embodiments, ring Y is as shown in the compounds of Table 1A or Table 1B below.

[0319] In some embodiments, ring Y is or am.

[0320] In some embodiments, ring Y is , or is. In some embodiments, ring Y is am.

[0321] As described above and defined in this specification, each R w is a halogen, -CN, -OR w1 , -N(R w1 )2, -(CH2) n C(O)NR2, -(CH2) n N(R)C(O)NR2, -(O) m -phenyl, C 1-4 A 6-membered monocyclic saturated or partially unsaturated heterocyclie having 1 to 3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 5-membered to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclie, or heteroaryl is a halogen, C 1-4 It is optionally substituted with aliphatic, -OR, or -C(O)NR2.

[0322] In some embodiments, R w is a halogen. In some embodiments, R w is fluoro, chloro, or bromo. In some embodiments, R w is a fluoro.

[0323] In some embodiments, R w is -CN.

[0324] In some embodiments, R w is -OR w1 is. In some embodiments, R w is -OR w1 and, here R w of R w1 C optionally substituted with hydrogen, one or more halogens, or -C(O)OR 1-4 It is an aliphatic phenyl, or a phenyl optionally substituted with one or more -OR groups. In some embodiments, R w is -OR w1 and, here R w R of w1 Silver is hydrogen or C 1-4 They are a regionalist.

[0325] In some embodiments, R w is -N(R w1 )2. In some embodiments, R w is -N(H)(R w1 ) is. In some embodiments, R w is -N(R w1 )2 and here R w Each R w1 is independently hydrogen, C 1-4 It is a six-membered monocyclic heteroaryl having one to three heteroatoms independently selected from aliphatic, or nitrogen, oxygen, or sulfur. In some embodiments, R w is -N(R w1 )2 and here R w Each R w1It is a six-membered monocyclic heteroaryl (e.g., pyridyl) having one to three heteroatoms independently selected from hydrogen or nitrogen, oxygen or sulfur.

[0326] In some embodiments, R w -(CH2) n It is C(O)NR2. In some embodiments, R w -(CH2) n It is C(O)N(H)R. In some embodiments, R w is -C(O)NR2. In some embodiments, R w is -(CH2)2C(O)NR2. In some embodiments, R w is -C(O)NH2. In some embodiments, R w is -C(O)N(CH3)2. In some embodiments, R w -(CH2) n It is C(O)N(CH3)2.

[0327] In some embodiments, R w -(CH2) n It is N(R)C(O)NR2. In some embodiments, R w is -N(R)C(O)NR2. In some embodiments, R w is -CH2N(R)C(O)NR2. In some embodiments, R w -(CH2) n It is N(H)C(O)N(CH3)2.

[0328] In some embodiments, R w -(O) m -Phenyl, where phenyl is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w -(O) m -phenyl, where phenyl is optionally substituted with a halogen, -OR, or -C(O)NR2. In some embodiments, R w is phenyl, where phenyl is a halogen, C 1-4It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is phenyl, where phenyl is optionally substituted with a halogen, -OR, or -C(O)NR2. In some embodiments, R w is -O-phenyl, where phenyl is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is phenyl, where phenyl is optionally substituted with -OR (e.g., -OCH3).

[0329] In some embodiments, R w is C 1-4 It is aliphatic. In some embodiments, R w is C 1-4 It is an alkyl.

[0330] In some embodiments, R w is a six-membered monocyclic saturated or partially unsaturated heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heterocyclile is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is a six-membered monocyclic saturated or partially unsaturated heterocyclile having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heterocyclile is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is a six-membered monocyclic saturated or partially unsaturated heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heterocyclile is C 1-4 It is selectively substituted with an aliphatic. In some embodiments, R wis piperidinyl, piperazinyl, tetrahydropyranil, 2H-pyranil, 4H-pyranil, 1,4-dioxanil, 1,4-dioxinyl, thianil, 2H-thiopyranil, 4H-thiopyranil, 1,3-ditanil, 1,4-ditanil, morpholinil, thiomophorinil, dihydropyridinyl, tetrahydropyridinyl, dihydropyranil, dihydrothiopyranil, or tetrahydrothiopyranil, and each of these is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is C 1-4 Aliphatic (e.g., C 1-4 It is a piperazinyl selectively substituted with an alkyl group.

[0331] In some embodiments, R w is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heteroaryl is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is a pentatonic monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heteroaryl is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is a pentatonic monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heteroaryl is optionally substituted with -C(O)NR2. In some embodiments, R w is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl, and each of these is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, Rw is an oxadiazolyl optionally substituted with -C(O)NR2 (e.g., -C(O)N(CH3)2). In some embodiments, R w is a six-membered monocyclic heteroaryl having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heteroaryl is a halogen, C 1-4 It is optionally substituted with an aliphatic, -OR, or -C(O)NR2. In some embodiments, R w is a six-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where the heteroaryl is C 1-4 It is selectively substituted with an aliphatic. In some embodiments, R w is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridinonyl, pyrazinonyl, or pyrimidinoyl. In some embodiments, R w is C 1-4 It is a pyridonyl selectively substituted with an aliphatic.

[0332] In some embodiments, R w is doing Table 1A or Table 1B As shown in the compound.

[0333] In some embodiments, R w is fluoro, chloro, -CN, -OH, -OMe, -OCH2CO2Me, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NMe2, -C(O)N(Me)Et, -C(O)N(Me)nPr, or am.

[0334] In some embodiments, R w-fluoro, chloro, -CN, methyl, -CF3, -CHF2, -OH, -OMe, -OCH2CO2Me, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NMe2, -C(O)N(Me)Et, -C(O)N(Me)nPr, , , or am.

[0335] In some embodiments, R w Is , or am.

[0336] In some embodiments, R w Is or am.

[0337] In some embodiments, R w is -CH2CH2CH3, , or am.

[0338] In some embodiments, R w Is , or am.

[0339] In some embodiments, R w is fluoro, chloro, -CN, -OH, -OMe, -OCF3, -OCH2CO2Me, -C(O)NH2, -C(O)NMe2, -(CH2)2C(O)NMe2, -CH2N(H)C(O)NMe2, , or am.

[0340] As described above and defined in this specification, each R w1 Silver is hydrogen, C 1-4Independently selected from 6-membered monocyclic heteroaryls having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR.

[0341] In some embodiments, each R w1 Silver is hydrogen or C 1-4 It is selected independently from the aliphatic.

[0342] In some embodiments, R w1 It is hydrogen.

[0343] In some embodiments, R w1 C 1-4 It is aliphatic, wherein the aliphatic is optionally substituted with a halogen, -OR, or -C(O)OR. In some embodiments, R w1 C 1-4 It is alkyl, wherein the alkyl is optionally substituted with a halogen, -OR, or -C(O)OR. In some embodiments, R w1 C 1-4 It is aliphatic (e.g., -CH3). In some embodiments, R w1 C 1-4 It is aliphatic, wherein the aliphatic is optionally substituted with a halogen (e.g., -CF3). In some embodiments, R w1 C 1-4 It is an aliphatic group, where the aliphatic group is optionally substituted with -C(O)OR (e.g., -CH2C(O)OCH3).

[0344] In some embodiments, R w1 is phenyl, where phenyl is optionally substituted with a halogen, -OR, or -C(O)OR. In some embodiments, R w1 is phenyl. In some embodiments, R w1 is phenyl, where phenyl is optionally substituted with -OR (e.g., -OCH3).

[0345] In some embodiments, Rw1 is a six-membered monocyclic heteroaryl having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR. In some embodiments, R w1 is a 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R w1 It is a six-membered monocyclic heteroaryl (e.g., pyridyl) having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0346] In some embodiments, R w1 Eun Hagi Table 1A or Table 1B As shown in the compound.

[0347] In some embodiments, R w1 Silver hydrogen, methyl, -CF3, -CH2C(O)OCH3, , or am.

[0348] As described above and defined in this specification, each R x C independently 1-4 It is an aliphatic, halogen, or -C(O)NR2. In some embodiments, R x is C 1-4 It is aliphatic. In some embodiments, R x is C 1-4 It is an alkyl. In some embodiments, R x is a halogen. In some embodiments, R x is a fluoro. In some embodiments, R x is -C(O)NR2. In some embodiments, R x is -C(O)N(H)(R). In some embodiments, R x is -C(O)N(CH3)2.

[0349] In some embodiments, R x is doing Table 1Aor Table 1B As shown in the compound.

[0350] As described above and defined in this specification, each R y C independently 1-4 It is aliphatic, halogen, -OR, or -C(O)NR2. In some embodiments, R y is C 1-4 It is aliphatic. In some embodiments, R y is C 1-4 It is an alkyl. In some embodiments, R y is a halogen. In some embodiments, R y is -OR. In some embodiments, R y is -C(O)NR2. In some embodiments, R y is -C(O)N(H)(R). In some embodiments, R y is -C(O)N(CH3)2. In some embodiments, R y is fluoro, chloro, bromo, iodo, methyl, ethyl, cyclopropyl, -OH, or -OMe.

[0351] In some embodiments, R y is doing Table 1A or Table 1B As shown in the compound.

[0352] As described above and defined in this specification, each R is independently hydrogen or C 1-4 It is aliphatic. In some embodiments, each R is independently hydrogen or C 1-4 Alkyl. In some embodiments, R is hydrogen. In some embodiments, R is C 1-4 It is aliphatic. In some embodiments, R is C 1-4 It is an alkyl (e.g., methyl).

[0353] In some embodiments, R is as follows Table 1A or Table 1B As shown in the compound.

[0354] As described above and defined in this specification, each m is independently 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0355] As described above and defined herein, each n is independently 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0356] As described above and defined in this specification, w, x, and y are each independently 0, 1, 2, 3, or 4.

[0357] In some embodiments, one or more of w, x, and y are 0. In some embodiments, one or more of w, x, and y are 1. In some embodiments, one or more of w, x, and y are 2. In some embodiments, one or more of w, x, and y are 3. In some embodiments, one or more of w, x, and y are 4.

[0358] In some embodiments, w is 0, 1, 2, or 3. In some embodiments, w is 0, 1, or 2. In some embodiments, w is 1, 2, or 3. In some embodiments, w is 0 or 1. In some embodiments, w is 1 or 2. In some embodiments, w is 2 or 3. In some embodiments, w is 3 or 4. 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.

[0359] In some embodiments, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 1, 2, or 3. In some embodiments, x is 0 or 1. In some embodiments, x is 1 or 2. In some embodiments, x is 2 or 3. In some embodiments, x is 3 or 4. 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.

[0360] In some embodiments, y is 0, 1, 2, or 3. In some embodiments, y is 0, 1, or 2. In some embodiments, y is 1, 2, or 3. In some embodiments, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 2 or 3. In some embodiments, y is 3 or 4. 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.

[0361] In some embodiments, m, n, w, x, and y are as follows Table 1A or Table 1B As shown in the compound.

[0362] In some embodiments, the present disclosure is a chemical formula II-a compounds of or provides a pharmaceutically acceptable salt thereof:

[0363] [Chemical Formula II-a]

[0364]

[0365] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0366] In some embodiments, the present disclosure is a chemical formula III-a Provides a compound of or a pharmaceutically acceptable salt thereof:

[0367] [Chemical Formula III-a]

[0368]

[0369] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0370] In some embodiments, the present disclosure is a chemical formula IV-a Provides a compound of or a pharmaceutically acceptable salt thereof:

[0371] [Chemical Formula IV-a]

[0372]

[0373] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0374] In some embodiments, the present disclosure is a chemical formula Ib-1 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0375] [Chemical Formula Ib-1]

[0376]

[0377] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0378] In some embodiments, the present disclosure is a chemical formula Ib-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0379] [Chemical Formula Ib-2]

[0380]

[0381] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0382] In some embodiments, the present disclosure is a chemical formula II-b Provides a compound of or a pharmaceutically acceptable salt thereof:

[0383] [Chemical Formula II-b]

[0384]

[0385] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0386] In some embodiments, the present disclosure is a chemical formula II-b-1 or II-b-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0387] [Chemical Formula II-b-1]

[0388]

[0389] [Chemical Formula II-b-2]

[0390]

[0391] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0392] In some embodiments, the present disclosure is a chemical formula III-b Provides a compound of or a pharmaceutically acceptable salt thereof:

[0393] [Chemical Formula III-b]

[0394]

[0395] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0396] In some embodiments, the present disclosure is a chemical formula III-b-1 or III-b-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0397] [Chemical Formula III-b-1]

[0398]

[0399] [Chemical Formula III-b-2]

[0400]

[0401] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0402] In some embodiments, the present disclosure is a chemical formula IV-b Provides a compound of or a pharmaceutically acceptable salt thereof:

[0403] [Chemical Formula IV-b]

[0404]

[0405] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0406] In some embodiments, the present disclosure is a chemical formula IV-b-1 or IV-b-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0407] [Chemical Formula IV-b-1]

[0408]

[0409] [Chemical Formula IV-b-2]

[0410]

[0411] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0412] In some embodiments, the present disclosure is a chemical formula Vb Provides a compound of or a pharmaceutically acceptable salt thereof:

[0413] [Chemical Formula Vb]

[0414]

[0415] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0416] In some embodiments, the present disclosure is a chemical formula Vb-1 or Vb-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0417] [Chemical Formula Vb-1]

[0418]

[0419] [Chemical Formula Vb-2]

[0420]

[0421] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0422] In some embodiments, the present disclosure is a chemical formula Vb-3 or Vb-4 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0423] [Chemical Formula Vb-3]

[0424]

[0425] [Chemical Formula Vb-4]

[0426]

[0427] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0428] In some embodiments, the present disclosure is a chemical formula VI-b Provides a compound of or a pharmaceutically acceptable salt thereof:

[0429] [Chemical Formula VI-b]

[0430]

[0431] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0432] In some embodiments, the present disclosure is a chemical formula VI-b-1 or VI-b-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0433] [Chemical Formula VI-b-1]

[0434]

[0435] [Chemical Formula VI-b-2]

[0436]

[0437] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0438] In some embodiments, the present disclosure is a chemical formula VII-b Provides a compound of or a pharmaceutically acceptable salt thereof:

[0439] [Chemical Formula VII-b]

[0440]

[0441] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0442] In some embodiments, the present disclosure is a chemical formula VII-b-1 or VII-b-2 Provides a compound of or a pharmaceutically acceptable salt thereof:

[0443] [Chemical Formula VII-b-1]

[0444]

[0445] [Chemical Formula VII-b-2]

[0446]

[0447] In the above chemical formulas, each variable is as defined above and described individually as well as in combination in this specification.

[0448] The exemplary compounds of the present invention are as follows: Table 1A, Table 1B, Table 2A, and Table 2B It is presented in.

[0449] [Table 1A]

[0450] Exemplary compounds

[0451]

[0452]

[0453]

[0454]

[0455] [Table 1B]

[0456] Exemplary compounds

[0457]

[0458]

[0459]

[0460]

[0461]

[0462] [Table 2A]

[0463] Exemplary compounds

[0464]

[0465]

[0466]

[0467] [Table 2B]

[0468] Exemplary compounds

[0469]

[0470] In some embodiments, the present invention is as follows: Table 1AThe present invention provides the compound presented in, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides the above Table 1A to The present invention provides the presented compound. In some embodiments, the present invention provides the above Table 1B The present invention provides the compound presented in, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides the above Table 1B The present invention provides the compound presented in [the invention]. In some embodiments, the present invention provides the above Table 2A The present invention provides the compound presented in, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides the above Table 2A The present invention provides the compound presented in [the invention]. In some embodiments, the present invention provides the above Table 2B The present invention provides the compound presented in, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides the above Table 2B Provides the compound presented in.

[0471] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (described alone and as in combination in the embodiments thereof) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. For example, in some embodiments, the present invention provides a provided compound (e.g., a chemical formula as defined above). Ia or Ib The present invention provides a pharmaceutical composition comprising a compound of), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a provided compound (e.g., a chemical formula as defined above). Ia or Ib The present invention provides a pharmaceutical composition comprising a compound of ) together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 1AThe present invention provides a pharmaceutical composition comprising the compound presented herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 1A The present invention provides a pharmaceutical composition comprising the compound presented herein together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 1B The present invention provides a pharmaceutical composition comprising the compound presented herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 1B The present invention provides a pharmaceutical composition comprising the compound presented herein together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 2A The present invention provides a pharmaceutical composition comprising the compound presented herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 2A The present invention provides a pharmaceutical composition comprising the compound presented herein together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 2B The present invention provides a pharmaceutical composition comprising the compound presented herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides the above Table 2B Provides a pharmaceutical composition comprising the compound presented in [the invention] together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0472] In some embodiments, the present invention relates to a provided compound (e.g., a chemical formula as defined above) for use as a medicine. Ia or Ib A compound of), or a pharmaceutically acceptable salt thereof, or a provided compound (e.g., a chemical formula as defined above). Ia or Ib Provides a pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0473] In some embodiments, the present invention also includes a compound described herein (e.g., chemical formula) for use in a method of controlling (e.g., inhibiting) STAT6 described herein. Ia or Ib The present invention provides a compound of), or a pharmaceutical composition as described herein. In some embodiments, the present invention also provides a compound as described herein (e.g., formula Ia or Ib Provides a compound of), or a pharmaceutical composition as described in this specification.

[0474] 4. General method of providing the present compound

[0475] The compounds of the present invention may be prepared or isolated by synthetic and / or semi-synthetic methods generally known to those skilled in the art for similar compounds, and by the methods described in detail in the examples of this specification.

[0476] 5. Uses, Formulation, and Administration

[0477] Pharmaceutically acceptable composition

[0478] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective for measurably controlling (e.g., inhibiting) the STAT6 protein or its mutant in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective for measurably controlling (e.g., inhibiting) the STAT6 protein or its mutant in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient who requires such composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0479] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0480] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffering substances, such as phosphate, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0481] "Pharmaceuticalally acceptable derivatives" means any non-toxic salt, ester, salt of an ester, or prodrug of the compound of the present invention that, when administered to a recipient, can directly or indirectly provide the compound of the present invention or its inhibitory active metabolites or residues. In some embodiments, "pharmaceutically acceptable derivatives" are pharmaceutically acceptable salts.

[0482] As used herein, the term “its inhibitory active metabolite or residue” means that the metabolite or residue is also an inhibitor of the STAT6 protein or its mutant.

[0483] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. As used herein, the term “parenterally” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intravertebral, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent that is acceptable for parenteral use, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents available for use are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixative oil is typically used as a solvent or suspension medium.

[0484] For this purpose, any mild (bland) fixative oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, and pharmaceutically acceptable natural oils, such as olive oil or castor oil, particularly polyoxyethylated versions, are also useful. Additionally, these oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0485] The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solvents. For oral tablets, carriers commonly used include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, specific sweeteners, flavorings, or colorings may be added.

[0486] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the formulation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts rectally to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0487] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly where the therapeutic target comprises a site or organ that is easily accessible by topical application, including the eyes, skin, or lower internal organs. Topical formulations suitable for each of these sites or organs are readily prepared.

[0488] Local application to the lower visceral tract can be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0489] For topical application, the provided pharmaceutically acceptable composition may be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the provided pharmaceutically acceptable composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldocecanol, benzyl alcohol, and water.

[0490] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a finely divided suspension in pH-adjusted isotonic sterile saline, or preferably as a solution in pH-adjusted isotonic sterile saline with or without a preservative such as benzyl alcoholonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum.

[0491] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0492] Most preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulation may be administered with or without food intake. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food intake. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food intake.

[0493] The amount of the compound of the present invention that can be combined with a carrier material to produce a single-dose composition will vary depending on the target of treatment and the specific method of administration. Preferably, the provided composition should be formulated so that a dose of the compound of 0.01 to 100 mg / kg / day of body weight can be administered to a patient receiving such composition.

[0494] In addition, it should be understood that the specific dosage and treatment regimen for any specific patient will depend on various factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, excretion rate, drug combination, and the judgment of the attending physician, as well as the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also vary depending on the specific compound in the composition.

[0495] Uses of compounds and pharmaceutically acceptable compositions

[0496] The compounds and compositions described herein are generally useful for regulating STAT6 protein activity, including phosphorylated or activated STAT6 protein (e.g., pSTAT6) activity.

[0497] According to one embodiment, the present invention relates to a method for inhibiting the activity of STAT6 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising said compound.

[0498] As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, STAT6 is obtained from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0499] Inhibition of the activity of STAT6 or its mutants in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen preservation, and biological analysis methods.

[0500] According to another embodiment, the present invention relates to a method for controlling (e.g., inhibiting) the activity of STAT6 or a mutant thereof in a patient, comprising the step of administering a compound of the present invention or a composition comprising said compound to said patient. In another embodiment, the present invention provides a method for treating a disorder mediated by STAT6 or a mutant thereof in a patient requiring treatment for such disorder, comprising the step of administering a compound according to the present invention or a pharmaceutically acceptable composition thereof to said patient. Such disorder is described in detail herein.

[0501] The activity of the compounds used in the present invention as regulators (e.g., inhibitors) of STAT6 or its mutants can be analyzed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the activity of the activated STAT6 protein or its mutants and / or the inhibition of subsequent functional outcomes. Alternative in vitro assays quantify the ability of the inhibitor to bind to the STAT6 protein. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / STAT6 complex, and determining the amount of the bound radiolabel. Alternatively, inhibitor binding can be determined by conducting a competitive experiment in which a novel inhibitor is incubated with a STAT6 protein bound to a known radioligand. Detailed conditions for analyzing the compounds utilized in the present invention as regulators (e.g., inhibitors) of STAT proteins or their mutants are presented in the following examples.

[0502] As used herein, the terms “treatment,” “to treat,” and “treating” refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before symptoms occur (e.g., considering a history of symptoms and / or genetic or other susceptibility factors). Additionally, treatment may be continued after symptoms have disappeared, for example, to prevent or delay the recurrence of symptoms.

[0503] The provided compound is a regulator (e.g., an inhibitor) of the STAT6 protein and is therefore useful for treating one or more disorders associated with the activity of the STAT6 protein. Accordingly, in certain embodiments, the present invention provides a method for treating a STAT6-mediated disorder comprising the step of administering the compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0504] As used herein, the term “STAT6-mediated” disorder, disease, and / or condition as used herein refers to any disease or other harmful condition known to involve STAT6 or a mutant thereof. Accordingly, another embodiment of the present invention relates to treating or alleviating the severity of one or more diseases known to involve STAT6 or a mutant thereof.

[0505] STAT6 functions as a transcription factor that induces gene expression and plays a crucial role in the IL-4 / IL-13 signaling pathway; therefore, it is critical in IL-4 / IL-13-mediated biological responses, including those in human malignancies (e.g., Patel, BKR, et al. "Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a region implicated in multiple solid tumors." Genomics 52.2 (1998): 192-200). STAT6-mediated signaling pathways are required for the development of T-helper type 2 (Th2) cells and Th2 immune responses, and have been shown to play an important role in the pathogenesis of asthma and Th2 pulmonary inflammatory responses, including the clearance of parasitic infections (e.g., Walford, HH and Doherty, TA "STAT6 and lung inflammation." Jak-stat 2.4 (2013): e25301). STAT6 has been found to induce the expression of BCL2L1 / Bcl-X(L), which is involved in the anti-apoptotic activity of IL-4, and has been shown to play an important role in adaptive immunity, such as providing innate immune signaling in response to viral infection (e.g., Chen, H., et al. "Activation of STAT6 by STING is critical for antiviral innate immunity." Cell 147.2 (2011): 436-446). Knockout studies in mice suggested a role for STAT6 in the differentiation of T helpers (Th2), the expression of cell surface markers, and the class switch of immunoglobulins. The STAT6 protein also regulates other transcription factors, such as Gata3, which is an important regulator of Th2 differentiation. STAT6 is also required for the development of IL-9-secreting T cells.

[0506] In some embodiments, biomarkers associated with the IL-4 / 13 pathway include IgE, thymus and activation-regulated chemokine (TARC), CD23, periostin, and eosinophils. TARC is a serum TH2 biomarker and a chemoattractant for TH2 cells. CD23 is a B cell activation marker and correlates with IgE class switching. Periostin is a serum TH2 biomarker and an ECM protein associated with tissue remodeling in atopic diseases.

[0507] In some embodiments, treatment with the provided compound results in less IL-4-induced TARC release compared to reference or standard levels. In some embodiments, treatment with the provided compound results in less IL-13-induced CD23 expression compared to reference or standard levels. In some embodiments, treatment with the provided compound results in less IL-13-induced periostin release compared to reference or standard levels.

[0508] In some embodiments, treatment with the provided compound inhibits IL-4-induced TARC release. In some embodiments, treatment with the provided compound inhibits IL-13-induced CD23 expression. In ISE, treatment with the provided compound inhibits IL-13-induced periostin release.

[0509] 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 cancer, neurodegenerative disorder, viral disease, autoimmune disease, inflammatory disorder, condition associated with organ transplantation, immunodeficiency disorder, infectious disease, thrombin-induced platelet aggregation, liver disease, or pathological immune condition involving T cell activation.

[0510] Diseases and conditions treatable according to the method of the present invention include, but are not limited to, viral diseases, autoimmune diseases, autoinflammatory syndromes, atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease, inflammation, acute and chronic gout and gouty arthritis, neurological disorders, immunodeficiency disorders, e.g., AIDS and HIV, osteoarthritis, infectious diseases, and pathological immune conditions involving T cell activation. In one embodiment, a human patient is treated with a compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, said compound being present in an amount to measurably regulate (e.g., inhibit) STAT6 or a mutant thereof.

[0511] The compounds according to the present invention are useful for the treatment of inflammatory or obstructive airway diseases, for example, resulting in a reduction of tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention may be applied include asthma of all types or origins, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma, and asthma that is exacerbated or induced after bacterial or viral infection. Asthma treatment should also be understood to include the treatment of subjects, for example, under the age of 4 or 5, who are diagnosed or diagnosable as "wheezing infants" (an established patient category of primary medical interest, currently commonly identified as patients with onset or early-stage asthma) due to exhibiting wheezing symptoms.

[0512] Another aspect of the present invention is a method for treating an allergic or inflammatory disease in a subject, comprising the step of administering a therapeutically effective amount of a compound of the present invention to the subject. The disease may be a lung disease, e.g., asthma, airway hyperresponsiveness (AHR), an allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD), reactive airway disease, chronic rhinosinusitis, or any other disease of the upper or lower airway that essentially causes airflow obstruction.

[0513] The prophylactic efficacy in asthma treatment will be demonstrated by a reduction in the frequency or severity of symptom attacks, e.g., acute asthma or bronchoconstrictor attacks, or by an improvement in lung function or airway hyperresponsiveness. This may also be demonstrated by a reduced need for other symptomatic therapies, such as anti-inflammatory drugs or bronchodilators, intended to limit or stop symptom attacks when they occur. The prophylactic benefit in asthma may be particularly evident in subjects with a tendency toward "morning dipping." "Morning dipping" is an asthma syndrome recognized as common to a significant proportion of asthma patients and is characterized, for example, between approximately 4 a.m. and 6 a.m., that is, at a time usually significantly separated from any previously administered symptomatic asthma therapy.

[0514] In some embodiments, STAT6 is recruited to a phosphotyrosine residue via the Src homology 2 (SH2) domain and phosphorylated on Tyr641. In some embodiments, STAT6 is then dimerized via mutual SH2 domain-pTyr641 interactions and translocated to the nucleus to be involved in gene expression that causes asthma and airway hyperresponsiveness (AHR).

[0515] In some embodiments, the present invention provides a method for treating asthma in a patient requiring treatment for asthma, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0516] In some embodiments, the present invention provides a method for treating airway hyperresponsiveness (AHR) in a patient requiring treatment for airway hyperresponsiveness (AHR), comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0517] In some embodiments, the present invention provides a method for treating allergic rhinitis in a patient requiring treatment for allergic rhinitis, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, the present invention provides a method for treating asthma in a patient requiring treatment for allergic asthma, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0519] In some embodiments, the present invention provides a method for treating emphysema in a patient requiring treatment for emphysema, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0520] In some embodiments, the present invention provides a method for treating chronic rhinosinusitis in a patient requiring treatment for chronic rhinosinusitis, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0521] In some embodiments, the present invention provides a method for treating COPD in a patient requiring treatment for COPD, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0522] The compounds of the present invention may be used for other inflammatory or obstructive airway diseases and conditions to which the present invention may be applied, such diseases and conditions include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive lung, airway or lung disease (COPD, COAD, or COLD) (including chronic bronchitis or associated dyspnea), emphysema, as well as exacerbation of airway hyperresponsiveness resulting from other drug therapies, particularly other inhaled drug therapies. The present invention may also be applied to the treatment of bronchitis of all types or origins, including but not limited to acute, arachnid, catarrhal, croupic, chronic, or tuberculous bronchitis. Additional inflammatory or obstructive airway diseases to which the present invention may be applied include pneumoconiosis of all types or origins (an inflammatory disease of the lungs that often occurs as an occupational disease, frequently accompanied by airway obstruction regardless of whether it is chronic or acute, and caused by repeated dust inhalation), which include, for example, alucentosis, carbonaceous effusion, asbestosis, pycnidiasis, pycnidiasis, iron deposition, silicosis, tobacco poisoning, and cotton pneumoconiosis.

[0523] The compound of the present invention is useful for the treatment of eosinophil-related disorders, e.g., eosinophil-related disorders of the airway (e.g., related to pathological eosinophil infiltration of lung tissue), including eosinophilia, particularly hypereosinophilia affecting the airway and / or lungs, as well as e.g., eosinophil-related disorders of the airway causing or accompanying Loeffler syndrome, eosinophilic lungitis, parasitic (particularly metazoan) infection (accompanied by tropical eosinophilia), bronchopulmonary aspergillosis, esophagitis, polyarteritis nodularis (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related disorders affecting the airway caused by drug reactions.

[0524] The compounds of the present invention are also useful for treating inflammatory or allergic conditions of the skin. In some embodiments, the present invention provides a method for treating an inflammatory or allergic condition of the skin in a patient requiring treatment for such condition, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0525] In some embodiments, inflammatory diseases of the skin are selected from psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermal bullous disease, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0526] The compounds of the present invention are for the treatment of other diseases or conditions having inflammatory components, such as diseases or conditions of the eye including ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose including allergic rhinitis; and autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease. Sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior), Sjögren's syndrome, dry keratoconjunctivitis 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 or without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirotic nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle wasting, catabolic disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, indeterminate ectodermal dysplasia, Behcet's disease, ataxia pigmentosa, Paget's disease, Pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitist and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis, ocular allergy, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperreactivity, remodeling or disease progression),Lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, myoinflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes mellitus, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryodermatitis, dermatitis, dermatitis myositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibroitis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, It may also be used to treat inflammatory diseases that are believed to be influenced by an autoimmune response or have autoimmune components or etiologies, including meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0527] In some embodiments, the present invention provides a method for 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.

[0528] In some embodiments, the present invention provides a method for treating idiopathic interstitial lung disease (IIP), including any type of pulmonary fibrosis, interstitial lung disease associated with rheumatic disease (including SSc), or IPF itself, in a patient requiring treatment for idiopathic interstitial lung disease (IIP), including any type of pulmonary fibrosis, interstitial lung disease associated with rheumatic disease (including SSc), or IPF itself, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0529] In some embodiments, the inflammatory disease that can be treated according to the method of the present 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 cyclic syndrome (CAPS), and osteoarthritis.

[0530] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is a TH17-mediated disease or a TH17-associated disease. In some embodiments, the TH17-mediated disease or a TH17-associated disease is selected from psoriasis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis), or graft-versus-host disease.

[0531] In some embodiments, inflammatory diseases that can be treated according to the method of the present invention are selected from ocular pathologies such as Sjögren's syndrome, allergic disorders, osteoarthritis, ocular allergies, conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0532] In some embodiments, the present invention provides a method for treating an autoimmune disease or inflammatory disorder selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic 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), vasculitis (e.g., vasculitis), and STAT6 gain-of-function (GOF) mutations.

[0533] In some embodiments, the present invention provides a method for treating a STAT6 gain-of-function (GOF) mutation in a patient requiring treatment for the STAT6 gain-of-function (GOF) mutation, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT6 GOF mutation is STAT6VT.

[0534] In some embodiments, cardiovascular diseases that can be treated according to the method of the present invention include, but are not limited to, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, unstable angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass surgery, restenosis after coronary artery bypass surgery, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[0535] In some embodiments, neurodegenerative diseases that can be treated according to the method 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 traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes, metabolic syndrome, obesity, organ transplantation, and neurodegenerative diseases caused by graft-versus-host disease.

[0536] In some embodiments, the present invention provides a method for treating, preventing, or alleviating the severity of Alzheimer's disease, comprising the step of administering a provided compound or a pharmaceutically acceptable salt or composition thereof to a patient in need thereof.

[0537] In some embodiments, the present invention provides a method for treating a disease or condition that commonly occurs in connection with transplantation. In some embodiments, the disease or condition that commonly occurs in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0538] In some embodiments, the present invention provides a method for treating a metabolic disease. In some embodiments, the metabolic disease is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0539] In some embodiments, the present invention provides a method for treating a viral disease. In some embodiments, the viral infection is HIV or COVID19 infection.

[0540] In some embodiments, the present invention provides a method for treating JAK-associated diseases other than cancer.

[0541] In addition, the present invention provides the use of a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof according to the definition in this specification for the manufacture of a medicine for the treatment of inflammatory diseases, obstructive respiratory diseases, neurodegenerative diseases, viral diseases, or disorders commonly occurring in association with transplantation.

[0542] Combination therapy

[0543] Depending on the specific condition or disease to be treated, additional therapeutic agents typically administered to treat such condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific disease or condition are known to be "appropriate for the disease or condition to be treated."

[0544] In certain embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent. It will be understood that the combination therapy described herein is intended solely for the treatment of the diseases, disorders, and conditions described herein.

[0545] In some embodiments, the present invention provides a method for treating a disclosed disease or condition, comprising the steps of administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a patient in need thereof, and administering an effective amount of one or more additional therapeutic agents, such as those described herein, in combination or sequentially. In some embodiments, the method comprises the step of administering one additional therapeutic agent in combination. In some embodiments, the method comprises the step of administering two additional therapeutic agents in combination. In some embodiments, the combination of the disclosed compound and additional therapeutic agents or therapeutic agents acts synergistically.

[0546] Examples of formulations that may also be used in combination with the combination of the present invention include, without limitation, the following: treatments for Alzheimer's disease, e.g., Aricept ® and Excelon ®; Treatment for HIV, e.g., ritonavir; treatment for Parkinson's disease, e.g., L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexaphendyl, and amantadine; agents for the treatment of multiple sclerosis (MS), e.g., beta interferon (e.g., Avonex ® and Rebif ® ), glatiramer acetate (Copaxone ® ), and mitoxantrone; treatment for asthma, e.g., albuterol and Singulair ® ; Agents for treating schizophrenia, e.g., Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, e.g., corticosteroids, TNF blockers, IL-1 RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; agents for treating cardiovascular disease, e.g., beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; Preparations for the treatment of liver disease, e.g., corticosteroids, cholestyramine, interferon, and antiviral agents; preparations for the treatment of blood disorders, e.g., corticosteroids that prolong or improve pharmacokinetics, e.g., cytochrome P450 inhibitors (i.e., metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketokenozol and ritonavir), pirfenidone (Esbriet) ® , nintedanib (Ofev ® ), intravenous immunoglobulin, bosentan (Tracleer ® ), Nifedipine (Procardia XL ® ), Sildenafil (Revatio ® ), Losartan (Cozaar® ), Iloprost (Ventavis ® ), topical nitroglycerin, N-acetylcysteine, anti-acid therapy, and preparations for treating immunodeficiency disorders, e.g., gamma globulin.

[0547] In certain embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0548] These additional agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, these agents may be mixed together with the compounds of the present invention in a single composition to form part of a single-dose formulation. When administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or from each other within a certain period of time, typically within 5 hours of each other.

[0549] As used herein, the terms “concurrent,” “concurrently used,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the concurrent agent of the present invention may be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form, or may be administered together in a single unit dosage form.

[0550] The amount of additional therapeutic agent present in the composition of the present invention will not exceed the amount typically administered in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition disclosed herein will be in the range of about 50% to 100% of the amount typically present in a composition containing said agent as the sole therapeutic active agent.

[0551] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple-dose regimen. Alternatively, one or more other therapeutic agents may be mixed together with the compound of the present invention in a single composition to form part of a single-dose regimen. When administered as a multiple-dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a set period from each other, for example, within 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, 18 hours, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, one or more other therapeutic agents and the compound or composition of the present invention are administered as a multiple-dose regimen at intervals of more than 24 hours.

[0552] In one embodiment, the present invention provides a composition comprising the provided compound and one or more additional therapeutic agents. The therapeutic agent may be administered together with the provided compound, or may be administered before or after the administration of the provided compound. Suitable therapeutic agents are described in further detail below. In certain embodiments, the 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 administration of the therapeutic agent. In another embodiment, the 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 after administering the therapeutic agent.

[0553] In another embodiment, the present invention provides a method for treating an inflammatory disease, disorder, or pathological condition by administering the provided compound and one or more additional therapeutic agents to a patient requiring treatment for an inflammatory disease, disorder, or pathological condition. These additional therapeutic agents may be small molecule or recombinant biological agents, 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, etc., probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarial agents, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, such as gold thioglucose (Solganal®), gold thiomaleate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents, e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), sertolizumab pegol (Cimzia®), and adalimumab (Humira®), "anti-IL-1" agents, e.g., anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors, e.g., tofacitinib, antibodies, e.g., rituximab (Rituxan®), "anti-T-cell" agents, e.g., abatacept (Orencia®), and "anti-IL-6" agents, e.g. Tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies, e.g., tanezumab, anticoagulants,For example, heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®); antidiarrheal agents, for example, diphenoxylate (Lomotil®) and loperamide (Imodium®); bile acid binders, for example, cholestyramine, alosetron (Lotronex®), rubiprostone (Amitiza®); laxatives, for example, milk of magnesia emulsion, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®; anticholinergics or antispasmodics, for example, dicyclomin (Bentyl®), Singulair®; beta-2 agonists, for example, albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol Zinapoate (Serevent®) and formoterol (Foradil®), anticholinergics, e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids, e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines, e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies, e.g., omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors, For example, zidavudine (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, e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors, e.g., tenofovir (Viread®), protease inhibitors, e.g., 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, e.g., enfuvirtide (Fuzeon®) and includes maraviroc (Selzentry®), dexamethasone (Decadron®) combined with integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and lenalidomide (Revlimid®), or any combination thereof.

[0554] In another embodiment, the present invention provides a method for treating gout comprising the step of administering to a patient in need one or more additional therapeutic agents selected from the provided compound and non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, and febuxostat (Uloric®).

[0555] In another embodiment, the present invention provides a method for treating rheumatoid arthritis comprising the provided compound, and non-steroidal anti-inflammatory drugs (NSADS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine (Azulfidine®), antimalarial agents, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, such as gold thioglucose (Solganal®), gold thiomaleate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), The present invention provides a method comprising the step of administering one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), sertolizumab 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®) to a patient who requires such agents.

[0556] In some embodiments, the present invention provides a method for treating osteoarthritis comprising the step of administering to a patient in need one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0557] In some embodiments, the present invention provides a method for treating lupus comprising the step of administering to a patient in need one or more additional therapeutic agents selected from the provided compound and non-steroidal anti-inflammatory drugs (NSADS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial agents, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants, such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0558] In some embodiments, the present invention provides a method for treating inflammatory bowel disease comprising the step of administering to a patient in need one or more additional therapeutic agents selected from the provided compound, and mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), rubiprostone (Amitiza®), laxatives such as magnesia emulsion, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0559] In some embodiments, the present invention provides a method for treating asthma, comprising the provided compound, and Singulair®, beta-2 agonists, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol inapoate (Serevent®) and formoterol (Foradil®), anticholinergics, 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®), The present invention provides a method comprising the step of administering one or more additional therapeutic agents selected from flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolin sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®) to a patient who requires it.

[0560] In some embodiments, the present invention provides a method for treating COPD, comprising the provided compound, and beta-2 agonists, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol inapoate (Serevent®) and formoterol (Foradil®), anticholinergics, 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®), The present invention provides a method comprising the step of administering one or more additional therapeutic agents selected from triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera® to a patient who requires it.

[0561] In some embodiments, the present invention provides a method for treating HIV, comprising the provided compound, and 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®), nevirapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors, such as tenofovir (Viread®), and protease inhibitors, such as amprenavir (Agenerase®), The present invention provides a method comprising the step of administering one or more additional therapeutic agents selected from 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®), and combinations thereof to a patient who requires such treatment.

[0562] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs) that interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0563] In some embodiments, one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent for inhibiting bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and prevents binding to its receptor RANK found in osteoclasts, their precursors, and osteoclast-like giant cells. Other approved therapeutic agents for inhibiting bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0564] In some embodiments, the present invention provides a method for treating Alzheimer's disease, comprising the provided compound and donepezil (Aricept ® ), Rivastigmine (Excelon ® ), Galantamine (Razadyne ® ), Tacrine (Cognex ® ), and memantine (Namenda ® The present invention provides a method comprising the step of administering one or more additional therapeutic agents selected from ) to a patient who requires them.

[0565] In some embodiments, one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include the anti-VEGF monoclonal antibody bevacizumab (Avastin®, Genentech / Roche); the anti-VEGFR-2 antibody ramucirumab (Cyramza®, Eli Lilly); and ziv-aflibercept (Zaltrap®; Regeneron / Sanofi), also known as the VEGF trap; 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); and dabrafenib (Tafinlar®, Novartis). and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, e.g., cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, e.g., imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, e.g., gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); apatinib (Gilotrif®, Boehringer Ingelheim); Osimertinib (targeted activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals);c-Met and VEGFR2 inhibitors, e.g., carbozanitip (Cometriq®, Exelexis); and multikinase inhibitors, e.g., sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, e.g., crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, e.g., ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, e.g., midostaurine (Rydapt®, Novartis).

[0566] Other kinase inhibitors and VEGF-R antagonists under development that may be used in the present invention include tibozantinib (Aveo Pharmaceuticals); vartalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dobitinib (TKI258, Novartis); chauanib (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); and foretinib (Exelexis, GlaxoSmithKline). Includes quizatinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0567] In another embodiment, the present invention provides a method for treating organ transplant rejection or graft-versus-host disease, comprising the step of administering the provided compound and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors to a patient in need thereof.

[0568] In another embodiment, the present invention provides a method for treating a disease or alleviating its severity, comprising the step of administering a provided compound and a BTK inhibitor to a patient in need thereof, wherein the disease is inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, Odd's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculomotor-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease. Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia generalized torticollis, Behcet's disease, chronic fatigue, autonomic dysfunction, membranous glomerulonephrosis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigus, neuromuscular dystonia, scleroderma, vulvodynia, rejection of transplanted organ or tissue, acquired immunodeficiency syndrome (also known as AIDS or HIV), type 1 diabetes mellitus, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach mites), 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, dacryodermatitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,Epididymitis, fasciitis, fibroitis, 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, pneumonia, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, joint inflammation and pain, bone and joint diseases resulting in cartilage and / or bone destruction as well as bone regeneration and fusion (without limitation, rheumatoid arthritis, seronegative Spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, thromboembolic disorders (e.g., myocardial infarction, unstable angina, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass surgery, restenosis after coronary artery bypass surgery, stroke, transient ischemic attack, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, idiopathic autoimmune hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative Colitis, Sjögren's disease, tissue graft rejection, hyperacute rejection of transplanted organ, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyathematous disease (also known as autoimmune polyathematous syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis,Selected from osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory response (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury) and Graves' disease.

[0569] In another embodiment, the present invention provides a method for treating a disease or alleviating its severity, comprising the step of administering a provided compound and a PI3K inhibitor to a patient in need thereof, wherein the disease is selected from neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, conditions associated with organ transplantation, immunodeficiency disorders, infectious diseases, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, and cardiovascular disorders.

[0570] In another embodiment, the present invention provides a method for treating a disease or alleviating its severity, comprising the step of administering the provided compound and a PI3K inhibitor to a patient in need thereof, wherein the disease is psoriasis or a disease in which the PI3K / PKB pathway is abnormally activated; asthma of any type or origin, including both endogenous (non-allergic) asthma and exogenous (allergic) asthma; mild asthma; moderate asthma; severe asthma; bronchitis; exercise-induced asthma; occupational asthma; and asthma induced or exacerbated after bacterial or viral infection; acute lung injury (ALI); adult / acute respiratory distress syndrome (ARDS); chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD) (including chronic bronchitis or associated dyspnea); emphysema; as well as exacerbation of airway hyperreactivity resulting from other drug therapies, particularly other inhaled drug therapies; acute, arachidonic, catarrhal, croupic, chronic, or tuberculous bronchitis. Bronchitis of all types or origins, including but not limited to alucentosis, carbonaceous bronchitis, asbestosis, pneumoconiosis, trichiasis, iron deposition, silicosis, tobacco poisoning, and cotton swab bronchitis of all types or origins (an inflammatory disease of the lungs that often occurs as an occupational disease, frequently accompanied by airway obstruction regardless of whether chronic or acute, and caused by repeated dust inhalation), Loeffler syndrome, eosinophilic lungitis, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, nodular polyarteritis (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, erythematous Diseases affecting the nose, including lupus, pemphigus, acquired epidermal bullosis, conjunctivitis, dry keratoconjunctivitis, vernal conjunctivitis, and allergic rhinitis,and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiologies (including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell aplasia, and idiopathic thrombocytopenia)), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or It is selected from neurodegenerative diseases induced by minimal change nephropathy, restenosis, cardiac hypertrophy, 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 traumatic injury, glutamate neurotoxicity, and hypoxia.

[0571] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitors are selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanilisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0572] Depending on the specific condition or disease to be treated, additional therapeutic agents typically administered for the treatment of said condition may also be present in the composition of the present invention. As used herein, additional therapeutic agents typically administered for the treatment of a specific disease or condition are known to be "appropriate for the disease or condition to be treated."

[0573] As used herein, the term “aromatase inhibitor” relates to a compound that inhibits the production of estrogen, for example, the conversion of substrates androstenedione and testosterone into estrogen and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane; and, particularly, nonsteroids, particularly aminoglutecithimide, rogletimide, pyridoglutetimide, trirostan, testolactone, ketoconazole, borozol, padrozol, anastrozol, and letrozol. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Padrozol is marketed under the trade name Afema™. Anastrozol is marketed under the trade name Arimidex™. Letrozol is marketed under the trade names Femara™ or Femar™. Aminoglutecimide is marketed under the brand name Orimeten™.

[0574] In some embodiments, one or more other therapeutic agents are mTOR inhibitors that inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitors are everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0575] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anatazol (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[0576] As used herein, the term “anti-estrogen” relates to compounds that antagonize the effects of estrogen 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 is administered under the trade name Faslodex™.

[0577] As used herein, the term "anti-androgen" relates to any substance capable of inhibiting the biological effects of androgen hormones, including but not limited to bicalutamide (Casodex™). As used herein, the term "gonadorelin agonist" includes but not limited to abarellix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0578] As used herein, the term “protein or lipid kinase activity; or a compound that targets / reduces protein or lipid phosphatase activity; or an additional anti-angiogenic compound” includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, for example, a) a compound that targets, reduces, or inhibits the activity of platelet-derived growth factor receptor (PDGFR), such as a compound that targets, reduces, or inhibits the activity of PDGFR, in particular a compound that inhibits PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) a compound that targets, reduces, or inhibits the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g., compounds that target, reduce, or inhibit the activity of IGF-IR, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, e.g., imatinib; h) Compounds that target, reduce, or inhibit the activity of C-Kit receptor tyrosine kinases that are part of the PDGFR family, such as compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit c-Kit receptors, such as imatinib;i) Compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., Bcr-Abl kinase), and mutants, such as compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) Compounds that target, reduce, or inhibit the activity of members of the cyclin-dependent kinase family (CDK), including protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK, and TEC families, and / or staurosporine derivatives, such as midostaurine; examples of additional compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosin; ilmophosin; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce, or inhibit the activity of protein-tyrosine kinase inhibitors, e.g., compounds that target, reduce, or inhibit the activity of protein-tyrosine kinase inhibitors (imatinib mesylate (Gleevec™) or tirfostine, e.g., tirfostine A23 / RG-50810; AG 99; tirfostine AG 213; tirfostine AG 1748; tirfostine AG 490; tirfostine B44; tirfostine B44 (+) enantiomers; tirfostine AG 555; AG 494;tyrpostine AG 556, AG957 and adafostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, including adafostine); l) compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, e.g., compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, particularly compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family such as EGF receptors, ErbB2, ErbB3, and ErbB4, or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; Trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, 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 that target, reduce, or inhibit the activity of c-Met receptors, e.g., compounds that target, reduce, or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of c-Met receptors, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce, or inhibit 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, pacitinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib);o) Compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K) (including, but not limited to, TU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalisib, pictrelisib, PF-4691502, BYL-719, doctolisib, XL-147, XL-765, and idellalisib); and q) Compounds that target, reduce, or inhibit the signaling effects of the Hedgehog protein (Hh) or smoothed receptor (SMO) pathway (including, but not limited to, cyclopamine, bismodegib, itraconazole, erythmodegib, and IPI-926 (saridegib).;

[0579] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or derivatives thereof.

[0580] In some embodiments, one or more other therapeutic agents are growth factor antagonists, such as platelet-derived growth factor (PDGF), or antagonists of epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly); panitumumab (Vectibix®, Amgen); and osimertinib (targeted activated EGFR, Tagrisso®, AstraZeneca).

[0581] The term “PI3K inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against one or more enzymes within 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 the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupharlisib, pictrelisib, PF-4691502, BYL-719, doctolosib, XL-147, XL-765, and idellalisib.

[0582] The term “BTK inhibitor” as used herein includes, but is not limited to, compounds having inhibitory activity against Bruton tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

[0583] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against splenic tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0584] Additional anti-angiogenic compounds include, for example, compounds having another mechanism of activity unrelated to protein or lipid kinase inhibition, such as Thalidomide™ and TNP-470.

[0585] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or derivatives thereof.

[0586] Compounds that induce the cell differentiation process include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol or α-γ- or δ-tocotrienol.

[0587] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib, which is 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid.

[0588] As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, chlordronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Ethridonic acid is commercially available under the trade name Didronel™. Chlordronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™.

[0589] The term "mTOR inhibitor" refers to compounds that represent the mammalian target of rapamycin (mTOR) and possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0590] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0591] As used herein, the term “telomerase inhibitor” refers to a compound that targets, reduces, or inhibits the activity of telomerase. A compound that targets, reduces, or inhibits the activity of telomerase is, in particular, a compound that inhibits telomerase receptors, such as telomestatin.

[0592] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, benzamide or derivatives thereof.

[0593] As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes, but is not limited to, collagen peptide-mimicking and non-peptide-mimicking inhibitors, tetracycline derivatives, e.g., hydroxamate peptide-mimicking inhibitor batimastat and its oral bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0594] As used herein, the term “HSP90 inhibitor” includes, but is not limited to, compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90; and degrade, target, reduce, or inhibit HSP90 client proteins through the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; and radicicol and HDAC inhibitors.

[0595] EDG binders and ribonucleotide reductase inhibitors are also included. As used herein, the term “EDG binder” refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720.

[0596] The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribin, 6-mercaptopurine (particularly with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0597] In particular, compounds, proteins, or monoclonal antibodies of VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or pharmaceutically acceptable salts thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilan amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and Bevacizumab (Avastin™) are also included.

[0598] As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as, for example, anecortabb, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrogen, and dexamethasone.

[0599] Implants containing corticosteroids refer to compounds such as fluosinolone and dexamethasone.

[0600] The compound of the present invention is also useful as a co-therapeutic compound for use in combination with other active pharmaceutical ingredients, such as anti-inflammatory, bronchodilating, or antihistamine active pharmaceutical ingredients, and is particularly useful in the treatment of obstructive or inflammatory airway diseases such as those mentioned above, for example, as a potentiator for the therapeutic activity of such drugs or as a means to reduce the required dosage or potential side effects of such drugs. The compound of the present invention may be mixed with other active pharmaceutical ingredients within a fixed pharmaceutical composition, administered separately from other active pharmaceutical ingredients, or administered before, simultaneously with, or after the administration of other active pharmaceutical ingredients. Accordingly, the present invention comprises the combination of the compound of the present invention as described above with anti-inflammatory, bronchodilating, antihistamine, or antitussive active pharmaceutical ingredients, wherein said compound and said active pharmaceutical ingredient of the present invention exist within the same or different pharmaceutical compositions.

[0601] Suitable anti-inflammatory drugs include steroids, particularly glucocorticosteroids, e.g., budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists, e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, e.g., montelukast and zafirlukast; PDE4 inhibitors, e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and in particular formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxytropium bromide, tiotropium salt and CHF 4226 (Chiesi), and glycopyrrolate.

[0602] Suitable antihistamine active ingredients include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastin, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0603] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs include chemokine receptor antagonists, 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, e.g., Schering-Plough antagonists SC-351125, SCH-55700, and SCH-D; and Takeda antagonists, e.g., N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium It is used in combination with chloride (TAK-770).

[0604] The structure of an active compound identified by a code number, generic name, or trademark name may be taken from the actual edition of the standard overview “The Merck Index” or from a database, for example, Patents International (e.g., IMS World Publications).

[0605] The compound of the present invention may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy may take the form of a fixed combination, or the administration of the compound of the present invention and one or more other therapeutic compounds may be staggered or provided independently of each other, or the form of the combined administration of a fixed combination and one or more other therapeutic compounds.

[0606] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be mixed together with the compound of the present invention in a single composition as part of a single-dose regimen. When administered as part of a multi-dose regimen, the two active agents may be provided simultaneously, sequentially, or within a certain period of time from each other, typically within 5 hours from each other.

[0607] As used herein, the terms “concurrent,” “concurrently used,” and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form, or administered together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0608] The amounts of both the compound of the present invention and additional therapeutic agents (in such compositions including additional therapeutic agents as described above) that can be combined with a carrier material to produce a single-dose formulation will vary depending on the target of treatment and the specific mode of administration. Preferably, the composition of the present invention should be formulated so that a dose of the compound of the present invention of 0.01 to 100 mg per kg of body weight per day can be administered.

[0609] In these compositions containing additional therapeutic agents, said additional therapeutic agents and the compounds of the present invention may act synergistically. Therefore, the amount of additional therapeutic agents in these compositions will be less than that required in monotherapy using only said therapeutic agents. In these compositions, an additional therapeutic agent may be administered in a dosage of 0.01 to 1,000 μg / kg / day.

[0610] The amount of one or more other therapeutic agents present in the composition of the present invention may be less than the amount typically administered in a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the composition disclosed herein will be in the range of about 50% to 100% of the amount typically present in a composition containing said agent as the sole therapeutic active agent. In some embodiments, one or more other therapeutic agents are administered at a dose 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 typically administered for said agent. As used herein, the phrase “typically administered” means that the amount of FDA-approved therapeutic agent is provided for administration according to the FDA label attachment.

[0611] The compounds of the present invention or pharmaceutical compositions thereof may also be included in compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (the narrowing of a blood vessel wall again after injury). However, there is a risk of thrombosis or platelet activation for patients using stents or other implantable devices. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with a compound of the present invention is another embodiment of the present invention.

[0612] Examples

[0613] General synthesis method

[0614] The following examples are intended to illustrate the invention and should not be construed as limiting the invention. Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporation is carried out under reduced pressure, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. The abbreviations used are those common in the art.

[0615] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention may be commercially available or prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention may be prepared by organic synthesis methods known to those skilled in the art, as shown in the following examples.

[0616] Unless otherwise noted, all reactions are carried out under nitrogen or argon.

[0617] Proton NMR 1 ¹H NMR) is performed in a deuterated solvent. In the specific compounds disclosed herein, one or more 1 H shift overlaps with the residual proteosolvent signal; such signals were not reported in the experiments provided below.

[0618] [Table 3]

[0619] Analysis device

[0620]

[0621] For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC / MSD or Shimadzu LCMS2020 equipped with a Chromolith Flash RP-18e 25*2.0 mm column, equipped with an electrospray ionization and quadrupole MS detector [ES+ve to provide MH+], eluted with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS were recorded on an Agilent 1290 Infinity RRLC equipped with an Agilent 6120 mass detector. The column used was a BEH C18 50*2.1 mm, 1.7 micron column. The column flow rate was 0.55 ml / min, and the mobile phases used were (A) 2 mM ammonium acetate in 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile.

[0622] For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC / MSD or Shimadzu LCMS 2020 equipped with an electrospray ionization and quadrupole MS detector [ES+ve to provide MH+] and fitted with an Xbridge C18 (2.1 x 50 mm) column packed with 5 mm C18-coated silica eluted in water with 0.05 vol% NH3·H2O (solvent A) and acetonitrile (solvent B), or a Kinetex EVO C18 (2.1 x 30 mm) column packed with 5 mm C18-coated silica.

[0623] HPLC analysis method: HPLC was performed on an X Bridge C18 (150*4.6 mm, 5 microns). The column flow rate was 1.0 ml / min, and the mobile phases used were (A) 0.1% ammonia in water and (B) 0.1% ammonia in acetonitrile.

[0624] Preparative HPLC Analysis Method: Compounds were purified using a Shimadzu LC-20AP and a UV detector. The column used was an X-BRIDGE C18 (250 x 19) mm, 5 μm column. The column flow rate was 16.0 ml / min. The mobile phase used was a basic method consisting of (A) 0.1% formic acid in water and (B) acetonitrile, or (A) 5 mM ammonium bicarbonate and 0.1% NH3 in water and (B) acetonitrile, or (A) 0.1% ammonium hydroxide in water and (B) acetonitrile. UV spectra were recorded at 202 nm and 254 nm.

[0625] NMR Method: 1H NMR spectra were recorded using a Bruker Ultra Shield Advance 400 MHz / 5 mm probe (BBFO). Chemical shifts were recorded in parts per million.

[0626] In some cases, the intermediates and compounds described in the examples contain one or more stereocenters and produced more than one enantiomer / diastereomer. In some embodiments, these enantiomers / diastereomers were separated and isolated, but their stereochemistry was not determined. Unless otherwise noted, stereochemistry was assigned arbitrarily. In the case of intermediates, each enantiomer / diastereomer having an arbitrarily assigned stereochemistry may produce a final compound (e.g., assigned an “I-” number), which also retains the arbitrarily assigned stereochemistry. Therefore, any compound having an arbitrarily assigned stereochemistry or any compound produced from an intermediate having an arbitrarily assigned stereochemistry may be indicated herein as a specific stereoisomer, but it is understood that such compound may be a different stereoisomer (i.e., an enantiomer or a diastereomer).

[0627] As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the general method describes the synthesis of specific compounds of the present invention, it will be understood that the following general method and other methods known to those skilled in the art may be applied to all compounds and their subclasses and species as described herein.

[0628] [Table 4]

[0629] Compounds synthesized through the coupling of corresponding amines and carboxylic acids

[0630]

[0631] [Table 5]

[0632] Compounds synthesized through the coupling of corresponding halogens and boronic acids

[0633]

[0634] l The coupling product was further hydrolyzed using LiOH in THF for 1 hour at rt.

[0635] [Table 6]

[0636] Compounds synthesized through other standard methodologies.

[0637]

[0638] Example 1. Uniform Time-Resolved Fluorescence (HTRF) Coupling Analysis

[0639] The HTRF binding assay was performed using a final volume of 20 μL of the test compound in an assay buffer consisting of 0.15 nM biotinylated truncated STAT6(123-632)-avi purified from E. coli, 1X streptavidin-terbium (CisBio) prepared by mixing SA-Tb in PPI detection buffer (CisBio), 20 nM proprietary fluorescein-labeled probe, and 50 mM HEPES-Na pH 7.5, 100 mM NaCl, 1 mM EDTA, 2 mM DTT, and 0.1% Tween-20. The compound stock was dissolved to 10 mM in 100% DMSO, and 11-point titrations were performed on a white, opaque 384-well microplate with 3-fold serial dilution. The reaction plates were incubated at room temperature for 30 minutes. The plates were centrifuged at low rpm for 5 minutes, and the fluorescence intensity ratio at the emission wavelengths of the fluorescein receptor (520 nm) and the terbium donor (495 nm) was measured using an Envision Plate reader. The inhibition percentage was calculated from the 520 / 495 ratio generated using a proprietary positive control compound for 100% inhibition and a DMSO-alone reaction for 0% inhibition. The data were processed, and dose-response curves were generated using GraphPad Prism to determine the concentration (IC10) required to inhibit 50% of the HTRF signal. 50 Decided on ).

[0640] The STAT6 HTRF results are Table 7 It is shown in IC 50 The character codes for (μM) include A (<0.1 μM); B (0.1 to 1 μM); C (>1 to 10 μM); D (>10 to 100 μM); and E (>100 μM or not tested).

[0641] [Table 7]

[0642] STAT6 HTRF results

[0643]

[0644] Example 2. Flow cytometry of phosphorylated STAT6 (pSTAT6) in human PBMCs

[0645] Phosphorylation of STAT6 in human PBMCs was quantitatively measured using flow cytometry. Human PBMCs were seeded into 96-well plates at a cell density of 0.3 to 0.5 million in 100 μl of fresh medium per well. Subsequently, compounds were added in a 1:3 dilution series at a total of nine concentrations, with a final peak concentration of up to 30 μM. The plates were incubated for 1 hour at 37°C under 5% CO2 conditions. The cells were then stimulated with 1 ng / ml IL-4 (R&D Systems, Cat# 6507-IL) for 15 minutes and fixed at 4°C for 30 minutes. The cells were spin-down at 350 g for 5 minutes. The supernatant was removed, and the cells were washed once with FACS buffer. The cells were permeated using 90% MeOH / H2O at 4°C for 30 minutes and washed once with FACS buffer. After blocking non-specific binding with human Fc at 4°C for 1 hour, the cells were washed once with FACS buffer. AF488-conjugated pSTAT6 antibody (BD Biosciences, Cat# 612600, 1:100 dilution) and PE-conjugated CD19 antibody (BD Biosciences, Cat# 341103, 1:50 dilution), diluted in 100 μl of FACS buffer, were added to each well and incubated overnight at 4°C. Subsequently, the cells were washed once with FACS buffer and resuspended in 200 μl of FACS buffer for flow cytometry to quantify pSTAT6 in CD19+ B cells. Data were analyzed by GraphPad Prism, and dose-dependent pSTAT6 inhibition was fitted using a 4-parameter inhibitor-versus-response nonlinear regression.

[0646] The STAT6 IL4 pSTAT6 results are Table 8 It is shown in IC50 The character codes for (μM) include A (<0.1 μM); B (0.1 to 1 μM); C (>1 to 10 μM); D (>10 to 100 μM); and E (>100 μM or not tested).

[0647] [Table 8]

[0648] STAT6 IL4 pSTAT6 results

[0649]

[0650] Example 3. Flow cytometry of phosphorylated STAT6 (pSTAT6) in human A549 cells.

[0651] Phosphorylation of STAT6 in human A549 cells was quantitatively measured using flow cytometry.

[0652] STAT6 IL4 pSTAT6 The result is Table 9 It is shown in IC 50 The letter codes for (μM) include A (<0.1 μM); B (0.1 - 1 μM); C (>1 - 10 μM); D (>10 - 100 μM); and E (>100 μM or not tested).

[0653] [Table 9]

[0654] STAT6 IL4 pSTAT6 results

[0655]

Claims

Claim 1 chemical formula Ia compounds of or a pharmaceutically acceptable salt thereof: [Chemical Formula Ia] (In the above chemical formula, is a single or double bond; ring W is a 5- to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur; a 9-membered bicyclic saturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic saturated or partially unsaturated heterocyclil having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 10-membered bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from naphthyl, nitrogen, oxygen, or sulfur; or a 13-membered tricyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R w is a halogen, -CN, -OR w1 , -N(R w1 )2, -(CH2) n C(O)NR2, -(CH2) n N(R)C(O)NR2, -(O) m -phenyl, C 1-4 A 6-membered monocyclic saturated or partially unsaturated heterocyclie having 1 to 3 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a 5-membered to 6-membered monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclie, or heteroaryl is a halogen, C 1-4 Optionally substituted with aliphatic, -OR, or -C(O)NR2; each R w1 Silver is hydrogen, C 1-4 Independently selected from six-membered monocyclic heteroaryls having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR; and each R x C independently 1-4 Aliphatic, halogen, or -C(O)NR2; each R is independently hydrogen or C 1-4 Aliphatic and;L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, wherein one methylene unit is optionally replaced with -NR-; ring Y is a pentary monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a decary bicyclic saturated or partially unsaturated heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R y C independently 1-4 Aliphatic, halogen, -OR, or -C(O)NR2; each m is independently 0 or 1; each n is independently 0, 1, 2, or 3; each w, x, and y is independently 0, 1, 2, 3, or 4). Claim 2 chemical formula Ib Compound of: [Chemical Formula Ib] (In the above chemical formula, the ring W' is or Igo;W 1 is O, NH, or NR w and; ring X is a pentatonic monocyclic heteroarylenyl, phenylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a pentatonic or heptacyclic heteroarylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and saturated or partially unsaturated monocyclic heterocyclylenyl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R w is a halogen, -CN, -OR w1 , -N(R w1 )2, -(CH2) n C(O)NR2, -(CH2) n N(R)C(O)NR2, -(O) m -phenyl, C 1-4 A six-membered saturated or partially unsaturated monocyclic heterocyclile having one to three heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur, or a five-membered to six-membered monocyclic heteroaryl having one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each phenyl, heterocyclile, or heteroaryl is a halogen, C 1-4 Optionally substituted with aliphatic, -OR, or -C(O)NR2; each R w1 Silver is hydrogen, C 1-4 Independently selected from six-membered monocyclic heteroaryls having 1 to 3 heteroatoms independently selected from aliphatic, phenyl, or nitrogen, oxygen, or sulfur, wherein each aliphatic, phenyl, or heteroaryl is optionally substituted with a halogen, -OR, or -C(O)OR; and each R x C independently 1-4 Aliphatic, halogen, or -C(O)NR2; each R is independently hydrogen or C 1-4 It is aliphatic; G is hydrogen or Igo;L XA is a covalent bond or a divalent straight chain or branched chain C 1-3 Aliphatic and; L XB is a divalent straight chain or branched chain C 1-3 It is aliphatic, wherein one methylene unit is optionally replaced with -NR-; ring Y is a pentary monocyclic heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a decary bicyclic saturated or partially unsaturated heterocyclile having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R y C independently 1-4 Aliphatic, halogen, -OR, or -C(O)NR2; each m is independently 0 or 1; each n is independently 0, 1, 2, or 3; each w, x, and y are independently 0, 1, 2, 3, or 4). Claim 3 In paragraph 1, the ring W is , or Phosphorus, compound. Claim 4 In paragraph 2, W 1 A compound that is O. Claim 5 In paragraph 2, W 1 -NH- or -NR w - Phosphorus, compound. Claim 6 In any one of Paragraph 2, Paragraph 4, or Paragraph 5, ring X is , or A compound that is (where # indicates the attachment point for G). Claim 7 A compound in which, in any one of paragraphs 2 or 4 through 6, G is hydrogen. Claim 8 In any one of paragraphs 2 or 4 through 6, G is Phosphorus, compound. Claim 9 In any one of paragraphs 1 through 6 or paragraph 8, ring Y is , or Phosphorus, compound. Claim 10 In any one of paragraphs 1 through 9, R in one case w -(O) m A compound in which -phenyl is optionally substituted with a halogen, -OR, or -C(O)NR2. Claim 11 In Paragraph 10, R in one case w A compound in which is phenyl, and phenyl is optionally substituted with a halogen, -OR, or -C(O)NR2. Claim 12 In any one of paragraphs 1 through 11, R in one case w is a fluorophosphate, a compound. Claim 13 A compound according to any one of paragraphs 1 to 12, wherein y is 0. Claim 14 In any one of paragraphs 1 through 12, R in one case y is a compound that is -C(O)NR2. Claim 15 A compound according to any one of paragraphs 1 to 14, wherein x is 0. Claim 16 In claim 1 or 3, the compound is a chemical formula II-a , III-a , or IV-a Compound that is a compound of or a pharmaceutically acceptable salt thereof: [Chemical Formula II-a] [Chemical Formula III-a] [Chemical Formula IV-a] . Claim 17 In any one of paragraphs 2 or 4 to 6, the compound is a chemical formula Ib-1 Compound that is a compound of or a pharmaceutically acceptable salt thereof: [Chemical Formula Ib-1] . Claim 18 In any one of paragraphs 2 or 4 to 6, the compound is a chemical formula Ib-2 Compound that is a compound or a pharmaceutically acceptable salt thereof: [Chemical Formula Ib-2] . Claim 19 In any one of paragraphs 2 or 4 to 6, the compound is a chemical formula II-b , III-b , IV-b , Vb , VI-b , or VII-b Compound that is a compound of or a pharmaceutically acceptable salt thereof: [Chemical Formula II-b] [Chemical Formula III-b] [Chemical Formula IV-b] [Chemical Formula Vb] [Chemical Formula VI-b] [Chemical Formula VII-b] . Claim 20 graph 1A , graph 1B , graph 2A , or table 2B A compound selected from any one of the compounds described in or a pharmaceutically acceptable salt thereof. Claim 21 A pharmaceutical composition comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Claim 22 A method for inhibiting STAT6, comprising the step of contacting STAT6 with a compound of any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21. Claim 23 In paragraph 22, the contact step occurs within the patient or biological sample.

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