Stat6 inhibitors and uses thereof

Abstract

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

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 617,310, filed January 3, 2024, and U.S. Provisional Application No. 63 / 649,869, filed May 20, 2024. Technical Field

[0002] This invention relates to inhibitory compounds and methods for inhibiting signal transduction and transcription activator 6 (“STAT6”). The invention also provides pharmaceutically acceptable compositions comprising the inhibitory compounds of this invention and methods for treating various disorders using said compositions. Background Technology

[0003] Signal transducer and activator of transcription 6 (STAT6 or interleukin-4-Stat / IL4-STAT) is a non-drugatable transcription factor belonging to the structurally conserved family of signal transducer and activator of transcription (STAT) proteins (STAT1-STAT6). Like other STAT proteins, STAT6 activation 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 residues leads to translocation from the cytosol to the nucleus and signal transduction, thereby activating gene expression.

[0004] STAT6 is involved in driving type 2 immunity and allergies. It may be involved in IL-4 / IL-13 mediated allergic responses and play an important role in the differentiation of type 2 helper T cells (Th2) (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 the inflammatory cytokines interleukin-4 (IL4) and interleukin-13 (IL13) and their homologous receptors. It is produced by Th2 cells, mast cells, and basophils. Human STAT6 mutations are associated with severe allergies such as asthma and eczema (Goenka and Kaplan, “Transcriptional regulation by STAT6.” Immunologic Research 50.1 (2011): 87-96).There is a need to discover and develop STAT6 drugs, for example, for the treatment of allergic / inflammatory diseases (Glosson et al., “Wheezing and itching: The requirement for STAT proteins in allergic inflammation.” Jak-Stat 1.1 (2012): 3-15; Loh et al., “Signal transducer and activator of transcription (STAT) proteins in cancer and inflammation: functions and therapeutic implication.” Frontiers in Oncology 9 (2019): 48). Therefore, there is still a need to find STAT6 inhibitors for use as therapeutic agents. Summary of the Invention

[0005] It has now been found that the compounds described herein and their pharmaceutically acceptable combinations are effective inhibitors of the STAT6 protein.

[0006] In some embodiments, the present invention provides inhibitor compounds having formula I′: Or its pharmaceutically acceptable salt, wherein each variable is as defined and described herein.

[0007] The inhibitory compounds and pharmaceutically acceptable combinations thereof described herein may be used to treat and modulate a variety of diseases, disorders, or conditions related to signaling pathways involving the STAT6 protein. Such diseases, disorders, or conditions include those described herein.

[0008] In some embodiments, the present invention provides a method of use related to an inhibitor compound having Formula I: Or its pharmaceutically acceptable salt, wherein each variable is as defined and described herein.

[0009] The inhibitor compounds described in this article can also be used to study the applications of STAT6 protein in biological and pathological phenomena; to study intracellular signal transduction pathways occurring in body tissues; and to conduct in vitro or in vivo comparative evaluations of new STAT6 inhibitors or other cell cycle, metastasis, angiogenesis, and immune cell evasion regulators. Detailed Implementation 1. General description of certain embodiments of the present invention:

[0010] The inhibitory compounds and compositions thereof described herein can be used as inhibitors of STAT6 proteins, including phosphorylated or activated STAT6 proteins, such as pSTAT6. In some embodiments, the provided inhibitory compounds inhibit and / or modulate STAT6, pSTAT6, or STAT6 and pSTAT6. 2. Compounds and definitions:

[0011] The compounds of this invention include those generally described herein, and are further illustrated by the categories, subclasses, and species disclosed herein. As used herein, unless otherwise stated, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0012] As used herein, the term "aliphatic" or "aliphatic group" means a fully saturated or branched (i.e., unbranched) or substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a fully saturated or non-aromatic monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "aliphatic group," or "cycloalkyl") having a single attachment point to the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in yet still other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, an "alicyclic group" (or "carbocyclic" or "cycloalkyl") refers to a fully saturated or non-aromatic monocyclic C3-C6 hydrocarbon containing one or more unsaturated units, having a single attachment point to the rest of the molecule. In some embodiments, the carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. The carbocyclic ring may contain one or more oxo (=O) or thio (=S) substituents. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0013] As used herein, the term "bridging bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbocyclic or heterocyclic system, saturated or partially unsaturated. According to the IUPAC definition, a "bridge" is an unbranched chain of atoms or atoms or valence bonds connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom in the ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridging bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridging bicyclic groups are well known in the art and include those listed below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridging bicyclic group may optionally be substituted with one or more substituents described for aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridging bicyclic group may optionally be substituted. Exemplary bridging bicyclic groups include:

[0014] The term "lower alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0015] The term "haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-6 Straight-chain or branched alkyl groups, "lower haloalkyl" refers to C groups substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0016] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR). - (e.g., in N-substituted pyrroleyl groups).

[0017] As used in this article, the term "unsaturated" means a portion having one or more unsaturated units.

[0018] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and ynylene chains as defined herein.

[0019] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n - 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 substituted aliphatic groups.

[0020] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene group containing at least one double bond (where one or more hydrogen atoms are replaced by a substituent). Suitable substituents include those described below for substituted aliphatic groups.

[0021] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl group having the following structure:

[0022] The term "halogen" refers to F, Cl, Br, or I.

[0023] The term "aryl," used alone or as part of a larger category such as "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. As used herein, the term "aryl" also includes groups within its scope where an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimide, naphthimidyl, phenanthridine, or tetrahydronaphthyl. The term "arylene" refers to a divalent aryl group (e.g., phenylene).

[0024] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger portion, such as "heteroarylalkyl" or "heteroarylalkoxy," refer to groups that: have 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; have 6, 10, or 14 π electrons shared in the cyclic array; and have one to five 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. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, indazinyl, purinyl, naphthidyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroaryl-” also include groups in which a heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclic rings. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaryl group," wherein any of these terms includes an optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently. The term "heteroarylide" refers to a divalent heteroaryl group (e.g., pyridylidene).

[0025] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic group,” and “heterocyclic” 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 has one or more, preferably 1 to 4, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or... + NR (e.g., in N-substituted pyrroleyl groups).

[0026] Heterocycles can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxalyl, dioxopentyl, diazaphenyl, oxazphenyl, thioazphenyl, morpholinyl, and quininecycloyl. The terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings, such as indololinyl, 3H-indolyl, chromyl, phenanthridine, or tetrahydroquinolinyl. In some embodiments, the heterocycle may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic. The heterocycle may include one or more oxo (=O) or thio (=S) substituents. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl moiety and the heterocyclic moiety are optionally substituted independently.

[0027] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moietyes as defined herein.

[0028] As described herein, the compounds disclosed may contain a “substituted” moiety. Generally, the term “substituted” means that one or more hydrogen atoms of the specified moiety are replaced by suitable substituents. Unless otherwise stated, an “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that result in the formation of stable or chemically viable compounds. As used herein, the term “stable” means a compound that does not undergo substantial changes when subjected to the conditions of its generation, detection, and, in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0029] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R o ;-(CH2) 0-4 OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ;-(CH2) 0-4 Ph (which can be R) o (Substitute); -(CH2) 0-4 O(CH2) 0-1 Ph (which can be R) o (replace); -CH=CHPh (which can be replaced by R) o (Substitute); -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which can be R) o (Substitution); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0- 4OC(O)R o ;-OC(O)(CH2) 0-4 S R o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ,-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)Ro ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2;-(CH2) 0-4 P(O)2R o ;-(CH2) 0-4 P(O)R o 2;-(CH2) 0-4 OP(O)R o 2;-(CH2) 0-4 OP(O)(OR o )2; SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be replaced by the following definition, and independently is hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring R o Together with one or more intermediate atoms, it forms a 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0030] R o Apply a suitable monovalent substituent (or through two independently occurring Rs) o The ring formed with the atoms in its middle is independently a halogen, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● )2、-O(halogenated R ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2C(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 alkylene)C(O)OR ● 、or -SSR ● , where each R ● It is either unsubstituted or, when preceded by "halogenated", substituted by one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R o Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0031] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2)) 2-3 O- or -S(C(R*2)) 2-3 S-, where each individually occurring R* is selected from hydrogen, C 1-6 An aliphatic group (which may be substituted as defined below), or an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to adjacent substituted carbons of the "optionally substituted" group include: -O(CR*2). 2- 3O-, where each individually occurring R* is selected from hydrogen, C 1-6 Aliphatic group (which may be substituted as defined below), or unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on the aliphatic group of R* include halogens, -R ● -(halogenated R) ●-OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2. or -NO2, where each R ● It is either unsubstituted or, when preceded by "halogenated", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Each of them Independently, it is hydrogen, C 1-6 Aliphatic group (which may be substituted as defined below), unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, although as defined above, two independently occurring Together with one or more intermediate atoms, it forms an unsubstituted 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2. or -NO2, where each R ● It is either unsubstituted or, when preceded by "halogenated", substituted by only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues within the bounds of reasonable medical judgment, without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with an amino group formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, 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 salts with an amino group formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, sodium benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0036] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. 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 considered herein and will be apparent to those skilled in the art.

[0037] Unless otherwise stated, the structures illustrated herein are also intended to include all isomers of that structure (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)); for example, R and S configurations for each asymmetry center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are all within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (including hydrogen replaced by deuterium or tritium, or carbon replaced by...) 13 C- or 14 C-enriched carbon substitutes are all within the scope of this invention. Such compounds can be used, for example, as analytical tools, probes in bioanalysis, or therapeutic agents according to the invention.

[0038] As used herein, the term “compound provided” means any class, subclass and / or species described herein.

[0039] As used herein, the terms “measurable affinity” and “measurable inhibition” refer to a measurable change in STAT6 protein activity between a sample containing the compound or a combination thereof of the present invention and the STAT6 protein and an equivalent sample containing the STAT6 protein but without the compound or the combination thereof.

[0040] As used herein, the term "reference" describes a standard or control relative to which comparisons are made. In some embodiments, a "reference" sample or subject is sufficiently similar to a particular sample or subject of interest to allow for relevant comparisons. For example, in some embodiments, a drug, animal, individual, population, sample, sequence, or value of interest is compared to a reference or control drug, animal, individual, population, sample, sequence, or value. In some embodiments, the testing and / or determination of the reference or control is performed substantially simultaneously with the testing or determination of interest. In some embodiments, the reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as those skilled in the art will understand, a reference or control is determined or characterized under conditions or circumstances equivalent to those conditions or circumstances being evaluated. Those skilled in the art will understand that there exists sufficient similarity to demonstrate reliance on a particular possible reference or control and / or comparison with it.

[0041] As used herein, an "inhibitor compound" is a compound that binds to a target protein. In some embodiments, the inhibitor compound binds to the target protein and reduces its activity. In some embodiments, the binding of the inhibitor compound to the target protein does not lead to the degradation of the target protein. In another embodiment, the inhibitor compound does not bind to the E3 ligase in a manner that leads to the degradation of the target protein. 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, the binding of the inhibitor compound to STAT6 does not lead to the degradation of STAT6. In another embodiment, the inhibitor compound does not bind to the E3 ligase in a manner that leads to the degradation of STAT6. In some embodiments, the inhibitor compound binds to the target protein (e.g., STAT6) but does not bind to the E3 ligase. In some embodiments, the E3 ligase is selected from cerebellar protein-type 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. It should be understood that throughout this disclosure, "compound" or "the compound provided" refers to the inhibitor compound as defined above.

[0042] In some embodiments, the E3 ligase is a cerebellar protein-type E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not contain a structure of formula I-aa′: Or its pharmaceutically acceptable salt, wherein: X 1 and X 5 Independently, it is a covalent bond, -CR2-, -SO2-, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)N(R)2-, -C(O)-, -C(S)- or X 2 It is N, CR B Si-R B Or P = O; X 3 and X 4 Independently, it is a covalent bond, -CR2-, -CF2-, -O-, -S-, or X 3 -X 4 It is -CR = CR-; Each R 1 Independently -H, R A, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR 2. -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP( O)(OR)2, -OP(O)(OR)(NR2), -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)S (O)2R, -NP(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)(NR2), -N(R)P(O)(NR2)2, -N(R)S(O)2R; or: Two Rs in ring A 1 The group together with the intermediate atom forms an optionally substituted ring selected from the following: a 3- to 10-membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; a benzo[a] group; or a 5- to 10-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Each R B Independently, it is 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 groups; L 1 Is it a covalent bond or C 1-3 A divalent hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -C(O)-, -C(S)-, -CR2-, -CF2-, -NR-, -O-, -S-, or -S(O)2; Ring A is a phenylene, naphthylene, pyridylene, 4-7 member saturated or partially unsaturated carbocyclic group, having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, or ... Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-10 saturated or partially unsaturated carbon ring, 3-10 3-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 5-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, comprising a 4-7 membered saturated or partially unsaturated heterocycle, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups or R groups on the same atom or adjacent atoms B The R group, together with the intermediate atom, forms an optional substituted 3-11 saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

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

[0044] In some embodiments, the E3 ligase is a VHL E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not contain the structure of formula I-ccc-3′: Or its pharmaceutically acceptable salt, wherein: X 4a and X 5a Each is independently selected from the following divalent moieties: -CH2-, -C(O)-, -C(S)-, or Each R 4a Independently, it is hydrogen, -R 6, Halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C( O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R; or: R 5a Is it hydrogen or C? 1-6 Aliphatic groups; Each R 6 Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-15 membered saturated or partially unsaturated tricyclic heterocyclic group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 8-15 membered tricyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring C a Selected from 6-membered aryl groups containing 0-2 nitrogen atoms, or 5-membered heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; q is 0, 1, 2, 3, or 4; and Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, comprising a 4-7 membered saturated or partially unsaturated heterocycle, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: The two R groups on the same nitrogen atom can optionally form a 4-7 saturated, partially unsaturated or heteroaryl ring together with the atom between them, which has 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to nitrogen.

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

[0046] In some embodiments, the E3 ligase is an MDM2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not contain the structures 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, respectively. Or its pharmaceutically acceptable salt, wherein: X is selected from -CR2-, -O-, -S-, -S(O)-, -S(O)2- and -NR-; Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: The two R groups on the same atom may optionally form a 4-7 saturated, partially unsaturated or heteroaryl ring together with the atom between them, the ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the atoms to which the two R groups are attached. Y and Z are independently selected from -CR= and -N=; The ring W is selected from the following fused rings: benzo[a], and 5-6 membered heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 1 and R 2 Independently, the alternatively substituted monocyclic or bicyclic compounds are selected from the following: phenyl, 5-10 aryl, and 5-10 heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 and R 4 Independently selected from hydrogen and C 1-6 alkyl; R 5 Selected from optional substituted monocyclic or bicyclic compounds selected from the following: phenyl, 5-10 aryl, and 5-10 heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 6 Selected from hydrogen, -C(O)R, -C(O)OR and -C(O)NR2; R 7 Selected from hydrogen and RA ; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 8 Selected from -C(O)R and R A ; R 9 It is a mono-, di-, or tri-substituent on the ring W, wherein each substituent is independently selected from halogens and optionally substituted C. 1-6 Aliphatic groups; R 10 Selected from optional substituted monocyclic or bicyclic compounds selected from the following: phenyl, 5-10 aryl, and 5-10 heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 11 It is -C(O)OR or -C(O)NR2; R 12 and R 13 Independently selected from hydrogen and R A ,or: R 12 and R 13 Optionally, together with the intermediate atoms, it can form an optional substituted 3-8 member saturated, partially unsaturated carbon ring or heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 14 It is R A ; R 15 It is -CN; R 16 Selected from 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 -S(O)2NR2; R 17 Selected from -(CR2) 0-6 -C(O)NR2; R 18 and R 19 Independently selected from hydrogen and RA ; R 20 and R 21 Independently selected from hydrogen, R A halogens and -OR, or: R 20 and R 21 Optionally, together with the atoms in the middle, it forms a fused 5-7 member partially unsaturated carbon ring or heterocycle (the heterocycle has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a fused 5-6 member heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. R 22 R 23 R 25 and R 27 Independently selected from hydrogen, R A , Halogen, -C(O)R, -C(O)OR, -C(O)NR2, -NR2, -OR, -S(O)R, -S(O)2R, -S(O)2NR2; R 24 R 26 and R 28 Independently selected from hydrogen, R A , -C(O)R, -C(O)OR, -C(O)NR2, -S(O)R, -S(O)2R and -S(O)2NR2; R 1′ and R 2′ Independently selected from halogens, -C≡CR, -CN, -CF3, and -NO2; R 3′ Yes - OR; R 4′ R 5′ R 6′ Independently selected from hydrogen, halogen, R A -CN, -CF3, -NR2, -OR, -SR and -S(O)2R; R 7′ It is a mono-, di-, or tri-substituent, wherein each of these substituents is independently selected from halogens; R 8′ It is a mono-, di-, or tri-substituent, wherein each of these substituents is independently selected from hydrogen, halogen, R. A -CN, -C≡CR, -NO2, and -OR; R 9′ It is R A ; Z 1 Selected from hydrogen, halogens, and -OR; R 10′ and R 11′ Independently selected from hydrogen and RA ; R 12′ Selected from -C(O)R, -C(O)OR, -C(O)NR2, -OR, -S(O)2R, -S(O)2NR2, and -S(O)R; and R 1″ Selected from hydrogen and R A .

[0047] In some embodiments, the E3 ligase is a DCAF E3 ubiquitin ligase (e.g., a DCAF1 E3 ubiquitin ligase). In some embodiments, the inhibitor compound does not contain a structure of formula Iba or Ibb. Or its pharmaceutically acceptable salt, wherein: Ring E 1 It is a phenyl, naphthyl, 4-9 membered unsaturated monocyclic, bicyclic or bridged bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a 5-9 membered monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Ring F 1 It is a 5-membered monocyclic heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Y 1 It is C 1-3 The hydrocarbon chain, wherein each methylene group is optionally replaced by: -CR2-, -CR(OR)-, -C(O)-, -C(NR)-, -C(NOR)-, -S(O)-, or -S(O)2-; or -C(OR)=, in formula Iba, where R d If it does not exist; R a It is hydrogen, with optional substitution of C 1-6 aliphatic groups, or Ring G is a phenyl group, a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R b It is hydrogen, with optional substitution of C 1-6 Aliphatic group, phenyl group, or 5-6 heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: R a and R b Together with the atoms in the middle, it forms a optionally substituted 9-10 saturated or partially unsaturated bicyclic ring (the bicyclic ring has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or: When Y 1 When it is -C(NR)-, R b Together with the R in -C(NR)- and the atoms in between, they form a 5-7 partly unsaturated heterocyclic group, which has 0-1 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the 2 heteroatoms in the heterocyclic group; R c It is -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 optionally substituted groups selected from: phenyl; 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-9 membered monocyclic or bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: -(CR2) 1-2 -X a , where X a It is a halogenated or optionally substituted ring selected from the following: phenyl; a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-9 membered monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: R b and R c Together with the intermediate atoms, it forms optionally substituted 4-6 member saturated or partially unsaturated carbocyclic or heterocyclic groups, the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: R a It does not exist and R b and R c Together with the atoms in the middle, it forms an optionally substituted phenyl group; or: When Y 1 When it is -C(OR)-, R c Together with the R in -C(OR)= and the atoms between them, they form a 5-7 partly unsaturated heterocyclic group, which has 0-1 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the 2 heteroatoms in the heterocyclic group; R d It is hydrogen or optionally substituted C 1-6 Aliphatic groups, or: When R cWhen it is -CR2CONR2, R d Together with the individual R atoms in -CR2CONR2 and the atoms between them, they form a 5-7 member saturated or partially unsaturated heterocyclic group, which, apart from R... d In addition to the attached heteroatom, it has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; R e R f and R g Each is independently selected from hydrogen, oxo group, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C( O)NR2, -C(O)NROR, -C(NOR)R, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR 2. -OP(O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR )2, -NRP(O)(OR)NR2, -NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2, -P(O)(OR)NR2 and -P(O)(NR2)2; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, naphthyl, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same atom, together with the atom between them, form a optionally substituted 3-7 membered saturated ring or a partially unsaturated ring, which, in addition to the atoms to which the two R groups are attached, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and e, f, and g are each independently 0, 1, 2, 3, or 4.

[0048] In some embodiments, the inhibitor compound does not contain the structure of formula Ibc: Or its pharmaceutically acceptable salt, wherein: The ring H is a 3-11 saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic group, which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring I is a phenylene or a 5- to 10-membered monocyclic or bicyclic heteroaryl group having 14 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring J is a 3-11 saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic subcarbonyl or subheterocyclic group, which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring K is phenyl, naphthyl, or a 5-13 membered monocyclic, bicyclic, or tricyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R h R i R j and R k Each is independently selected from hydrogen, oxo group, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C (O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP( O)(NR2)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, -NRS(O)2R, -NP(O)R2, -NRP(O)(OR)2, - NRP(O)(OR)NR2, -NRP(O)(NR2)2, -P(O)R2, -P(O)(OR)2, -P(O)(OR)NR2, and -P(O)(NR2)2, or: The Ri group on ring I and the R group on ring J j The group may optionally form, together with the intermediate atom, a 5-8 member saturated, partially unsaturated, or aromatic ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or: X 1 and X 2 Each is an independent covalent bond, X 1 or X 2 The helical fusion between two connected loops, or divalent, saturated or unsaturated, straight or branched C 1-6 Hydrocarbon chain, in which X 1 and X 2The 0-4 methylene units are independently replaced by the following: -CR2-, -CR(OR)-, -CRF-, -CF2-, -C(NR)-, -C(O)-, -O-, -N(R)-, -S-, -S(O)-, or -S(O)2-; "s" is 0 or 1; and w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0049] In some embodiments, the E3 ligase is a DC2 E3 ubiquitin ligase. In some embodiments, the inhibitor compound does not contain a structure of formula Ica-1 or Ica-2: Or its pharmaceutically acceptable salt, wherein: SBM and L are as defined and described above and in this article; R 1Z It is hydrogen or optionally substituted C 1-6 Aliphatic groups; R aZ R bZ and R cZ Each 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(N R Z 2) -C(O)R Z -C(O)OR Z 、or -C(O)NR Z 2; Each R AZ Independently, the optional substituted groups are selected from the following: C 1-10Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R Z Independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, comprising a 4-7 membered saturated or partially unsaturated heterocycle, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two Rs on the same atom Z The group may optionally form, together with the intermediate atom, an optionally substituted 4-11 member saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridged bicyclic, spirocyclic, or heteroaryl ring, wherein the ring, except for the two R groups, forms a 4-11 member saturated or partially unsaturated carbocyclic or heterocyclic monocyclic, bicyclic, bridging bicyclic, spirocyclic, or heteroaryl ring. Z In addition to the atoms to which the group is attached, it also has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each ring A Z Independently selected from the following divalent rings: phenylene, naphthylene, 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or 5-10 membered monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each ring B Z Independently selected from the following divalent rings: phenylene, 3-10 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic (the heterocyclic has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L aZ It does not exist, covalent bond, or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein 1-3 methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R)-. Z )2-、-CH(R Z )-、-CF(R Z -, -C(F)2, -N(R) Z -, -S-, -S(O)2- or -CR Z =CR Z -; z1, z2, and z3 are each independently 0, 1, 2, 3, or 4; z4 and z5 are each independently 0 or 1.

[0050] In some embodiments, the inhibitory compound binds to and / or inhibits the STAT6 protein with measurable affinity. In some embodiments, the inhibitory compound has an IC50 concentration 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 binding constant. 3a. Description of exemplary embodiments related to the method of use:

[0051] In some embodiments, the present invention provides a method of use related to an inhibitor compound having Formula I: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 X 5 and X 6 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 X 5 and X 6 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates with L x The key; Ring Y is selected from the following rings: phenyl, naphthyl, 3-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 member monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Lx is in Indicates the bond with ring Y; R w Selected from hydrogen, R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R Z It is R A -OR or NR2; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B-Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2 The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0052] It should be understood that Formula I cannot be extended beyond the formulas described below and herein as in this section (3a). It should be understood that all references to “defined and described herein” refer only to this section (3a) of this application. Additionally, all chemical formulas and examples in section 3a are applicable only to and in combination with the formulas and examples derived from this section (3a).

[0053] In some embodiments, the present invention provides a method of use relating to an inhibitor compound having formula I, wherein the inhibitor compound has formula I′: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates bonds with the rest of the molecule; Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R w Selected from hydrogen, R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2 The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0054] In some embodiments, the present invention provides a method of use relating to an inhibitor compound having Formula I, wherein the inhibitor compound has Formula II: Or its pharmaceutically acceptable salt, wherein: Ring W and its R wSubstituents are X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates bonds with the rest of the molecule; Ring Y is selected from the following rings: naphthyl, 5-10 saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 8-10 saturated bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R ww Selected from hydrogen, R A R B, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2 The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0055] In some embodiments, the present invention provides a method of use relating to an inhibitor compound having Formula I, wherein the inhibitor compound has Formula III: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates with L x The key; Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic groups (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-6 membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic groups (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 8-10 membered bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Lx is in Indicates the bond with ring Y; R w Selected from hydrogen, R A R B, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R Z It is R A -OR or NR2; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2 The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0056] In some embodiments, the present invention provides a method of use relating to an inhibitor compound having formula I, wherein the inhibitor compound has formula IV: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 X 5 and X 6 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 X 5 and X 6 At most one of them is N; Y 1 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates bonds with the rest of the molecule; Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R ww Selected from hydrogen, R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R Z It is R A -OR or NR2; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 - Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

[0057] In some embodiments, the present invention provides a method of use related to: an inhibitor compound having formula I′, wherein: (i) When ring X and its Rx substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 and Y 3 Not NH, NR w Or N; (ii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y 2 and Y 3 Each is CH, CR w CH2, CH(R) w ) or C(R w When )2, then Y 1 Not CH, CR w CH2, CH(R) w ) or C(R w )2; (iii) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is S, then ring Y is not a phenyl group or a 3-8 member saturated or partially unsaturated monocyclic carbocyclic group or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur); (iv) When ring X and its R x Substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 3 Not S; (v) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is O, then Y 2 Not NH, NR w Or N; (vi) When ring X and its Rx substituents are X 1 It is N, Y 1 It is NH, NR ww Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w If z = 2, then z is neither 0 nor 1; (vii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y2 is CH and CR. w CH2, CH(R) w ) or C(R w When )2, then Y 2 and Y 3 Only one of them is O; (viii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X3 Each is C, Y 1 It is O, NH, NR w Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w When z = 2, then z is neither 0 nor 1; and (ix) When ring X and its R x Substituents are X 5 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 Not NH, NR w Or N.

[0058] In some embodiments, inhibitor compounds having formula I, I′, II, III, or IV are not compounds of structure ABC defined by a combination of structural units A, B, and C in the table below:

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

[0060] In some embodiments, the inhibitory compounds having formula I, I′, II, III or IV are not selected from the compounds in Table A. Table A: Or its salts or free bases / acids.

[0061] As described above and defined in this paper, the ring W and its R w Substituents are Where X 1 X 4 X 5 and X 6 Each is independently CH and CR w Or N; X 2 and X 3 Each is independently C or N, where X 1 X 2 X 3 X 4 X 5 and X 6 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; and each Indicates a single bond or a double bond.

[0062] In some embodiments, the ring W and its R w Substituents are Where X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is independently C or N, where X 1 X 2 X 3 X 4 and X 4 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CRw CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; and each Indicates a single bond or a double bond.

[0063] In some embodiments, the ring W and its R w Substituents are Where X 1 X 4 X 5 and X ６ Each is independently CH and CR w Or N; X 2 and X 3 Each is independently C or N, where X 1 X 2 X 3 X 4 X 5 and X ６ At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; and each Indicates a single bond or a double bond.

[0064] In some embodiments, X is included 2 X 3 Y 1 Y 2 and Y 3 The ring is aromatic or heteroaromatic, that is, Y 1 Y 2 Y 3 and The definition is chosen to satisfy the valence of an aromatic or heteroaromatic ring. In some embodiments, X contains 2 X3 Y 1 Y 2 and Y 3 The ring is not aromatic or heteroaromatic, that is, Y 1 Y 2 Y 3 and The definition was chosen to satisfy the valence of partially unsaturated rings.

[0065] In some embodiments, the ring W and its R w The substituents are:

[0066] In some embodiments, the ring W and its R w The substituents are:

[0067] As defined above and described in this article, X 1 X 4 X 5 and X ６ Each is independently CH and CR w Or N. In some embodiments, X 1 X 4 X 5 and X ６ Each is CH or CR w In some embodiments, X 1 X 4 and X 5 Each is CH or CR w In some embodiments, X 1 It is CH. In some embodiments, X 1 It is CR w In some embodiments, X 1 It is N. In some embodiments, X 4 It is CH. In some embodiments, X 4 It is CR w In some embodiments, X 4 It is N. In some embodiments, X 5 It is CH. In some embodiments, X 5 It is CR w In some embodiments, X 5 It is N. In some embodiments, X ６ It is CH. In some embodiments, X ６ It is CR w In some embodiments, X ６ It is N.

[0068] As defined above and described in this article, X 2 and X 3 Each is independently C or N. In some embodiments, X 2 and X 3 All are C. In some embodiments, X 2 It is C. In some embodiments, X 2 It is N. In some embodiments, X 3 It is C. In some embodiments, X 3 It is N.

[0069] In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w And X 2 and X 3 It is C. In some embodiments, X 1 It is N, X 2 and X 3 It is C, and X 4 and X 5 Is it CH or CR? w In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w X 2 It is N, and X 3 It is C. In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w X 2 It is C, and X 3 It is N. In some embodiments, X 1 and X 5 Is it CH or CR? w X 2 and X 3 It is C, and X 4 It is N. In some embodiments, X 1 and X 4 Is it CH or CR? w X 2 and X 3 It is C, and X 5 It is N.

[0070] In some embodiments, X 1 X 4 X 5 and X ６ Is it CH or CR? wAnd X 2 and X 3 It is C. In some embodiments, X 1 It is N, X 2 and X 3 It is C, and X 4 X 5 and X ６ Is it CH or CR? w In some embodiments, X 1 X 4 X 5 and X ６ Is it CH or CR? w X 2 It is N, and X 3 It is C. In some embodiments, X 1 X 4 X 5 and X ６ Is it CH or CR? w X 2 It is C, and X 3 It is N. In some embodiments, X 1 X 5 and X ６ Is it CH or CR? w X 2 and X 3 It is C, and X 4 It is N. In some embodiments, X 1 X 4 and X ６ Is it CH or CR? w X 2 and X 3 It is C, and X 5 It is N. In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w X 2 and X 3 It is C, and X ６ It is N.

[0071] As defined above and described in this article, Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CRw CH2, CH(R) w ) or C(R w 2. In some embodiments, Y 2 and Y 3 Both are CH and CR w CH2, CH(R) w ) or C(R w 2. In some embodiments, Y 1 Y 2 and Y 3 Each is independently CH and CR w NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH or CR w In some embodiments, Y 1 It is CH. In some embodiments, Y 1 It is CR w In some embodiments, Y 1 It is CH2. In some embodiments, Y 1 It is CH(R) w In some embodiments, Y 1 It is C(R) w 2. In some embodiments, Y 1 It is NH. In some embodiments, Y 1 It is NR w In some embodiments, Y 1 It is N. In some embodiments, Y 1 It is O. In some embodiments, Y 1 It is S. In some embodiments, Y 2 It is CH. In some embodiments, Y 2 It is CR w In some embodiments, Y 2 It is CH2. In some embodiments, Y 2 It is CH(R) w In some embodiments, Y 2 It is C(R) w 2. In some embodiments, Y 2 It is NH. In some embodiments, Y 2 It is NR w In some embodiments, Y 2 It is N. In some embodiments, Y 2 It is O. In some embodiments, Y 2 It is S. In some embodiments, Y 3 It is CH. In some embodiments, Y 3 It is CRw In some embodiments, Y 3 It is CH2. In some embodiments, Y 3 It is CH(R) w In some embodiments, Y 3 It is C(R) w 2. In some embodiments, Y 3 It is NH. In some embodiments, Y 3 It is NR w In some embodiments, Y 3 It is N. In some embodiments, Y 3 It is O. In some embodiments, Y 3 It is S.

[0072] In some embodiments, Y 1 Is it NH or NR? w And Y 2 and Y 3 Is it CH or CR? w In some embodiments, Y 1 It is O, and Y 2 and Y 3 Is it CH or CR? w In some embodiments, Y 1 It is S, and Y 2 and Y 3 Is it CH or CR? w .

[0073] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0074] In some embodiments, the ring W and its R w Substituents are

[0075] In some embodiments, the ring W and its R w Substituents are

[0076] In some embodiments, the ring W and its R w Substituents are

[0077] In some embodiments, the ring W and its R w Substituents are

[0078] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its Rw Substituents are In some embodiments, the ring W and its R w Substituents are

[0079] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0080] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0081] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0082] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0083] In some embodiments, the ring W and its R w Substituents are

[0084] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0085] In some embodiments, the ring W and its R w Substituents are

[0086] In some embodiments, the ring W and its R W Substituents are

[0087] In some embodiments, ring W is as illustrated in the compounds in Table 1A below.

[0088] In some embodiments, the ring W and its Rw Substituents are

[0089] In some embodiments, the ring W and its R w Substituents are

[0090] In some embodiments, the ring W and its R w Substituents are

[0091] In some embodiments, the ring W and its R w Substituents are

[0092] In some embodiments, the ring W and its R w Substituents are

[0093] As described above and defined in this paper, the ring X and its R x Substituents are in Indicates the key with ring W, and Indicates with L x Or the bonds of the rest of the molecule.

[0094] In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are

[0095] In some embodiments, ring X is illustrated in the compounds shown in Table 1A below.

[0096] In some embodiments, ring X and its R x Substituents are

[0097] In some embodiments, ring X and its R x Substituents are

[0098] In some embodiments, ring X and its R x Substituents are

[0099] As described above and defined herein, ring Y is selected from the following rings: phenyl, naphthyl, 3-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 member monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0100] In some embodiments, ring Y is selected from the following rings: phenyl, 3-8 saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 saturated monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0101] In some embodiments, ring Y is selected from the following rings: naphthyl, 5-10 saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 8-10 saturated bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0102] In some embodiments, ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic groups (the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic groups (the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0103] In some embodiments, ring Y is phenyl. In some embodiments, ring Y is naphthyl. In some embodiments, ring Y is a 3-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic group. In some embodiments, ring Y is a 5-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-10 member monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-10 member monocyclic or bicyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, ring Y is a 3-8 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 3-6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is cyclopropyl. In some embodiments, ring Y is cyclobutyl. In some embodiments, ring Y is cyclopentyl. In some embodiments, ring Y is hexyl.

[0105] In some embodiments, ring Y is a 5-6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 6-7 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 3 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 4 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 5 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 7 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0106] In some embodiments, ring Y is a 5-10 quinary saturated or partially unsaturated bicyclic or bridged bicyclic carbonyl group.

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

[0108] In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having 2-3 nitrogen heteroatoms.

[0109] In some embodiments, ring Y is a 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 6-membered monocyclic heteroaryl group having 1-4 nitrogen heteroatoms. In some embodiments, ring Y is pyridyl, pyrimidinyl, pyridazinyl, or triazinyl.

[0110] In some embodiments, ring Y is a 3-8 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0111] In some embodiments, ring Y is an 8-11 member saturated or partially unsaturated bicyclic, bridged bicyclic, or spirocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-10 member saturated or partially unsaturated bicyclic or bridged bicyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is an 8-11 member saturated or partially unsaturated bicyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 9-10 member saturated or partially unsaturated bicyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 9-member saturated or partially unsaturated bicyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 10-member saturated or partially unsaturated bicyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is tetrahydroisoquinolinyl or tetrahydroquinolinyl.

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

[0113] In some embodiments, ring Y is

[0114] In some embodiments, ring Y is

[0115] In some embodiments, ring Y is

[0116] In some embodiments, ring Y is

[0117] In some embodiments, ring Y is illustrated in the compounds shown in Table 1A below.

[0118] In some embodiments, ring Y and its R y Substituents are

[0119] In some embodiments, the ring Y and its Ry substituents are

[0120] In some embodiments, ring Y is

[0121] In some embodiments, ring Y and its R y Substituents are

[0122] As described above and defined in this article, R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0123] In some embodiments, R x and R y Independently selected from R A, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0124] As described above and defined in this paper, each R w Independently selected from hydrogen, R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0125] In some embodiments, each R w Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0126] In some embodiments, each R w Independently selected from R A R B, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0127] In some embodiments, R w R x and R y One or more of them are hydrogen. In some embodiments, R w R x and R y One or more of them are R A In some embodiments, R w R x and R y One or more of them are halogens. In some embodiments, R w R x and R y One or more of them are -CN. In some embodiments, R w R x and R y One or more of them are -NO2. In some embodiments, R w R x and R y One or more of them are -OR. In some embodiments, R w R x and R y One or more of them are -SR. In some embodiments, R w R x and R y One or more of them are -NR2. In some embodiments, R w R x and R y One or more of them are -SiR3. In some embodiments, R w R x and R y One or more of them are -S(O)2R. In some embodiments, R w R x and R y One or more of them are -S(O)2NR2. In some embodiments, R w R x and Ry One or more of them are -S(O)(NR)R. In some embodiments, R w R x and R y One or more of them are -S(O)R. In some embodiments, R w R x and R y One or more of them are -C(O)R. In some embodiments, R w R x and R y One or more of them are -C(O)OR. In some embodiments, R w R x and R y One or more of them are -C(O)NR2. In some embodiments, R w R x and R y One or more of them are -C(O)NROR. In some embodiments, R w R x and R y One or more of them are -OC(O)R. In some embodiments, R w R x and R y One or more of them are -OC(O)NR2. In some embodiments, R w R x and R y One or more of them are -OP(O)R2. In some embodiments, R w R x and R y One or more of them are -OP(O)(OR)2. In some embodiments, R w R x and R y One or more of them are -NRC(O)OR. In some embodiments, R w R x and R y One or more of them are -NRC(O)R. In some embodiments, R w R x and R y One or more of them are -NRC(O)N(R)2. In some embodiments, R w R x and R y One or more of them are -NRS(O)2R.

[0128] In some embodiments, R w It is -C(O)OR. In some embodiments, Rw It is -C(O)NR2. In some embodiments, R w It is an optionally substituted phenyl group. In some embodiments, R w It is an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1 - (4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0129] In some embodiments, R w It is R B In some embodiments, R w It is R A .

[0130] In some embodiments, R w It is fluorine, chlorine, or bromine.

[0131] In some embodiments, R w It is -C(O)NHR. In some embodiments, R w It is -C(O)NHR, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NHR, where R w R in C 1-6 Aliphatic groups, optionally replaced by -CN.

[0132] In some embodiments, R w It is an optional replacement for C 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally substituted with -C(O)N(R) o )2 replaces. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally covered by -NR o (O)N(R o )2 replaces. In some embodiments, R w yes In some such embodiments, R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 The aliphatic group is optionally replaced by a halogen (e.g., fluorine). In some embodiments, R wIt is -CH2F, -CHF2, or -CF3.

[0133] In some embodiments, R w It is C 1-6 The aliphatic group is optionally replaced by a halogen (e.g., fluorine). In some embodiments, R w yes In some embodiments, R w It is C 1-6 Aliphatic groups, optionally halogenated (e.g., fluorine) or -NR o 2. Replacement. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally with halogens (e.g., fluorine) and -NR o 2. Replacement. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally halogenated (e.g., fluorine) or -NR o 2 replacements, where each R o Independently hydrogen or C 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally with halogens (e.g., fluorine) and -NR o 2 replacements, where each R o Independently hydrogen or C 1-6 Aliphatic group. In some embodiments, R w yes

[0134] In some embodiments, R w It is an optional substituted phenyl group.

[0135] In some embodiments, R w It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R w It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R w It is an optional substituted cyclopropyl group. In some embodiments, R w It is an optional substituted cyclobutyl group. In some embodiments, R w It is an optional substituted cyclopentyl group. In some embodiments, R w It is an optional substituted cyclohexyl group. In some embodiments, R w It is an optionally substituted cyclopropene group. In some embodiments, R w It is an optional substituted cyclobutenyl group. In some embodiments, R w It is an optional substituted cyclopentenyl group. In some embodiments, R w It is an optional substituted cyclohexene group.

[0136] In some embodiments, R w It is a 3- to 7-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is a 5-6 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0137] In some embodiments, R w It is a tetra-membered saturated or partially unsaturated heterocycle with one or two independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It can be optionally substituted with nitrogen-heterocyclic butyl, oxocyclic butyl, or thiocyclic butyl.

[0138] In some embodiments, R w It is a 5-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It can be optionally substituted with pyrrolidinyl, pyrrolinyl, pyrazolylyl, pyrazolylyl, imidazoalkyl, or imidazolinyl. In some embodiments, R w It can be optionally substituted with dihydropyridyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, or tetrahydrothiophenyl.

[0139] In some embodiments, R w It is a 6-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It may be optionally substituted with piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxyl, 1,4-dioxinyl, thiaalkyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,3-dithiaalkyl, 1,4-dithiaalkyl, morpholinyl, or thiomorpholinyl. In some embodiments, R w It can be optionally substituted with dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, or tetrahydrothiaranyl.

[0140] In some embodiments, R w It is an optional replacement In some embodiments, R w It is an optional replacement In some embodiments, R w It is an optional replacement In some embodiments, R w yes In some embodiments, R w It is an optional replacement Among them Wm Is it O, S, C(O), or NR? o , where R o It is as described above and defined herein. In some embodiments, R w yes In some embodiments, R w It is an optional replacement In some embodiments, R w yes In some embodiments, R w yes In some embodiments, R w yes In some embodiments, W m It is O. In some embodiments, W m It is S. In some embodiments, W m It is C(O). In some embodiments, W m It is NR o In some embodiments, W m It is NR o , where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0141] In some embodiments, R w It is an optionally substituted 5-6 membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is a 5-membered heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It can be optionally substituted with a pyrazolyl, imidazole, triazole, or tetraazole group. In some embodiments, R w It is an optional substituted imidazole group, optionally replaced by -C(O)N(R) o )2 replaces. In some embodiments, R w It can be optionally substituted with furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, R w It is furanyl, optionally converted to -C(O)N(R) o )2 replaces.

[0142] In some embodiments, R w It is a 6-membered heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is an optionally substituted 6-membered heteroaryl group having 1-4 nitrogen atoms. In some embodiments, R w It can be optionally substituted with pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, Rw It can be optionally substituted with a pyridone group, a pyrazinone group, or a pyrimidinone group.

[0143] In some embodiments, R w It is -NHR, where R is an optional 5-6 membered heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -NHR, where R is a 6-membered heteroaryl group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0144] In some embodiments, R w It is -S(O)2NH2. In some embodiments, R w It is -S(O)2NHR, where R is the C with optional substitution. 1-6 Aliphatic group. In the embodiment, R w It is -S(O)2NHR, where R is an optionally substituted phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0145] In the embodiment, R w It is -S(O)2(NH)R. In some embodiments, R w It is -S(O)2(NH)H. In some embodiments, R w It is -S(O)2(NH)R, where R is an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -S(O)2(NH)R, where R is an optionally substituted phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

[0147] In some embodiments, R w It is -C(O)H. In some embodiments, R w It is -C(O)R, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)R, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... w It is -C(O)R, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -C(O)R, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0148] In some embodiments, R w It is -C(O)R, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)R, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... wIt is -C(O)R, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -C(O)R, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0149] In some embodiments, R w It is -C(O)OH. In some embodiments, R w It is -C(O)OR, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)OR, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... w It is -C(O)OR, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -C(O)OR, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0150] In some embodiments, R w It is -C(O)NH2. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted 4-7 member saturated or partially unsaturated heterocycle (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0151] In some embodiments, R wIt is -C(O)NHR, where R is the C with optional substitution. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NHR, where R is C 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NHR, where R is methyl, ethyl, or cyclopropyl. In some embodiments, R w It is -C(O)NR2, where R w The two R groups, together with the intermediate atom, form a 3-7 saturated or partially unsaturated monocycle, which, in addition to the atoms attached to or adjacent to the two R groups, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -C(O)NR2, where R w The two R groups, together with the intermediate atom, form a 3-7 nucleotide saturated or partially unsaturated monocycle, which has 0 heteroatoms other than the atoms attached to or adjacent to the two R groups. In some embodiments, R w It is -C(O)NR2, where R w The two R groups together with the middle atom form acridine, aziridine, diaziridine, pyrrolidinyl, or piperidinyl.

[0152] In some embodiments, R w It is -C(O)NROR, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NROR, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -C(O)NROR, where R w Each R in the equation is independently hydrogen or an optionally substituted 4-7 member saturated or partially unsaturated heterocycle (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is -C(O)NROR, where R w Each R in the equation is independently hydrogen or an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0153] In some embodiments, R w It is -OC(O)H. In some embodiments, R w It is -OC(O)R, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, Rw It is -OC(O)R, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... w It is -OC(O)R, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -OC(O)R, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0154] In some embodiments, R w It is -OC(O)NR2, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -OC(O)NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -OC(O)NR2, where R w Each R in the equation is independently hydrogen or a 4-7 member saturated or partially unsaturated heterocycle with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -OC(O)NR2, where R w Each R in the group is independently hydrogen or a 5-6 membered heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0155] In some embodiments, R w It is -NRC(O)OR, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -NRC(O)OR, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -NRC(O)OR, where R w Each R in the equation is independently hydrogen or an optionally substituted 4-7 member saturated or partially unsaturated heterocycle (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is -NRC(O)OR, where R w Each R in the equation is independently hydrogen or an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0156] In some embodiments, R w It is -NRC(O)R, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -NRC(O)R, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -NRC(O)R, where R w Each R in the equation is independently hydrogen or a 4-7 member saturated or partially unsaturated heterocycle with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -NRC(O)R, where R w Each R in the group is independently hydrogen or a 5-6 membered heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0157] In some embodiments, R w It is -NRC(O)N(R)2, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -NRC(O)N(R)2, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -NRC(O)N(R)2, where R w Each R in the equation is independently hydrogen or a 4-7 member saturated or partially unsaturated heterocycle with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -NRC(O)N(R)2, where R w Each R in the group is independently hydrogen or a 5-6 membered heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0158] In some embodiments, R w It is -NRS(O)2R, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -NRS(O)2R, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -NRS(O)2R, where R wEach R in the equation is independently hydrogen or an optionally substituted 4-7 member saturated or partially unsaturated heterocycle (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is -NRS(O)2R, where R w Each R in the equation is independently hydrogen or an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0159] In some embodiments, R w It is -S(O)H. In some embodiments, R w It is -S(O)R, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -S(O)R, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... w It is -S(O)R, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -S(O)R, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0160] In some embodiments, R w It is -S(O)2H. In some embodiments, R w It is -S(O)2R, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -S(O)2R, where R w R in this context is an optionally substituted phenyl group. In some embodiments, R... w It is -S(O)2R, where R w R in the figure is a 4-7 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -S(O)2R, where R w R in the R is a 5-6 membered heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0161] In some embodiments, R w It is -S(O)(NR)R, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6Aliphatic group. In some embodiments, R w It is -S(O)(NR)R, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -S(O)(NR)R, where R w Each R in the equation is independently hydrogen or a 4-7 member saturated or partially unsaturated heterocycle with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -S(O)(NR)R, where R w Each R in the group is independently hydrogen or a 5-6 membered heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0162] In some embodiments, R w It is -S(O)2NR2, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -S(O)2NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -S(O)2NR2, where R w Each R in the equation is independently hydrogen or a 4-7 member saturated or partially unsaturated heterocycle with optional substitutions of 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -S(O)2NR2, where R w Each R in the group is independently hydrogen or a 5-6 membered heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0163] In some embodiments, R w It is an optionally substituted 3-7 member saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is a 3-7 membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, R w It is a 5-6 membered monocyclic heteroaryl ring with optional substitutions of 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is a 5-6 membered monocyclic heteroaryl ring with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur, and is substituted with =O. In some embodiments, R w It is an optional replacement:

[0164] In some embodiments, R w yes: In some such embodiments, R o Is it hydrogen or C1? -6 Aliphatic groups.

[0165] In some embodiments, R w yes:

[0166] In some embodiments, R w It is an optional replacement:

[0167] In some embodiments, R w yes: Among them, ring W 1 It is an optional substituted 3-7 member saturated or partially unsaturated heterocycle (the heterocycle has one additional heteroatom selected from nitrogen, oxygen and sulfur), or a 5-6 member monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0168] As defined above and described in this article, the ring W 1 It is an optionally substituted 3-7 member saturated or partially unsaturated heterocycle (the heterocycle has one additional heteroatom selected from nitrogen, oxygen, and sulfur), or a 5-6 member monocyclic heteroaryl ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W 1 It is an optionally substituted 3-7 member saturated or partially unsaturated heterocycle (the heterocycle has one additional heteroatom selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 1 It is an optionally substituted 5-6 member saturated or partially unsaturated heterocycle (the heterocycle has one additional heteroatom selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 1 It is an optionally substituted 5-6 membered monocyclic heteroaryl ring (the heteroaryl ring has 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 1 It is an optionally substituted 5-membered monocyclic heteroaryl ring (the heteroaryl ring has 1-3 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 1 It is an optional substituted 6-membered monocyclic heteroaryl ring (the heteroaryl ring has 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0169] In some embodiments, R w yes:

[0170] In some embodiments, R w yes: Among them, ring W 2 It is an optional substituted 3-7 member partially unsaturated heterocycle, or a 5-6 member monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0171] As defined above and described in this article, the ring W 2 It is an optionally substituted 3-7 membered partially unsaturated heterocycle, or a 5-6 membered monocyclic heteroaryl ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring W 2 It is an optional substituted 3-7 nucleotide partially unsaturated heterocyclic ring. In some embodiments, ring W 2 It is an optional substituted 5-6 partially unsaturated heterocyclic ring. In some embodiments, ring W 2 It is an optionally substituted 5-6 membered monocyclic heteroaryl ring (the heteroaryl ring has 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 2 It is a 5-membered monocyclic heteroaryl ring (the heteroaryl ring has 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, ring W 2 It can be optionally substituted with oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, 2-imidazolinyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl.

[0172] In some embodiments, R w The alternative rings are selected from the following:

[0173] In some embodiments, R w yes: Each R o It is as defined above and described in this article (e.g., hydrogen or C). 1-6 Aliphatic groups).

[0174] In some embodiments, R w yes:

[0175] In some embodiments, R wIt is an optionally substituted 7-11 membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is an optionally substituted 9-10 membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is optionally substituted with benzo[d][1,3]dioxacyclopentenyl. In some embodiments, R w It is an optional substituted 11-membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0176] In some embodiments, R w It is an optionally substituted 8-11 membered bicyclic aryl or heteroaryl group (the heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is an optionally substituted naphthyl group. In some embodiments, R w It is an optional substituted dihydrobenzodioxane-heptyl group. In some embodiments, R w It can be optionally substituted with indene or dihydroindene.

[0177] In some embodiments, R w It is an optional substituted 9-10 membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0178] In some embodiments, R w It is an optionally substituted 9-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It may be optionally substituted with indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzooxazolyl, thiophenopyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[2,3,-b]pyridyl, pyrazolo[1,5-a]pyridyl, or imidazo[1,2-a]pyridyl, azainzolyl (e.g., 4-, 5-, 6-, or 7-azainzolyl), pyrrolo[2,3-c]pyridyl, or inazinyl.

[0179] In some embodiments, R w It is an optionally substituted 10-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It can be optionally substituted with quinolinyl, isoquinolinyl, quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cyclolinyl, or 1,8-naphthidyl.

[0180] In some embodiments, R wIt contains fluorine, chlorine, -CN, -OH, -OMe, -OCH2CO2Me, -CO2H, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, -C(O)NMe2, -C(O)N(Me)Et, -C(O)N(Me)nPr, -CH2NHMe,

[0181] In some embodiments, R w It contains fluorine, chlorine, -CN, methyl, -CF3, -CHF2, -OH, -OMe, -OCH2CO2Me, -CO2H, -C(O)NH2, -C(O)NHMe, -C(O)NHEt, -C(O)NHnPr, -C(O)NHCH2CH2OH, -C(O)NMe2, -C(O)N(Me)Et, -C(O)N(Me)nPr, -CH2NHMe,

[0182] In some embodiments, R w yes

[0183] In some embodiments, R w It is -S(O)2NH2, -S(O)2N(CH3)2, -S(O)(NH)CH3,

[0184] In some embodiments, R w yes

[0185] In some embodiments, R w yes

[0186] In some embodiments, R w It is -CH2CH2CH3,

[0187] In some embodiments, R w yes

[0188] In some embodiments, R w It is -C(O)NH2. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optional substituted C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted phenyl group. In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optionally substituted 4-7 member saturated or partially unsaturated heterocycle (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is -C(O)NR2, where R w Each R in the equation is independently hydrogen or an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0189] In some embodiments, R w yes

[0190] In some embodiments, each R x Independently selected from R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0191] In some embodiments, R x It is -CO2Me or -CH2OH.

[0192] In some embodiments, R x It is -C(O)R or -C(O)OR. In some embodiments, R x It is -C(O)R. In some embodiments, R x It is -C(O)R, where R x R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R xIt is -C(O)R, where R x R in C 1-6 Aliphatic groups, optionally -C(O)OR o -OR o halogen (e.g., fluorine), or =O substitution. In some embodiments, R... x It is -C(O)OR. In some embodiments, R x It is -C(O)OR, where R x R in the equation is an optional substitution for C. 1-6 Aliphatic groups.

[0193] In some embodiments, R x yes

[0194] In some embodiments, R x It is an optional replacement for C 1-6 Aliphatic group. In some embodiments, R x It is C 1-6 Aliphatic groups, optionally -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0195] In some embodiments, R x It is -CO2Me, -CH2OH, -C(O)Me, -C(O)Et, -C(O)iPr, -C(O)cyclopropyl, -C(O)oxacyclobutane, -C(O)tetrahydropyranyl, or pyridyl.

[0196] In some embodiments, R x It is fluorine. In some embodiments, R x It is -S(O)2CH3. In some embodiments, R x It is -C(O)N(CH3)2.

[0197] In some embodiments, R x It is -C(O)R, where R x R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R x It is -C(O)R, where R x R in C 1-6 Aliphatic group. In some embodiments, R x It is -C(O)R, where R x R in this context is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R... x It is -C(O)R, where R x R in -ORo or -C(O)OR o Replacement C 1-6 Aliphatic groups, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R x It is -C(O)R, where R x R in -OR o Replacement C 1-6 Aliphatic groups, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R x It is -C(O)R, where R x R in -C(O)OR o Replacement C 1-6 Aliphatic groups, where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0198] In some embodiments, R x yes

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

[0200] In some embodiments, R y It contains fluorine, chlorine, bromine, iodine, methyl, ethyl, cyclopropyl, -CF3, -CN, CH2O, -CO2H, -CO2Me, -CO2tBu, -C(O)Me, -NH2, -NHMe, -NHAc, -NHC(O)Et, -OH, -OMe, -OCH2CH2NH2, -CH2OH, -CH2OMe, -CH2NHMe, -CH2NHAc, -CH2SO2Me, -SO2Me, -SO2NH2, -SO2NHMe.

[0201] In some embodiments, R y It is -C(O)H.

[0202] In some embodiments, R w R x and R y The compounds are shown in Table 1A below.

[0203] As described above and defined in this paper, each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0204] In some embodiments, R A It is an optional replacement for C 1-6 Aliphatic group. In some embodiments, R A It is an optionally substituted phenyl group. In some embodiments, R A It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R A It is a 3- to 7-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R A It is an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0205] In some embodiments, R A It is C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl). In some embodiments, R A It is C 1-6 Halogenated alkyl groups (e.g., -CF3, -CHF2).

[0206] In some embodiments, R A The compounds are shown in Table 1A below.

[0207] As described above and defined in this paper, each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 .

[0208] In some embodiments, R B Yes -L B -Cy B1 -H. In some embodiments, R B Yes -L B -CyB1 -Cy B2 .

[0209] In some embodiments, R B yes In some embodiments, R B yes

[0210] In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes

[0211] In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes In some embodiments, R B yes

[0212] In some embodiments, R B The compounds are shown in Table 1A below.

[0213] In some embodiments, R B yes

[0214] In some embodiments, R B yes

[0215] In some embodiments, R B yes

[0216] As described above and defined in this document, each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-.

[0217] In some embodiments, each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-.

[0218] In some embodiments, L B It is a covalent bond. In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)-, or -CR=CR-. In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -NR-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by -O-, -C(O)-, or -NR-. In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one methylene unit in the chain is optionally replaced by: -O-, -C(O)-, -NR-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L B It is C 1-3A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one methylene unit in the chain is optionally replaced by -O-, -C(O)-, or -NR-. In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one methylene unit in the chain is replaced by -C(O)-. In some embodiments, L B It is -C(O)-.

[0219] In some embodiments, L B It is C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain. In some embodiments, L B It is -CH2-.

[0220] In some embodiments, L B It is -C(O)-, -C(S)-, -C(NR)R-, -S(O)-, -S(O)2-, or -S(O)(NR)-. In some embodiments, L B It is -C(O)-, -C(S)-, or -C(NR)R-. In some embodiments, L B It is -C(O)-, --S(O)-, -S(O)2-, or -S(O)(NR)-. In some embodiments, L B It is -C(S)-. In some embodiments, L B It is -C(NR)R-. In some embodiments, L B It is -S(O)-. In some embodiments, L B It is -S(O)2-. In some embodiments, L B It is -S(O)(NR)-.

[0221] As described above and defined in this article, each Cy B1 Independently, the ring may be optionally substituted with one of the following: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic groups (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic, or tricyclic carbocyclic, heterocyclic, arylene, or heteroarylene (the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0222] In some embodiments, each Cy B1Independently, the alternatively substituted ring is selected from the following: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0223] It should be understood that Cy B1 All embodiments may refer to having -L B -Cy B1 (That is, when RB is -L) B -Cy B1 The terminal loop (or alternatively, a ring) in the structure of -H (or further connected to Cy) B2 If it presents a structure-L B -Cy B1 -Cy B2 A ring, regardless of how it is presented. For example, Cy B1 The example is phenylene, which refers to -L B -Cy B1 -Cy B2 The phenylene in, and -L B -Cy B1 The phenyl group in -H. Similarly, Cy B1 The embodiment is It refers to -L B -Cy B1 -Cy B2 In and -L B -Cy B1 -H Similarly, Cy B1 The embodiment is It refers to -L B -Cy B1 -Cy B2 In and -L B -Cy B1 -H

[0224] In some embodiments, each Cy B1 Independently, the alternatively substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0225] In some embodiments, Cy B1It is an optionally substituted phenylene. In some embodiments, Cy B1 It is a phenylene oxide.

[0226] In some embodiments, Cy B1 It is an optionally substituted 3-7 member saturated or partially unsaturated carbocyclic or heterocyclic group (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optional substituted 5-10 member monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0227] In some embodiments, Cy B1 It is an optionally substituted 3-7 member saturated or partially unsaturated heterocyclic group (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 nitrogen atoms). In some embodiments, Cy RB It can be optionally substituted with piperidinyl or piperazine.

[0228] In some embodiments, Cy B1 It is a 3-7 member saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is a 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is a 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is a 6-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 nitrogen atoms). In some embodiments, Cy B1 It is piperidinyl or piperazineyl. In some embodiments, Cy B1 yes

[0229] In some embodiments, Cy B1It can be optionally substituted with a piperidinone group or a piperazinone group. In some embodiments, Cy B1 It is optionally substituted with a dihydropyridyl group. In some embodiments, Cy B1 It is an optional substituted thiomorpholino group.

[0230] In some embodiments, Cy B1 It is an optional substituted morpholino group.

[0231] In some embodiments, Cy B1 It is a 3-10 saturated or partially unsaturated monocyclic or bicyclic subheterocyclic group (the subheterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0232] In some embodiments, Cy B1 It is an optionally substituted 8-10 member saturated or partially unsaturated bicyclic heterocyclic group (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optional substituted 8-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optional substituted 8-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optional substituted 8-membered saturated or partially unsaturated heterocyclic group (the heterocyclic group has 1-2 nitrogen atoms). In some embodiments, Cy B1 It is an optional replacement In some embodiments, Cy B1 It is an optional replacement

[0233] In some embodiments, Cy B1 It is an optional substituted indazole group. In some embodiments, Cy B1 It is an optional substituted pyrrolo[2,3-b]pyridine.

[0234] In some embodiments, Cy B1 It is an optionally substituted 5-6 membered monocyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optionally substituted 6-membered monocyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It can be optionally substituted with a pyridone group, a pyrazinone group, or a pyrimidinone group.

[0235] In some embodiments, CyB1 It is an optional substituted furanyl group. In some embodiments, Cy B1 It is an optional substituted isoxazolyl group. In some embodiments, Cy B1 It is an optional substituted pyrrole group. In some embodiments, Cy B1 It is an optional substituted pyridinone group. In some embodiments, Cy B1 It is an optionally substituted pyridazinyl group. In some embodiments, Cy B1 It is an optional substituted 5-15 saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0236] In some embodiments, Cy B1 It is optionally substituted with a 10-15 member saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group, or heteroaryl group (the heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optionally substituted 10-15 member saturated or partially saturated tricyclic heterocyclic group (the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is an optional substituted 10-15-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0237] In some embodiments, Cy B1 It is a 13-membered saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group, or heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B1 It is a 15-membered saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group, or heteroaryl group (the heteroaryl group has 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0238] As described above and defined in this article, each Cy B2 Independently, the ring may be optionally substituted with one of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic rings (the heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0239] In some embodiments, each Cy B2The ring is independently optionally substituted with one of the following: phenyl, 3-10 saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic rings (the heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 saturated or bicyclic aryl or heteroaryl rings (the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0240] In some embodiments, each Cy B2 Independently selected from the following optional rings: phenyl, 3-7 membered saturated or partially unsaturated carbon rings or heterocycles (the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0241] In some embodiments, Cy B2 It is an optionally substituted phenyl group. In some embodiments, Cy B2 It is phenyl. In some embodiments, Cy B2 It is a phenyl group, optionally prefixed with -CN, halogen, or -R. o 、or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0242] In some embodiments, Cy B2 It is an optional substituted 3-7 member saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0243] In some embodiments, Cy B2 It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, Cy B2 It is an optional substituted cyclopropyl group. In some embodiments, Cy B2 It is cyclopropyl. In some embodiments, Cy B2 It is an optional substituted cyclobutyl group. In some embodiments, Cy B2 It is cyclobutyl.

[0244] In some embodiments, Cy B2 It is an optional substituted cyclopentyl group. In some embodiments, Cy B2 It is cyclopentyl. In some embodiments, Cy B2 It is an optional substituted cyclohexyl group. In some embodiments, Cy B2 It is cyclohexyl.

[0245] In some embodiments, Cy B2It is an optional substituted 5-10 member monocyclic or bicyclic aryl or heteroaryl (the heteroaryl has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0246] In some embodiments, Cy B2 It is an optionally substituted 5-6 membered monocyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optionally substituted 5-6 membered monocyclic heteroaryl group (the heteroaryl group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optionally substituted pyridinyl group. In some embodiments, Cy B2 It is pyridyl, optionally prefixed with -CN, halogen, or -R. o -OR o -N(R) o )2、-C(O)OR o Replace, where each R o It is hydrogen on its own; C 1-6 Aliphatic group, the C 1-6 The aliphatic group can be optionally replaced by halogens, -(CH2). 0-2 OH, or -(CH2) 0- 2OR · Replace, where R · It is C 1-4 Aliphatic group; or 5-6-membered saturated, partially unsaturated or aryl ring (e.g., phenyl or morpholino) having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0247] In some embodiments, Cy B2 It is an optionally substituted 6-membered monocyclic heteroaryl group (the heteroaryl group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It can be optionally substituted with pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl.

[0248] In some embodiments, Cy B2 It is an optional substituted pyridone group, pyrazinone group or pyrimidinone group.

[0249] In some embodiments, Cy B2 It is an optionally substituted 5-membered monocyclic heteroaryl group (the heteroaryl group has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It can be optionally substituted with pyrazolyl, imidazole or triazole.

[0250] In some embodiments, Cy B2It is an optional substituted 8-10 membered bicyclic aryl or heteroaryl (the heteroaryl has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0251] In some embodiments, Cy B2 It is an optionally substituted 9-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optionally substituted 9-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 nitrogen atoms). In some embodiments, Cy B2 It is optionally substituted with benzimidazolyl, indazolyl, or azidoindolyl (e.g., pyrrolo[2,3-c]pyridyl or pyrrolo]2,3-b]pyridyl). In some embodiments, Cy B2 It is benzimidazolyl, indazolyl, or azaindolyl (e.g., pyrrolo[2,3-c]pyridyl or pyrrolo]2,3-b]pyridyl), optionally marked with -CN, halogen, or -R. o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, Cy B2 It can be an optional substituted indole or a azidoindole.

[0252] In some embodiments, Cy B2 It is an optional substituted [1,2,4]triazolo[4,3-a]pyridyl.

[0253] In some embodiments, Cy B2 It is an optionally substituted 10-membered bicyclic aryl or heteroaryl group (the heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optionally substituted 10-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 nitrogen atoms). In some embodiments, Cy B2 It can be optionally substituted with quinoxalinyl, isoquinoxalinyl, 2,6-naphthidyl, or 2,7-naphthidyl. In some embodiments, Cy B2 It is quinoxalinyl, isoquinoxalinyl, 2,6-naphthidyl, or 2,7-naphthidyl, optionally prefixed with -R o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0254] In some embodiments, Cy B2 It is an optionally substituted naphthyl group. In some embodiments, Cy B2 It is naphthyl, optionally with -R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0255] In some embodiments, Cy B2 It is an optional substituted benzo[d][1,3]dioxacyclopentenyl.

[0256] In some embodiments, Cy B2 yes

[0257] In some embodiments, Cy B2 It is an optional substituted 5-15 saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0258] In some embodiments, Cy B2 It is an optionally substituted 10-15 member saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group, or heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optionally substituted 10-15 member saturated or partially saturated tricyclic heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is an optional substituted 10-15-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0259] In some embodiments, Cy B2 It is a 13-membered saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group, or heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Cy B2 It is a 15-membered saturated or partially saturated tricyclic carbocyclic group, heterocyclic group, aryl group or heteroaryl group (the heteroaryl group has 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0260] As described above and defined herein, each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same atom or adjacent atoms optionally together with the atom between them to form a 3-7 membered saturated or partially unsaturated ring, the ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the atoms or adjacent atoms to which the two R groups are attached.

[0261] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C. 1-6 Aliphatic group. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 4-7 member saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-7 member saturated or partially unsaturated heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R is an optionally substituted 5-6 member heteroaryl ring (the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, two R groups on the same atom may optionally form a 3-7 member saturated or partially unsaturated ring together with the atom between them, the ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the atoms to which the two R groups are attached. In some embodiments, two R groups on adjacent atoms may optionally form a 3-7 member saturated or partially unsaturated ring together with the atom between them, the ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the adjacent atoms to which the two R groups are attached.

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

[0263] In some embodiments, R is the compound shown in Table 1A below.

[0264] As described above and defined in this article, L x yes in This indicates a bond with ring Y.

[0265] In some embodiments, Lx is in This indicates a bond with ring Y.

[0266] In some embodiments, L x It is -C(O)(CH2) 1-3 -

[0267] In some embodiments, Lx is in This indicates a bond with ring Y.

[0268] In some embodiments, L xis -C(O)-, -C(O)CH2-, -S(O)2CH2-, -C(O)CH2CH2-, -C(O)OCH2-, -C(O)CH2O-, -C(O)CH2CH2CH2-, -C(O)CH2NHC(O)-,

[0269] In some embodiments, L x yes

[0270] In some embodiments, L x It is -C(O)CH2CH2-.

[0271] In some embodiments, L x It is -S(O)2CH2CH2-.

[0272] In some embodiments, L x The compounds are shown in Table 1A below.

[0273] As described above and defined in this article, R Z It is R A -OR, or -NR2. In some embodiments, R Z It is R A In some embodiments, R Z Yes - OR. In some embodiments, R Z It is -NR2.

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

[0275] 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.

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

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

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

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

[0280] In some embodiments, w, x, y, and z are those shown in the compounds depicted in Table 1A below.

[0281] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-1 or Ia-2: Or a pharmaceutically acceptable salt thereof, wherein cyclic X, cyclic Y, R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0282] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-3 or Ia-4: Or a pharmaceutically acceptable salt thereof, wherein cyclic X, cyclic Y, R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0283] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-5 or Ia-6: Or a pharmaceutically acceptable salt thereof, wherein cyclic X, cyclic Y, R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0284] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formulas Ia-7: Or a pharmaceutically acceptable salt thereof, wherein ring W, ring X, or ring R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0285] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formulas Ia-8: Or a pharmaceutically acceptable salt thereof, wherein ring W, ring X, ring Y, or ring R w R x R y w, x, and y are individually and in combination as defined above and described herein.

[0286] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-9 or Ia-10: Or a pharmaceutically acceptable salt thereof, wherein the rings Y and R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0287] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-11 or Ia-12: Or a pharmaceutically acceptable salt thereof, wherein the rings Y and R w R x R y L x w, x, and y are individually and in combination as defined above and described herein.

[0288] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-13 or Ia-14: Or a pharmaceutically acceptable salt thereof, wherein the rings Y and R w R x R y L xw, x, and y are individually and in combination as defined above and described herein.

[0289] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-15: Or a pharmaceutically acceptable salt thereof, wherein ring W, ring Y, or ring R w R x R y w, x, and y are individually and in combination as defined above and described herein.

[0290] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has formula Ia-16: Or a pharmaceutically acceptable salt thereof, wherein the rings W and R w R x R y w, x, and y are individually and in combination as defined above and described herein.

[0291] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has one of formula Ia-1a, Ia-2a, Ia-1b or Ia-2b: Or its pharmaceutically acceptable salts, wherein each variable is defined individually and in combination as defined above and described herein, and wherein: R w’ It is R w , where R w It is both individually and in combination as defined above and described herein.

[0292] In some embodiments, R w’ It is optionally substituted with a ring selected from the following: phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0293] In some embodiments, R w’ It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R w’ It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R w’It is an optional substituted cyclopropyl group. In some embodiments, R w’ It is an optional substituted cyclobutyl group. In some embodiments, R w’ It is an optional substituted cyclopentyl group. In some embodiments, R w’ It is an optional substituted cyclohexyl group. In some embodiments, R w’ It is an optionally substituted cyclopropene group. In some embodiments, R w’ It is an optional substituted cyclobutenyl group. In some embodiments, R w’ It is an optional substituted cyclopentenyl group. In some embodiments, R w’ It is an optional substituted cyclohexene group.

[0294] In some embodiments, R w’ It is an optionally substituted 3-7 member saturated or partially unsaturated heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is a 5-6 member saturated or partially unsaturated heterocycle with optional substitution (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0295] In some embodiments, R w’ It is a tetra-membered saturated or partially unsaturated heterocycle with one or two independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It can be optionally substituted with nitrogen-heterocyclic butyl, oxocyclic butyl, or thiocyclic butyl.

[0296] In some embodiments, R w’ It is a 5-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It can be optionally substituted with pyrrolidinyl, pyrrolinyl, pyrazolylyl, pyrazolylyl, imidazoalkyl, or imidazolinyl. In some embodiments, R w’ It can be optionally substituted with dihydropyridyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, or tetrahydrothiophenyl.

[0297] In some embodiments, R w’ It is a 6-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It may be optionally substituted with piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxyl, 1,4-dioxinyl, thiaalkyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,3-dithiaalkyl, 1,4-dithiaalkyl, morpholinyl, or thiomorpholinyl. In some embodiments, R w’It can be optionally substituted with dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, or tetrahydrothiaranyl.

[0298] In some embodiments, R w’ It is a 5-6 membered heteroaryl group with optional substitutions having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It is an optionally substituted 5-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It can be optionally substituted with pyrazolyl, imidazole, triazole, or tetrazolyl. In some embodiments, R w’ It is optional to be -C(O)N(R) o )2-substituted with an optional imidazole group. In some embodiments, R w’ It can be optionally substituted with furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, R w’ It is optional to be -C(O)N(R) o )2-substituted furanyl group.

[0299] In some embodiments, R w’ It is an optionally substituted 6-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optionally substituted 6-membered heteroaryl group having 1-4 nitrogen atoms. In some embodiments, R w’ It can be optionally substituted with pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R w’ It can be optionally substituted with a pyridinone group, a pyridazinone group, or a pyrimidinone group.

[0300] In some embodiments, R w’ It is an optionally substituted 7-11 membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optionally substituted 9-10 membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is optionally substituted with benzo[d][1,3]dioxacyclopentenyl. In some embodiments, R w’ It is an optional substituted 11-membered bicyclic heterocycle (the heterocycle has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0301] In some embodiments, R w’ It is an optionally substituted 8-11 membered bicyclic aryl or heteroaryl group (the heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Rw’ It is an optionally substituted naphthyl group. In some embodiments, R w’ It is an optional substituted dihydrobenzodioxane-heptyl group. In some embodiments, R w’ It can be optionally substituted with indene or dihydroindene.

[0302] In some embodiments, R w’ It is an optional substituted 9-10 membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0303] In some embodiments, R w’ It is an optionally substituted 9-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It may be optionally substituted with indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzooxazolyl, thiophenopyridyl, pyrrolo[3,2-b]pyridyl, pyrrolo[2,3,-b]pyridyl, pyrazolo[1,5-a]pyridyl, or imidazo[1,2-a]pyridyl, azainzolyl (e.g., 4-, 5-, 6-, or 7-azainzolyl), pyrrolo[2,3-c]pyridyl, or inazinyl.

[0304] In some embodiments, R w’ It is an optionally substituted 10-membered bicyclic heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It can be optionally substituted with quinolinyl, isoquinolinyl, quinazinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cyclolinyl, or 1,8-naphthidyl.

[0305] In some embodiments, R w’ yes

[0306] In some embodiments, R w’ yes

[0307] In some embodiments, R w’ yes

[0308] In some embodiments, R w’ It is an optionally substituted phenyl group. In some embodiments, R w’It is a phenyl group, optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C substituted optionally with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a phenyl group, which may be converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution.

[0309] In some embodiments, R w’ It is a 5-membered saturated or partially unsaturated heterocyclic group having 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It is an optional substituted pyrroleyl group. In some embodiments, R w’ It is a pyrroleyl group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C, optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyrroleyl group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is a 6-membered saturated or partially unsaturated heterocyclic group having 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w’ It is an optionally substituted piperidinyl group. In some embodiments, R w’ It is a piperidinyl group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a piperidinyl group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optionally substituted piperazine group. In some embodiments, R w’ It is a piperazine group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a piperazine group, which is optionally dimethyl halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution.

[0310] In some embodiments, R w’ It is an optionally substituted 5-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen and oxygen). In some embodiments, R w’ It can be optionally substituted with pyrrole, pyrazol, imidazole, or triazole. In some embodiments, R w’ It is a pyrrole, pyrazol, imidazolyl, or triazolyl group, optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, or C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyrrole, pyrazol, imidazole, or triazole group, optionally coated with a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optional substituted pyrazolyl group. In some embodiments, R w’ It is a pyrazolyl group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyrazolyl group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optional imidazole group. In some embodiments, R w’ It is an imidazole group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’It is an imidazole group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution.

[0311] In some embodiments, R w’ It is an optionally substituted 6-membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen and oxygen). In some embodiments, R w’ It can be optionally substituted with pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl. In some embodiments, R w’ It is a pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl group, optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, or C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl, optionally coated with a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optionally substituted pyridinyl group. In some embodiments, R w’ It is a pyridyl group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyridyl group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optionally substituted pyridazinyl group. In some embodiments, R w’ It is a pyridazinyl group, which is optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, and C optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyridazinyl group, which is optionally coated with a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’It can be optionally substituted with a pyridinone group, a pyridinone group, a pyrimidinone group, a pyridinone group, or a triazinone group. In some embodiments, R w’ It is a pyridone, pyridazinone, pyrimidinone, pyridazinone, or triazinone group, optionally substituted with a halogen (e.g., fluorine or chlorine), -CN, or optionally further substituted with a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyridinone group, pyridazinone group, pyrimidinone group, pyridazinone group, or triazinone group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution. In some embodiments, R w’ It is an optional substituted pyridinone group. In some embodiments, R w’ It is a pyridinone group, which is optionally replaced by a halogen (e.g., fluorine or chlorine), -CN, and C optionally further replaced by a halogen (e.g., fluorine or chlorine). 1-6 Aliphatic group, -S(O)2R o or -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w’ It is a pyridinone group, which is optionally converted by a halogen (e.g., fluorine or chlorine) or C. 1-6 Aliphatic group substitution.

[0312] In some embodiments, R w’ It is an optional substituted cyclopropyl group. In some embodiments, R w’ It is an optional substituted 5-membered saturated or partially unsaturated carbocyclic group. In some embodiments, R w’ It may be optionally substituted with cyclopentyl or cyclopentenyl. In some embodiments, R w’ It is an optional substituted hexacyclic saturated or partially unsaturated carbocyclic group. In some embodiments, R w’ It can be optionally substituted with cyclohexyl or cyclohexenyl. In some embodiments, R w’ It is an optional substituted naphthyl group.

[0313] In some embodiments, R w’ It is an optionally substituted 9-membered bicyclic heteroaryl group (the heteroaryl group has 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It can be optionally substituted with indole, azaindole, isoindole, azaisoindole, indazole, azaindazole, benzimidazole, or azabenzimidazole. In some embodiments, R w’It is an optionally substituted indole group. In some embodiments, R w’ It can be optionally substituted with benzothiophene, benzofuran, isobenzofuran, benzoisoxazol, benzoisothiazolyl, benzoxazol, benzothiazolyl, or benzothiadiazol.

[0314] In some embodiments, R w’ It is an optional substituted 8-11 member saturated or partially unsaturated spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optionally substituted 9-11 member saturated or partially unsaturated spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optionally substituted 9-membered saturated or partially unsaturated spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optional substituted 9-membered saturated or partially unsaturated spiroheterocyclic group having 1-3 nitrogen atoms. In some embodiments, R w’ It is an optional substituted 4,6-spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0315] In some embodiments, R w’ It is an optionally substituted 10-membered saturated or partially unsaturated spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optional substituted 10-membered saturated or partially unsaturated spiroheterocyclic group having 1-3 nitrogen atoms. In some embodiments, R w’ It is an optional substituted 5,6-spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0316] In some embodiments, R w’ It is an optionally substituted 11-membered saturated or partially unsaturated spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w’ It is an optional substituted 11-membered saturated or partially unsaturated spiroheterocyclic group having 1-3 nitrogen atoms. In some embodiments, R w’ It is an optional substituted 6,6-spiroheterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0317] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has one of formulas Ib-1 to Ib-6: Or its pharmaceutically acceptable salts, wherein each variable is individually and in combination as defined above and described herein.

[0318] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has one of formulas Ic-1 to Ic-6: Or its pharmaceutically acceptable salts, wherein each variable is individually and in combination as defined above and described herein.

[0319] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has one of formulas Id-1 to Id-6: Or its pharmaceutically acceptable salts, wherein each variable is individually and in combination as defined above and described herein.

[0320] In some embodiments, the present invention provides a method of use relating to a compound having formula I, wherein the compound has one of formulas Ie-1 to Ie-6: Or its pharmaceutically acceptable salts, wherein each variable is individually and in combination as defined above and described herein.

[0321] Exemplary compounds used in the methods provided in this invention are listed in Tables 1A and 2A below. Table 1A. Exemplary Compounds Table 2A. Exemplary Compounds

[0322] In some embodiments, the present invention provides methods for inhibiting STAT6 or its mutants, methods comprising administering compounds listed in Table 1A above or pharmaceutically acceptable salts thereof.

[0323] In some embodiments, the present invention provides methods for treating STAT6-mediated diseases, disorders, or conditions described herein, methods comprising administering a compound listed in Table 1A above or a pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the present invention provides methods for inhibiting STAT6 or its mutants, methods comprising administering compounds listed in Table 2A above or pharmaceutically acceptable salts thereof.

[0325] In some embodiments, the present invention provides methods for treating STAT6-mediated diseases, disorders, or conditions described herein, methods comprising administering a compound listed in Table 2A above or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the present invention provides methods for inhibiting STAT6 or its mutants, methods comprising administering compounds described herein (e.g., compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides methods for inhibiting STAT6 or its mutants, methods comprising administering compounds described herein (e.g., compounds having formula I, I′, II, III, or IV).

[0327] In some embodiments, the present invention provides methods for treating STAT6-mediated diseases, disorders, or conditions described herein, including the administration of compounds described herein (e.g., compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides methods for treating STAT6-mediated diseases, disorders, or conditions described herein, including the administration of compounds described herein (e.g., compounds having formula I, I′, II, III, or IV).

[0328] In some embodiments, the present invention provides compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, adjuvants, or mediators, for use as medicaments for inhibiting STAT6 or its mutants. In some embodiments, the present invention provides compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, adjuvants, or mediators, for use as medicaments for treating STAT6-mediated diseases, disorders, or conditions as described herein.

[0329] In some embodiments, the present invention also provides compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutical compositions described herein for use in methods for modulating (e.g., inhibiting) STAT6 as described herein. In some embodiments, the present invention also provides compounds described herein (such as compounds having formula I, I′, II, III, or IV) or pharmaceutical compositions described herein for use in methods for treating STAT6-mediated disorders as described herein. Use of compounds and pharmaceutically acceptable compositions

[0330] The compounds and compositions described herein are generally used to modulate STAT6 protein activity, including phosphorylated or activated STAT6 protein (e.g., pSTAT6) activity.

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

[0332] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. In some embodiments, STAT6 is derived from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0333] Inhibiting the activity of STAT6 or its mutants in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioassay.

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

[0335] The activity of compounds used in this invention as regulators (e.g., inhibitors) of STAT6 or its mutants can be determined in vitro, in vivo, or in cell lines. In vitro assays include determinations of inhibition of the activity of activated STAT6 protein or its mutants and / or subsequent functional consequences. Alternative in vitro assays quantify the ability of an inhibitor to bind to a STAT6 protein. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / STAT6 complex, and determining the amount of radiolabeled material bound. Alternatively, inhibitor binding can be determined by running a competition experiment in which a novel inhibitor is incubated with a STAT6 protein known to bind to a radioligand. Detailed conditions for determining compounds used in this invention as regulators (e.g., inhibitors) of STAT6 protein or its mutants are listed in the following examples.

[0336] As used herein, the term "treatment (treatment and treating)" refers to reversing or alleviating a disease or disorder or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have already appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0337] The provided compounds are regulators (e.g., inhibitors) of the STAT6 protein and are therefore useful for treating one or more disorders associated with the activity of the STAT6 protein. Accordingly, in some embodiments, the present invention provides a method for treating STAT6-mediated disorders, the method comprising the step of administering the compounds of the present invention or pharmaceutically acceptable compositions thereof to a patient in need.

[0338] As used herein, the term "STAT6-mediated" disorder, disease, and / or condition refers to any disease or other harmful condition in which STAT6 or its mutants are known to play a role. Therefore, another embodiment of the invention relates to treating or alleviating the severity of one or more diseases in which STAT6 or its mutants are known to play a role.

[0339] STAT6 acts as a transcription factor to induce gene expression and plays an important role in the IL-4 / IL-13 signaling pathway, and is therefore crucial in IL-4 / IL-13 mediated biological responses, including 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 have been shown to be essential for the development of T helper type 2 (Th2) cells and Th2 immune responses, and to play a key role in Th2 lung inflammatory responses (including clearance of parasitic infections) and the pathogenesis of asthma (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 responsible for the anti-apoptotic activity of IL-4) and has shown to play a prominent 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 have shown the role of STAT6 in T helper 2 (Th2) differentiation, cell surface marker expression, and immunoglobulin class switching. STAT6 also regulates other transcription factors such as Gata3, a key regulator of Th2 differentiation. STAT6 is also essential for the development of IL-9-secreting T cells.

[0340] In some embodiments, biomarkers associated with the IL-4 / 13 pathway include IgE, thymus and activation-regulated chemokines (TARC), CD23, periosteal protein, and eosinophils. TARC is a serum TH2 biomarker and a chemical inducer for TH2 cells. CD23 is a marker of B cell activation and is associated with IgE class switching. Periosteal protein is a serum TH2 biomarker and an ECM protein associated with tissue remodeling in atopic diseases.

[0341] 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 periosteal protein release compared to reference or standard levels.

[0342] In some embodiments, treatment with the provided compounds inhibits IL-4-induced TARC release. In some embodiments, treatment with the provided compounds inhibits IL-13-induced CD23 expression. ISE, treatment with the provided compounds inhibits IL-13-induced periosteal protein release.

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

[0344] Diseases and conditions treatable by the methods according to the 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 (such as AIDS and HIV), osteoarthritis, infectious diseases, and pathological immune conditions involving T-cell activation. In one embodiment, a human patient is treated with the compounds of the invention and a pharmaceutically acceptable carrier, adjuvant, or mediator, wherein the compounds are present in a measurably modulating (e.g., inhibiting) amount of STAT6 or a mutant thereof.

[0345] The compounds according to the invention can be used to treat inflammatory or obstructive airway diseases, thereby reducing, for example, tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the invention applies include asthma of any type or cause, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma exacerbated or induced by bacterial or viral infections. Treatment of asthma should also be understood to include treatment, for example, subjects under 4 or 5 years of age who present with wheezing symptoms and have been diagnosed or can be diagnosed as “wheezing infants,” which are established patient categories of primary medical concern and are now commonly identified as patients with initial or early-stage asthma.

[0346] Another aspect of the invention relates to a method of treating an allergic or inflammatory disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of the invention. The disease may be a lung disease, such as asthma, airway hyperresponsiveness (AHR), allergic disease, allergic rhinitis, emphysema, chronic obstructive pulmonary disease (COPD), reactive airway disease, chronic sinusitis, or essentially any other upper or lower airway disease that causes airflow obstruction.

[0347] The preventative effects of asthma treatment will be demonstrated by a reduction in the frequency or severity of symptom attacks (e.g., acute asthma or bronchoconstrictor attacks), improvement in lung function, or improvement in airway hyperresponsiveness. This can be further demonstrated by a reduction in the need for other symptomatic therapies, such as those used to limit or stop symptom attacks (e.g., anti-inflammatory or bronchodilator therapies). The benefits of asthma prevention may be particularly evident in subjects prone to “morning drops.” “Morning drops” are a recognized asthma syndrome common in a significant proportion of asthma patients, characterized by asthma attacks, for example, occurring between approximately 4 and 6 a.m., typically a considerable time after any previously administered symptomatic asthma treatment.

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

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

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

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

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

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

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

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

[0356] The compounds of this invention can be used for other inflammatory or obstructive airway diseases and conditions to which this invention applies, including acute lung injury (ALI), adult-onset / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway, or lung diseases (COPD, COAD, or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbations of airway hyperresponsiveness due to other pharmacological therapies, particularly other inhaled pharmacological therapies. This invention is also applicable to the treatment of bronchitis of any type or cause, including but not limited to acute bronchitis, peanut inhalation bronchitis, catarrhal bronchitis, grob's bronchitis, chronic or tuberculous bronchitis. Other inflammatory or obstructive airway diseases to which this invention applies include any type or cause of pneumoconiosis (an inflammatory, often occupational, lung disease frequently accompanied by airway obstruction (whether chronic or acute) and caused by repeated inhalation of dust), including, for example, aluminum deposition disease, carbon deposition disease, asbestos deposition disease, stone deposition disease, ostrich pneumoconiosis, iron deposition disease, silica deposition disease, smoke deposition disease, and cotton wool deposition disease.

[0357] Regarding anti-inflammatory activity, particularly in relation to the inhibition of eosinophil activation, the compounds of the present invention can also be used to treat eosinophil-related disorders, such as eosinophilia, particularly eosinophil-related airway disorders (e.g., morbid eosinophilic infiltration involving lung tissue), including hypereosinophilia affecting the airways and / or lungs, and eosinophil-related airway disorders, such as those associated with or accompanying the following: Löffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Chag-Strauss syndrome), eosinophilic granulomas, and eosinophil-related airway disorders affecting the airways caused by drug reactions.

[0358] The compounds of the present invention can also be used to treat inflammatory or allergic skin conditions. In some embodiments, the present invention provides a method for treating inflammatory or allergic skin conditions in patients in need, the method comprising administering the compounds of the present invention or pharmaceutically acceptable salts thereof.

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

[0360] The compounds of this invention can also be used to treat other diseases or conditions, such as those with inflammatory components, for example, eye diseases and conditions, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Schleck-Jones syndrome, idiopathic stomatitis diarrhea, and autoimmune diseases. Inflammatory bowel disease (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 allergic pneumonia, multiple sclerosis, primary biliary cirrhosis or primary biliary cholangitis, uveitis (anterior and posterior uveitis), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryoinflammatory hormone-related periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change disease, chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolism disorders, obesity, fetal growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigmentary disorders, Paget's disease, pancreatitis, hereditary periodic fever syndrome, and asthma (allergic and non-allergic asthma). Mild asthma, moderate asthma, severe asthma, bronchial asthma, or exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, allergic reactions, sinusitis, ocular allergies, silica-induced diseases, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroid diseases. Adenitis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Hensch's purpura, hepatitis, hidradenitis suppurativa. Immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

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

[0362] In some embodiments, the present invention provides a method for treating idiopathic interstitial pneumonia (IIP) in patients of need, including any type of pulmonary fibrosis, i.e., interstitial lung disease associated with rheumatic diseases (including SSc) or IPF itself, the method comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the inflammatory diseases that can be treated according to the method of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryoinflammatory-related periodic syndrome (CAPS), and osteoarthritis.

[0364] 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-related disease. In some embodiments, the TH17-mediated disease or TH17-related 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.

[0365] In some embodiments, the inflammatory diseases that can be treated according to the method of the present invention are selected from Sjögren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergies, conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0366] 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-associated disease (IgG4-RD), chronic organ rejection (e.g., lung transplantation), vasculitis (e.g., vasculitis), and STAT6 gain-of-function (GOF) mutations.

[0367] In some embodiments, the present invention provides a method for treating a patient in need of a STAT6 gain-of-function (GOF) mutation, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the STAT6GOF mutation is STAT6VT.

[0368] In some embodiments, cardiovascular diseases that can be treated by the method according to the present invention include, but are not limited to: restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, post-angioplasty restenosis, post-angioplasty restenosis, post-coronary artery bypass grafting restenosis, stroke, transient ischemic attack, peripheral artery occlusive disorder, pulmonary embolism, and deep vein thrombosis.

[0369] 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 neurodegenerative diseases caused by trauma, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0370] In some embodiments, the present invention provides a method for treating, preventing, or reducing the severity of Alzheimer's disease, the method comprising administering the provided compound or a pharmaceutically acceptable salt or composition thereof to a patient in need.

[0371] In some embodiments, the present invention provides a method for treating diseases or conditions commonly associated with transplantation. In some embodiments, diseases or conditions commonly associated with transplantation are selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0372] In some embodiments, the present invention provides a method for treating metabolic diseases. In some embodiments, metabolic diseases are selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0373] In some embodiments, the present invention provides a method for treating a viral disease. In some embodiments, the viral infection is HIV or COVID-19 infection.

[0374] In some embodiments, the present invention provides a method for treating JAK-related diseases other than cancer.

[0375] Furthermore, this invention provides the use of compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the preparation of medicaments for the treatment of inflammatory diseases, obstructive respiratory diseases, neurodegenerative diseases, viral diseases, or disorders commonly associated with transplantation. Combination therapy

[0376] Depending on the specific condition or disease to be treated, additional therapeutic agents (typically applied to treat that condition) may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically applied to treat a specific disease or condition are referred to as “the disease or condition to be treated”.

[0377] In some embodiments, the provided combination or a combination thereof is administered in combination with another therapeutic agent. It should be understood that this disclosure contemplates the use of the combination therapies described herein solely for the treatment of the diseases, disorders, and conditions described herein.

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

[0379] Examples of pharmaceutical agents that can be combined with the combination of the present invention include, but are not limited to, drugs for the treatment of Alzheimer's disease, such as... and HIV treatment drugs, such as ritonavir; Parkinson's disease treatment drugs, such as L-DOPA / carbidopa, entacapone, ropinilol, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; multiple sclerosis (MS) treatment drugs, such as beta-interferon (e.g., and Grammer acetate And mitoxantrone; asthma medications, such as salbutamol and Treatments for schizophrenia include medications such as Zyprexa, Risperidone, Seroquel, and Haloperidol; anti-inflammatory drugs such as corticosteroids, TNF blockers, IL-1RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, and ion channel blockers. Drugs for treating hepatitis include steroids, riluzole, and anti-Parkinson's disease agents; agents for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; and agents for treating hematologic disorders that prolong or improve pharmacokinetics, such as corticosteroids, cytochrome P450 inhibitors (i.e., metabolic catabolism inhibitors), CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and pirfenidone. Nidanip Intravenous immunoglobulin and bosentan Nifedipine Sildenafil losartan Iloprost Topical nitroglycerin, N-acetylcysteine, antacids, and medications used to treat immunodeficiency disorders, such as gamma globulin.

[0380] In some 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.

[0381] These additional agents can be administered separately from the provided combination therapy as part of a multi-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents can be administered simultaneously, sequentially, or over a period of time (typically within five hours of each other).

[0382] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, combinations of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit formulations or together in a single unit formulation.

[0383] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally applied in compositions containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed in the present invention ranges from about 50% to 100% of the amount normally present in compositions containing the pharmaceutical agent as the sole active agent.

[0384] One or more other therapeutic agents may be administered separately from the compounds or compositions of the present invention as part of a multiple-dose regimen. Alternatively, one or more other agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered in a multiple-dose regimen, one or more other therapeutic agents and the compounds or compositions of the present invention may be administered simultaneously, sequentially, or over time intervals (e.g., at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours). In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are administered as a multiple-dose regimen at intervals greater than 24 hours.

[0385] 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 some 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 therapeutic agent. In other 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 after the therapeutic agent.

[0386] In another embodiment, the present invention provides a method for treating an inflammatory disease, disorder, or condition by administering the provided compound and one or more additional therapeutic agents to a patient in need. Such additional therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. Celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and phenxostatine. sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as glucose thiogold gold thiomalate and acetic acid thioglucan D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporin Leflunomide And "anti-TNF" drugs such as etanercept Infliximab Golimumab Pego-Setorizumab and adalimumab Anti-IL-1 drugs such as anakinin and Lilosipp Canageninumab Anti-Jak inhibitors such as toxitinib, antibodies such as rituximab Anti-T cell drugs such as atacicept Anti-IL-6 drugs such as tocilizumab Diclofenac, cortisone, hyaluronic acid or Monoclonal antibodies such as tanezilumab, and anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine and alosetron Rubiprostone Laxatives such as milk of magnesium and polyethylene glycol and Anticholinergic agents or antispasmodics such as bicyclic amine β-2 agonists such as salbutamol ( HFA, HFA), L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol Naphthylphenol and Formotero Anticholinergic agents such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as beclomethasone dipropionate ( and ), Triamcinolone Momison Buddyne and flunisulfanil Sodium cromoglycate Methylxanthine, like theophylline And aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacave Abacave / Lamivudine Abacavir / Lamivudine / Zidovudine Dehydroxyinosine Enqutabin Lamivudine Lamivudine / Zidovudine Staffidin Hezashitabin Non-nucleoside reverse transcriptase inhibitors such as diraviridine Ifeveren Nevellappi He Yiquweilin Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as ampravir Azanavir Darunavir Fosanavir Indinavir Lopinavir and ritonavir Nefernavir Litonavir Saquinavir or ) and telanavir Entry inhibitors such as entfuviride and Malawi Integrase inhibitors such as retigvir Doxorubicin Changchun New Alkali Bortezomib and dexamethasone With lenalidomide A combination of, or any combination of.

[0387] In another embodiment, the present invention provides a method for treating gout, the method comprising administering the provided compound and one or more additional therapeutic agents to a patient in need, the therapeutic agents being selected from nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. Celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and phenxostatol

[0388] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering the provided compound and one or more additional therapeutic agents to a patient in need, the therapeutic agents being selected from nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. And celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as glucose thiogold gold thiomalate and acetic acid thioglucan D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporin Leflunomide And "anti-TNF" drugs such as etanercept Infliximab Golimumab Pego-Setorizumab and adalimumab Anti-IL-1 drugs such as anakinin and Lilosipp Antibodies such as rituximab Anti-T cell drugs such as atacicept And "anti-IL-6" drugs such as tocilizumab

[0389] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need a provided compound and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. And celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) as well as monoclonal antibodies such as tanezilumab.

[0390] In some embodiments, the present invention provides a method for treating lupus, the method comprising administering to a patient in need a provided compound and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. And celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., and antimalarial drugs such as hydroxychloroquine. and chloroquine Cyclophosphamide Methotrexate azathioprine And anticoagulants such as heparin ( or ) and warfarin

[0391] In some embodiments, the present invention provides a method for treating inflammatory bowel disease, the method comprising administering to a patient in need a provided compound and one or more additional therapeutic agents selected from mesalazine. sulfasalazine Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine and alosetron Rubiprostone Laxatives such as milk of magnesium and polyethylene glycol and and anticholinergics or antispasmodics such as bicyclic amine Anti-TNF therapy, steroids, and antibiotics such as metronidazole or ciprofloxacin.

[0392] In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need a provided compound and one or more additional therapeutic agents selected from... β-2 agonists such as salbutamol ( HFA, HFA), L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol Naphthylphenol and Formotero Anticholinergic agents such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as prednisone, prednisolone, and beclomethasone dipropionate ( and ), Triamcinolone Momison Buddyne Flunipine and Sodium cromoglycate Methylxanthine, like theophylline And aminophylline, and IgE antibodies such as omelizumab

[0393] In some embodiments, the present invention provides a method for treating COPD, the method comprising administering to a patient in need a provided compound and one or more additional therapeutic agents selected from β-2 agonists such as salbutamol. HFA, HFA), L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol Naphthylphenol and Formotero Anticholinergic agents such as ipratropium bromide and tiotropium bromide Methylxanthine, like theophylline And aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), Triamcinolone Momison Buddyne Flunipine and

[0394] In some embodiments, the present invention provides a method for treating HIV, the method comprising administering the provided compound and one or more additional therapeutic agents to a patient in need, the therapeutic agents being selected from nucleoside reverse transcriptase inhibitors such as zidovudine. Abacave Abacave / Lamivudine Abacavir / Lamivudine / Zidovudine Dehydroxyinosine Enqutabin Lamivudine Lamivudine / Zidovudine Staffidin Hezashitabin Non-nucleoside reverse transcriptase inhibitors such as diraviridine Ifeveren Nevellappi He Yiquweilin Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as ampravir Azanavir Darunavir Fosanavir Indinavir Lopinavir and ritonavir Nefernavir Litonavir Saquinavir or ) and telanavir Entry inhibitors such as entfuviride and Malawi Integrase inhibitors such as retigvir and their combinations.

[0395] 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 this invention include raloxifene (…). Eli Lilly and Company).

[0396] In some embodiments, one or more other therapeutic agents are bone resorption inhibitors. One approved therapeutic agent that inhibits bone resorption is dinosumab (…). Amgen (the company behind this product) is an antibody that binds to RANKL, preventing it from binding to its receptor RANK, which is present on the surface of osteoclasts, their precursors, and osteoclast-like giant cells. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (…). Novartis).

[0397] In some embodiments, the present invention provides a method for treating Alzheimer's disease, the method comprising administering a provided compound and one or more additional therapeutic agents selected from donepezil to a patient in need. Lis's Ming Galantham Taklin Hemei King Kong

[0398] In some embodiments, one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in this invention include: bevacizumab (… Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly, Inc., developed an anti-VEGFR-2 antibody and aflibercept, also known as VEGF Trap. Regeneron / Sanofi). VEGFR inhibitors, such as renlafenib ( Bayer (A&D); Vanditanil AstraZeneca); Axitinib Pfizer; and lenvatinib Eisai); Raf inhibitors, such as sorafenib ( Bayer AG and Onyx; Dabrafenib Novartis; and Verafenib ( Genentech / Roche); MEK inhibitors, such as comitinib ( Exelexis (Genentech / Roche); Trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis); Nilotinib Novartis); Dasatinib Bristol-Myers Squibb (BMS); Betaine (BMS) Pfizer; and ponatinib ( Ariad Pharmaceuticals; Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca); Erlotinib Genentech / Roche / Astellas); Lapatinib Novartis); Afatinib Boehringer Ingelheim; Osimertinib (targeting activated EGFR, AstraZeneca); and brigatinib ( Ariyad Pharmaceuticals; c-Met and VEGFR2 inhibitors, such as cabozanitib ( Iclexis (the company behind Iclexis); and multi-kinase inhibitors, such as sunitinib (…). Pfizer; Pazopani Novartis); ALK inhibitors, such as crizotinib ( Pfizer; Celitinib Novartis; and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics (Janssen); and Flt3 receptor inhibitors, such as midotolin ( Novartis).

[0399] Other kinase inhibitors and VEGF-R antagonists under development and applicable to this invention include tevozanib (Aveo Pharmaceuticals); vataranib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); and radiutinib (…). IY5511, Il-Yang Pharmaceuticals (South Korea); Lulitinib ( Incyte Corporation; PTC299 (PTC Therapeutics); CP-547, 632 (Pfizer); Furitinib (Icrlysis, GlaxoSmithKline); Quizatinib (Daiichi Sankyo); and Motsani (Amgen / Takeda).

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

[0401] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering the provided compound and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Stiebel's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, and Ord's thyroiditis. Thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, neurolyme disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, strabismus-oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasseur syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Ritter syndrome, aortitis. (Takayasu's sarteritis), temporal arteritis, warm antibody-type autoimmune hemolytic anemia, Wechsler's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic dysfunction, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes mellitus, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies (e.g.,Allergies to plant pollen, latex, medications, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes; Type I hypersensitivity reactions; allergic conjunctivitis; allergic rhinitis; atopic dermatitis; asthma; appendicitis; blepharitis; bronchiolitis; bronchitis; bursitis; cervicitis; cholangitis; cholecystitis; chronic graft rejection; colitis; conjunctivitis; Crohn's disease; cystitis; dacryoadenitis; dermatitis; dermatomyositis; encephalitis; endocarditis; endometritis; enteritis; enterocolitis; epicondylitis; epididymitis; fasciitis; fibrositis; gastritis; gastroenteritis; Hensch's purpura; hepatitis; hidradenitis suppurativa; immunoglobulin A nephropathy; interstitial lung disease; laryngitis; mastitis; meningitis; myelitis; myocarditis; myositis; nephritis. Ovarian inflammation, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, bone and joint diseases (causing joint inflammation and pain, cartilage and / or bone destruction, and bone regeneration and fusion) (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Rytter disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis), thromboembolic disorders (e.g.,Myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, stroke, transient ischemic attack, peripheral artery occlusive disorder, pulmonary embolism, deep vein thrombosis, inflammatory pelvic inflammatory 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 transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular disease). Autoimmune polyglandular syndrome, autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpass syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0402] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering the provided compound and PI3K inhibitor to a patient in need, wherein the disease is selected from neurodegenerative disorders, angiogenesis disorders, viral diseases, autoimmune diseases, inflammatory disorders, organ transplant-related conditions, immunodeficiency disorders, infectious diseases, thrombin-induced platelet aggregation, liver diseases, pathoimmune diseases involving T cell activation, and cardiovascular disorders.

[0403] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising administering the provided compound and a PI3K inhibitor to a patient in need, wherein the disease is selected from psoriasis, or a disease in which the PI3K / PKB pathway is abnormally activated; asthma of any type or cause, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced or aggravated by bacterial or viral infection; acute lung injury (ALI), adult-onset / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD), including chronic bronchitis or associated dyspnea, emphysema, and airway hyperresponsiveness due to other drug therapies, particularly other inhaled drug therapies. Exacerbations of bronchitis; any type or cause of bronchitis, including but not limited to acute bronchitis, peanut inhalation bronchitis, catarrhal bronchitis, groborrhea, chronic or tuberculous bronchitis; any type or cause of pneumoconiosis (an inflammatory, often occupational, lung disease frequently accompanied by airway obstruction (whether chronic or acute) and caused by repeated inhalation of dust), including, for example, aluminum deposition disease, carbon deposition disease, asbestos deposition disease, stone deposition disease, ostrich feather pneumoconiosis, pulmonary iron deposition disease, silica deposition disease, tobacco deposition disease and cotton wool deposition disease, Löffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Chag-Strauss syndrome), eosinophilic granuloma, and eosinophilic-associated disorders affecting the airways caused by drug reactions;Psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis) and inflammatory diseases among them that are related to or have autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Schoen-Johnson syndrome, idiopathic stomatitis, inflammatory diarrhea. Autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease or fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change disease); 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, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0404] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from allalis (… Gilead Sciences, Apelis (BYL719, Novartis), Taselis (GDC-0032, Genentech / Roche); Pitilis (GDC-0941, Genentech / Roche); Copanlis (BAY806946, Bayer); Duvelix (formerly known as IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly known as RP5230, TG Therapeutics).

[0405] Depending on the specific condition or disease to be treated, the compositions of the present invention may also contain additional therapeutic agents that are normally applied to treat that condition. As used herein, additional therapeutic agents that are normally applied to treat a specific disease or condition are referred to as “the disease or condition to be treated”.

[0406] As used herein, the term "aromatase inhibitor" refers to compounds that inhibit estrogen production, such as those that inhibit the conversion of substrates androstenedione and testosterone into estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestan, exemestan, and formestan, and especially nonsteroids, particularly aminoglutethimide, roglethimide, pyrglutethimide, tralostertan, testrolide, ketoconazole, vortexilazole, fazodazole, anastrozole, and letrozole. Exemestan is marketed under the trade name Aromasin. TM Sales. Formistan is marketed under the trade name Lentaron. TM Sales. Fazodazole is marketed under the brand name Afema. TM Anastrozole is sold under the brand name Arimidex. TM Sales. Letrozole is marketed under the brand name Femara. TM or Femar TM Sales. Ammonia glutathione is marketed under the trade name Orimeten. TM Sale.

[0407] 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 inhibitor is erlotinib (…). Novartis; Tromos ( Pfizer; and Sirolimus ( Pfizer.

[0408] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane (… Pfizer; Anatolizard AstraZeneca) and letrozole ( Novartis).

[0409] As used herein, the term "anti-estrogenic" refers to compounds that antagonize the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the brand name Nolvadex. TM Raloxifene hydrochloride is sold under the brand name Evista. TM Sales. Fluvestralc can be sold under the trade name Faslodex. TM Apply.

[0410] As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens, including but not limited to casodex. TMAs used herein, the term "goserelin agonist" includes, but is not limited to, abaric, goserelin, and goserelin acetate. Goserelin is available under the brand name Zoladex. TM Apply.

[0411] As used herein, the term "compounds that target / reduce the activity of protein or lipid kinases; or protein or lipid phosphatases; or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce, or inhibit platelet-derived growth factor receptor (PDGFR) activity, such as compounds that target, reduce, or inhibit PDGFR activity, particularly compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinylamine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) compounds that target, reduce, or inhibit fibroblast growth factor receptor (FGFR) activity; c) compounds that target, reduce, or inhibit insulin-like growth factor receptor I (IGF-IR) activity, such as compounds that target, reduce, or inhibit IGF-IR activity, particularly compounds that inhibit the kinase activity of IGF-I receptors, or antibodies that target the extracellular domain of IGF-I receptors or their growth factors; d) compounds that target, reduce, or inhibit Compounds targeting, reducing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, reducing, or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, reducing, or inhibiting the activity of the Ret receptor tyrosine kinase family; g) compounds targeting, reducing, or inhibiting the activity of the Kit / SCFR receptor tyrosine kinase family, such as imatinib; h) compounds targeting, reducing, or inhibiting the activity of the C-kit receptor tyrosine kinase family (belonging to the PDGFR family), such as compounds targeting, reducing, or inhibiting the activity of the c-Kit receptor tyrosine kinase family, especially compounds inhibiting the c-Kit receptor, such as imatinib; i) compounds targeting, reducing, or inhibiting the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, such as compounds targeting, reducing, or inhibiting the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (Parke Davis); or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of serine / threonine kinases, protein kinase C (PKC) and Raf family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family members, and / or cyclin-dependent kinase family (CDK) members, including astrone derivatives such as midotolin; other examples of compounds include UCN-01, safungo, BAY43-9006, bryostatin 1, perifoxin; imofoxin; RO 318220 and RO 320432;GO 6976; Isis 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, such as imatinib mesylate (Gleevec); TM Or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adaphostin); 1) Compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR1ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family (such as EGF receptor, ErbB2, ErbB3, and ErbB4) or bind to EGF or EGF-related ligands, such as CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin) TM ), cetuximab (Erbitux) TM(i) Iressa, Tarceva, OSI-774, C1-1033, 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; (ii) Compounds that target, reduce or inhibit c-Met receptor activity, such as compounds that target, reduce or inhibit c-Met activity, especially compounds that inhibit c-Met receptor kinase activity, or antibodies that target the c-Met extracellular domain or bind HGF; (iii) Compounds that target, reduce or inhibit the activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) kinases, including but not limited to PRT-062070, SB-1578, and baricitinib. The following are included: o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalixib, pictrelisib, PF-4691502, BYL-719, datolixib, XL-147, XL-765 and alalipis; and q) compounds that target, reduce or inhibit the signaling activity of the hedgehog protein (Hh) or smooth receptor (SMO) pathway, including but not limited to cyclopamine, vemodilution, itraconazole, sondilution and IPI-926 (saridegib).

[0412] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0413] In some embodiments, one or more other therapeutic agents are growth factor antagonists, such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or antagonists of their receptor (EGFR). Approved PDGF antagonists that can be used in this invention include olatuzumab (…). Eli Lilly and Company). Approved EGFR antagonists that can be used in this invention include cetuximab (…). Eli Lilly and Company); Nesetumab ( Eli Lilly and Company), panitumumab ( Amgen); and osimertinib (a targeted EGFR inhibitor); AstraZeneca.

[0414] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3K8, 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 useful PI3K inhibitors in this invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalis, pictrelisib, PF-4691502, BYL-719, datolisib, XL-147, XL-765, and allalis.

[0415] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

[0416] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and phosmetinib.

[0417] Other anti-angiogenic compounds include those with a different mechanism of activity, such as those unrelated to protein or lipid kinase inhibition, such as thalidomide. TM ) and TNP-470.

[0418] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

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

[0420] As used herein, cyclooxygenase inhibitors include, but are not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and their derivatives, such as celecoxib (Celebrex). TM ), Vioxx TM ), etoricoxib, vardicoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2′-chloro-6′-fluoroaniline)phenylacetic acid, rumicoxib.

[0421] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid, clodronic acid, teludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM Sales. Chlorphosphonic acid is marketed under the trade name Bonefos. TM Sales. Tiludronic acid is marketed under the brand name Skelid. TM Pamidronic acid is sold under the brand name Aredia. TM Sales. Alendronate is marketed under the brand name Fosamax. TM Ibandronic acid is sold under the trade name Bondranat. TM Risedronic acid is sold under the trade name Actonel. TM Zoledronic acid is sold under the trade name Zometa. TM Sale.

[0422] The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus. Certican TM ), CCI-779 and ABT578.

[0423] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modulator" refers to lymphokines or interferons.

[0424] As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0425] 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, bengamide or its derivatives.

[0426] As used herein, the term “matrix metalloproteinase inhibitor” or “MMP” inhibitor includes, but is not limited to, collagen peptide mimic inhibitors and non-peptide mimic inhibitors, tetracycline derivatives such as the hydroxamic acid peptide mimic inhibitor palmastat and its oral bioavailable analogs, mamasstat (BB-2516), promasstat (AG3340), metastastat (NSC683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0427] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldmycin (17AAG) (a geldmycin derivative); other geldmycin-related compounds; rhizocarpine and HDAC inhibitors.

[0428] This also includes EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720.

[0429] The term "nucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytarabine (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for the treatment of ALL), and / or pentose glycosides. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0430] This also specifically includes compounds, proteins, or monoclonal antibodies that contain VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM Endostatin TM o-aminobenzoic acid amide; 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 IgG1 antibodies, angiozyme (RPI 4610), and bevacizumab (Avastin).TM ).

[0431] As used in this article, angiotensin-blocking steroids refer to compounds that block or inhibit angiogenesis, such as anechodine, triamcinolone, hydrocortisone, 11-α-epiocorticosteroids, corticosterone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0432] Implants containing corticosteroids refer to compounds such as fluocinolone acetonide and dexamethasone.

[0433] The compounds of the present invention can also be used as co-therapeutic compounds in combination with other pharmaceutical substances (such as anti-inflammatory, bronchodilator, or antihistamine substances), particularly for the treatment of obstructive or inflammatory airway diseases (such as those mentioned above), for example as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention can be mixed with other pharmaceutical substances in a fixed pharmaceutical composition, or can be administered alone, before, simultaneously with, or after other pharmaceutical substances. Therefore, the present invention includes combinations of the above-described compounds of the present invention with anti-inflammatory, bronchodilator, antihistamine, or antitussive pharmaceutical substances, wherein the compounds of the present invention and the pharmaceutical substances are present in the same or different pharmaceutical compositions.

[0434] Suitable anti-inflammatory drugs include steroids, particularly glucocorticoids such as budesonide, beclomethasone dipropionate, fluticasone propionate, cicosone, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, and SB 209247; LTD4 antagonists such as montelukast and zafirlukast; and PDE4 inhibitors such as cimetidine. GlaxoSmithKline (GSK), Lomistar (BykGulden, Germany), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), and Almirall (Almirall, Spain) Prodesfarma), PD189659 / PD168787 (Parker Davis), AWD-12-281 (AstaMedica), CDC-801 (Cell Gene), SeICID™, CC-10004 (Cell Gene), VM554 / UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as albuterol, osinerol, terbutaline, salmeterol, fenoterol, procaterol, especially formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium bromide, CHF4226 (Chiesi), and glycopyrronium bromide.

[0435] Suitable antihistamines include cetirizine hydrochloride, acetaminophen, chlormastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine, fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and terfenadine.

[0436] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs are with 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 such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0437] The structure of an active compound identified by its code number, generic name, or trade name can be taken from the actual version of the standard compilation "Merck Index" or a database such as Patents International (e.g., IMS World Publications).

[0438] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds may be interspersed or administered independently of each other, or a fixed combination and a combination of one or more other therapeutic compounds may be administered.

[0439] These additional agents can be administered separately from the composition containing the compounds of the present invention as part of a multi-dosing regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multi-dosing regimen, the two active agents can be administered simultaneously, sequentially, or over a period of time (typically within five hours of each other).

[0440] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, the compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the invention provides a single unit dosage form comprising the compounds of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0441] The amounts of the compounds of the present invention and additional therapeutic agents that can be combined with carrier materials to produce a single dosage form (in those compositions containing additional therapeutic agents as described above) will vary depending on the host being treated and the specific administration method. Preferably, the compositions of the present invention are formulated such that the dosage of the compounds of the present invention can be administered at a dose between 0.01 and 100 mg / kg body weight / day.

[0442] In those compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in such a composition will be less than that required for a single therapy using only the therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose of 0.01-1,000 μg / kg body weight / day.

[0443] The amount of one or more other therapeutic agents present in the compositions of the present invention may not exceed the amount normally administered in compositions containing that therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the compositions disclosed herein ranges from about 50% to 100% of the amount normally present in compositions containing that pharmaceutical agent as the sole 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 normally administered dose of that therapeutic agent. As used herein, the phrase “normally administered” means the dose provided in the FDA label insert for an FDA-approved therapeutic agent.

[0444] The compounds of this invention or pharmaceutical compositions thereof can also be incorporated into 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 the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with the compounds of this invention are another embodiment of the invention. 3b. Description of exemplary compounds and composition examples

[0445] In some embodiments, the present invention provides inhibitor compounds having formula I′: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R)w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Cyclone X and its Rx substituents are in Indicates the key with ring W, and Indicates bonds with the rest of the molecule; Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. R w Selected from hydrogen, R A , RB, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NR OR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; Each R A Independently, the optional substituted groups are selected from the following: C 1-6Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle (the heterocycle has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently of: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group (the heterocyclic group has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene (the heteroarylene has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each Cy B2 The ring is optionally substituted independently of the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic (the heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), 5-10 membered monocyclic or bicyclic aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl (the heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur); Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4, and where: (i) When ring X and its R x Substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 and Y 3 Not NH, NR w Or N; (ii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y 2 and Y 3 Each is CH, CR w CH2, CH(R) w ) or C(R w When )2, then Y 1 Not CH, CR w CH2, CH(R) w ) or C(R w )2; (iii) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is S, then ring Y is not a phenyl group or a 3-8 member saturated or partially unsaturated monocyclic carbocyclic group or heterocyclic group (the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur); (iv) When ring X and its R x Substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 3 Not S; (v) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is O, then Y 2Not NH, NR w Or N; (vi) When ring X and its R x Substituents are X 1 It is N, Y 1 It is NH, NR w Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w If z = 2, then z is neither 0 nor 1; (vii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y 2 It is CH, CR w CH2, CH(R) w ) or C(R w When )2, then Y 2 and Y 3 Only one of them is O; (viii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, Y 1 It is O, NH, NR w Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w When z = 2, then z is neither 0 nor 1; and (ix) When ring X and its R x Substituents are X 5 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 Not NH, NR w Or N, and The inhibitor compound is not a compound whose structure ABC is defined by the combination of structural units A, B, and C in the table below:

[0446] In some embodiments, inhibitory compounds having formula I′ specifically achieve (as their primary mechanism of action) inhibition of STAT6.

[0447] It should be understood that formula I′ cannot be extended beyond the formulas described below and herein as in this section (3b). It should be understood that all references to “defined and described herein” refer only to this section (3b) of this application. Additionally, all chemical formulas and examples in section 3b are applicable only to and can be combined with formulas and examples derived from this section (3b).

[0448] In some embodiments, the inhibitory compound having formula I′ is not any of compounds I-1 to I-1548 or a pharmaceutically acceptable salt thereof described in PCT / US2024 / 044544. In some embodiments, the inhibitory compound having formula I, I', II, III, or IV is not a compound in Table 1 of International Application No. PCT / US2024 / 044544 or a pharmaceutically acceptable salt thereof.

[0449] In some embodiments, the inhibitor compound having formula I′ is not selected from the compounds in Table B. Table B: Or its salts or free bases / acids.

[0450] As described above and defined in this paper, the ring W and its R w Substituents are or Where X 1 X 4 and X 5Each is independently CH and CR w Or N; X 2 and X 3 Each is independently C or N, where X 1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; and each Indicates a single bond or a double bond.

[0451] In some embodiments, X is included 2 X 3 Y 1 Y 2 and Y 3 The ring is aromatic or heteroaromatic, that is, Y 1 Y 2 Y 3 and The definition is chosen to satisfy the valence of an aromatic or heteroaromatic ring. In some embodiments, X contains 2 X 3 Y 1 Y 2 and Y 3 The ring is not aromatic or heteroaromatic, that is, Y 1 Y 2 Y 3 and The definition was chosen to satisfy the valence of partially unsaturated rings.

[0452] In some embodiments, the ring W and its R w The substituents are:

[0453] As defined above and described in this article, X 1 X 4 and X 5 Each is independently CH and CR w Or N. In some embodiments, X1 X 4 and X 5 Each is CH or CR w In some embodiments, X 1 It is CH. In some embodiments, X 1 It is CR w In some embodiments, X 1 It is N. In some embodiments, X 4 It is CH. In some embodiments, X 4 It is CR w In some embodiments, X 4 It is N. In some embodiments, X 5 It is CH. In some embodiments, X 5 It is CR w In some embodiments, X 5 It is N.

[0454] As defined above and described in this article, X 2 and X 3 Each is independently C or N. In some embodiments, X 2 and X 3 All are C. In some embodiments, X 2 It is C. In some embodiments, X 2 It is N. In some embodiments, X 3 It is C. In some embodiments, X 3 It is N.

[0455] In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w And X 2 and X 3 It is C. In some embodiments, X 1 It is N, X 2 and X 3 It is C, and X 4 and X 5 Is it CH or CR? w In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w X 2 It is N, and X 3 It is C. In some embodiments, X 1 X 4 and X 5 Is it CH or CR? w X 2 It is C, and X3 It is N. In some embodiments, X 1 and X 5 Is it CH or CR? w X 2 and X 3 It is C, and X 4 It is N. In some embodiments, X 1 and X 4 Is it CH or CR? w X 2 and X 3 It is C, and X 5 It is N.

[0456] As defined above and described in this article, Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w 2. In some embodiments, Y 2 and Y 3 Both are CH and CR w CH2, CH(R) w ) or C(R w 2. In some embodiments, Y 1 Y 2 and Y 3 Each is independently CH and CR w NH, NR w , N, O or S, where Y 2 and Y 3 At least one of them is CH or CR w In some embodiments, Y 1 It is CH. In some embodiments, Y 1 It is CR w In some embodiments, Y 1 It is CH2. In some embodiments, Y 1 It is CH(R) w In some embodiments, Y 1 It is C(R) w 2. In some embodiments, Y 1 It is NH. In some embodiments, Y 1 It is NRw In some embodiments, Y 1 It is N. In some embodiments, Y 1 It is O. In some embodiments, Y 1 It is S. In some embodiments, Y 2 It is CH. In some embodiments, Y 2 It is CR w In some embodiments, Y 2 It is CH2. In some embodiments, Y 2 It is CH(R) w In some embodiments, Y 2 It is C(R) w 2. In some embodiments, Y 2 It is NH. In some embodiments, Y 2 It is NR w In some embodiments, Y 2 It is N. In some embodiments, Y 2 It is O. In some embodiments, Y 2 It is S. In some embodiments, Y 3 It is CH. In some embodiments, Y 3 It is CR w In some embodiments, Y 3 It is CH2. In some embodiments, Y 3 It is CH(R) w In some embodiments, Y 3 It is C(R) w 2. In some embodiments, Y 3 It is NH. In some embodiments, Y 3 It is NR w In some embodiments, Y 3 It is N. In some embodiments, Y 3 It is O. In some embodiments, Y 3 It is S.

[0457] In some embodiments, Y 1 Is it NH or NR? w And Y 2 and Y 3 Is it CH or CR? w In some embodiments, Y 1 It is O, and Y 2 and Y 3 Is it CH or CR? w In some embodiments, Y 1 It is S, and Y 2 and Y 3 Is it CH or CR? w .

[0458] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0459] In some embodiments, the ring W and its R w Substituents are

[0460] In some embodiments, the ring W and its R w Substituents are

[0461] In some embodiments, the ring W and its R w Substituents are

[0462] In some embodiments, the ring W and its R w Substituents are

[0463] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0464] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0465] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0466] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0467] In some embodiments, the ring W and its R w Substituents are In some embodiments, the ring W and its R w Substituents are

[0468] In some embodiments, the ring W and its R w Substituents are

[0469] In some embodiments, the ring W and its R w Substituents are

[0470] In some embodiments, ring W is as illustrated in the compounds in Table 1B below.

[0471] In some embodiments, the ring W and its R w Substituents are

[0472] In some embodiments, the ring W and its R w Substituents are

[0473] In some embodiments, the ring W and its R w Substituents are

[0474] In some embodiments, the ring W and its R w Substituents are

[0475] In some embodiments, the ring W and its R w Substituents are

[0476] As described above and defined in this paper, the ring X and its R x Substituents are in Indicates the key with ring W, and This represents the bonds with the rest of the molecule.

[0477] In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are In some embodiments, ring X and its R x Substituents are

[0478] In some embodiments, ring X is illustrated in the compounds shown in Table 1B below.

[0479] In some embodiments, ring X and its R x Substituents are

[0480] In some embodiments, ring X and its R x Substituents are

[0481] In some embodiments, ring X and its R x Substituents are

[0482] As described above and defined herein, ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic groups (the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur), and 5-6 membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0483] In some embodiments, ring Y is a phenyl group.

[0484] In some embodiments, ring Y is a 3-8 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 3-6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is cyclopropyl. In some embodiments, ring Y is cyclobutyl. In some embodiments, ring Y is cyclopentyl. In some embodiments, ring Y is hexyl.

[0485] In some embodiments, ring Y is a 5-6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 6-7 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 3 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 4 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 5 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 6 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is a 7 member saturated or partially unsaturated monocyclic carbocyclic group. In some embodiments, ring Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

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

[0487] In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 5-membered monocyclic heteroaryl ring having 2-3 nitrogen heteroatoms.

[0488] In some embodiments, ring Y is a 6-membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring Y is a 6-membered monocyclic heteroaryl group having 1-4 nitrogen heteroatoms. In some embodiments, ring Y is pyridyl, pyrimidinyl, pyridazinyl, or triazinyl.

[0489] In some embodiments, ring Y is a 3-8 member saturated or partially unsaturated monocyclic heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0490] In some embodiments, ring Y is

[0491] In some embodiments, ring Y is

[0492] In some embodiments, ring Y is

[0493] In some embodiments, ring Y is

[0494] In some embodiments, ring Y is illustrated in the compounds shown in Table 1B below.

[0495] In some embodiments, ring Y and its R y Substituents are

[0496] In some embodiments, ring Y and its R y Substituents are

[0497] In some embodiments, ring Y is

[0498] In some embodiments, ring Y and its R y Substituents are

[0499] As described above and defined in this article, R x and R y Independently selected from hydrogen, R A, Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0500] In some embodiments, R x and R y Independently selected from R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0501] As described above and defined in this paper, each R w Independently selected from hydrogen, R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

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

[0503] In some embodiments, each R w Independently selected from R A R B , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

[0504] In some embodiments, R w R x and R y One or more of them are hydrogen. In some embodiments, R w R x and R y One or more of them are R A In some embodiments, R w R x and R y One or more of them are halogens. In some embodiments, R w R x and R y One or more of them are -CN. In some embodiments, R w R x and R y One or more of them are -NO2. In some embodiments, R w R x and R y One or more of them are -OR. In some embodiments, R w R x and R y One or more of them are -SR. In some embodiments, R w Rx and R y One or more of them are -NR2. In some embodiments, R w R x and R y One or more of them are -SiR3. In some embodiments, R w R x and R y One or more of them are -S(O)2R. In some embodiments, R w R x and R y One or more of them are -S(O)2NR2. In some embodiments, R w R x and R y One or more of them are -S(O)(NR)R. In some embodiments, R w R x and R y One or more of them are -S(O)R. In some embodiments, R w R x and R y One or more of them are -C(O)R. In some embodiments, R w R x and R y One or more of them are -C(O)OR. In some embodiments, R w R x and R y One or more of them are -C(O)NR2. In some embodiments, R w R x and R y One or more of them are -C(O)NROR. In some embodiments, R w R x and R y One or more of them are -OC(O)R. In some embodiments, R w R x and R y One or more of them are -OC(O)NR2. In some embodiments, R w R x and R y One or more of them are -OP(O)R2. In some embodiments, R w R x and R y One or more of them are -OP(O)(OR)2. In some embodiments, R w R x and R yOne or more of them are -NRC(O)OR. In some embodiments, R w R x and R y One or more of them are -NRC(O)R. In some embodiments, R w R x and R y One or more of them are -NRC(O)N(R)2. In some embodiments, R w R x and R y One or more of them are -NRS(O)2R.

[0505] In some embodiments, R w It is -C(O)OR. In some embodiments, R w It is -C(O)NR2. In some embodiments, R w It is an optionally substituted phenyl group. In some embodiments, R w It is an optional substituted 5-6 membered heteroaryl ring (the heteroaryl ring has 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0506] In some embodiments, R w It is R B In some embodiments, R w It is R A .

[0507] In some embodiments, R w It is fluorine, chlorine, or bromine.

[0508] In some embodiments, R w It is -C(O)NHR. In some embodiments, R w It is -C(O)NHR, where R w R in the equation is an optional substitution for C. 1-6 Aliphatic group. In some embodiments, R w It is -C(O)NHR, where R w R in C 1-6 Aliphatic groups, optionally replaced by -CN.

[0509] In some embodiments, R w It is an optional replacement for C 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally substituted with -C(O)N(R) o )2 replaces. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally covered by -NR o (O)N(Ro )2 replaces. In some embodiments, R w yes In some such embodiments, R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally -OR o Replace, where R o Is it hydrogen or C? 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 The aliphatic group is optionally replaced by a halogen (e.g., fluorine). In some embodiments, R w It is -CH2F, -CHF2, or -CF3.

[0510] In some embodiments, R w It is C 1-6 The aliphatic group is optionally replaced by a halogen (e.g., fluorine). In some embodiments, R w yes In some embodiments, R w It is C 1-6 Aliphatic groups, optionally halogenated (e.g., fluorine) or -NR o 2. Replacement. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally with halogens (e.g., fluorine) and -NR o 2. Replacement. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally halogenated (e.g., fluorine) or -NR o 2 replacements, where each R o Independently hydrogen or C 1-6 Aliphatic group. In some embodiments, R w It is C 1-6 Aliphatic groups, optionally with halogens (e.g., fluorine) and -NR o 2 replacements, where each R o Independently hydrogen or C 1-6 Aliphatic group. In some embodiments, R w yes

[0511] In some embodiments, R w It is an optional substituted phenyl group.

[0512] In some embodiments, R w It is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R wIt is an optional substituted 3-7 nucleotide saturated or partially unsaturated carbon ring. In some embodiments, R w It is an optional substituted cyclopropyl group. In some embodiments, R w It is an optional substituted cyclobutyl group. In some embodiments, R w It is an optional substituted cyclopentyl group. In some embodiments, R w It is an optional substituted cyclohexyl group. In some embodiments, R w It is an optionally substituted cyclopropene group. In some embodiments, R w It is an optional substituted cyclobutenyl group. In some embodiments, R w It is an optional substituted cyclopentenyl group. In some embodiments, R w It is an optional substituted cyclohexene group.

[0513] In some embodiments, R w It is a 3- to 7-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is a 5-6 member saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0514] In some embodiments, R w It is a tetra-membered saturated or partially unsaturated heterocycle with one or two independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It can be optionally substituted with nitrogen-heterocyclic butyl, oxocyclic butyl, or thiocyclic butyl.

[0515] In some embodiments, R w It is a 5-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It can be optionally substituted with pyrrolidinyl, pyrrolinyl, pyrazolylyl, pyrazolylyl, imidazoalkyl, or imidazolinyl. In some embodiments, R w It can be optionally substituted with dihydropyridyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, or tetrahydrothiophenyl.

[0516] In some embodiments, R w It is a 6-membered saturated or partially unsaturated heterocycle with 1-2 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R wIt may be optionally substituted with piperidinyl, piperazinyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxyl, 1,4-dioxinyl, thiaalkyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,3-dithiaalkyl, 1,4-dithiaalkyl, morpholinyl, or thiomorpholinyl. In some embodiments, R w It can be optionally substituted with dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiaranyl, or tetrahydrothiaranyl.

[0517] In some embodiments, R w It is an optional replacement In some embodiments, R w It is an optional replacement In some embodiments, R w It is an optional replacement In some implementations, R w yes In some embodiments, R w It is an optional replacement Among them W m Is it O, S, C(O), or NR? o , where R o It is as described above and defined herein. In some embodiments, R w yes In some embodiments, R w It is an optional replacement In some embodiments, R w yes In some embodiments, R w yes In some embodiments, R w yes In some embodiments, W m It is O. In some embodiments, W m It is S. In some embodiments, W m It is C(O). In some embodiments, W m It is NR o In some embodiments, W m It is NR o , where R o Is it hydrogen or C? 1-6 Aliphatic groups.

[0518] In some embodiments, R w It is an optionally substituted 5-6 membered heteroaryl group (the heteroaryl group has 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R w It is a 5-membered heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Rw It can be optionally substituted with a pyrazolyl, imidazole, triazole, or tetraazole group. In some embodiments, R w It is an optional substituted imidazole group, optionally replaced by -C(O)N(R) o )2 replaces. In some embodiments, R w It can be optionally substituted with furanyl, thiophene, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, R w It is furanyl, optionally converted to -C(O)N(R) o )2 replaces.

[0519] In some embodiments, R w It is a 6-membered heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is an optionally substituted 6-membered heteroaryl group having 1-4 nitrogen atoms. In some embodiments, R w It can be optionally substituted with pyridinyl, pyrimidinyl, pyridazinyl, or triazinyl. In some embodiments, R w It can be optionally substituted with a pyridone group, a pyrazinone group, or a pyrimidinone group.

[0520] In some embodiments, R w It is -NHR, where R is an optional 5-6 membered heteroaryl group having 1-4 independently substituted heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R w It is -NHR, where R is a 6-membered heteroaryl group with 1 to 4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

[0521] In some embodiments, R w It is -S(O)2NH2. In some embodiments, R w It is -S(O)2NHR, where R is the C with optional substitution. 1-6 Aliphatic group. In the embodiment, R w It is -S(O)2NHR, where R is an optionally substituted phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (the heterocyclic ring has 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur), or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0522] In the embodiment, R w It is -S(O)2(NH)R. In some embodiments, R w It is -S(O)2(NH)H. In some embodiments, R w It is -S(O)2(NH)R, where R is an optional substituted C. 1-6 Aliphatic group...

Claims

1. A compound having formula I′: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 and X 5 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 and X 5 At most one of them is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates bonds with the rest of the molecule; Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R w selected from hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle—the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently from the following: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 5-10 membered monocyclic or bicyclic arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Each Cy B2 The ring is independently optionally substituted from the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic rings—the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 5-10 membered monocyclic or bicyclic aryl or heteroaryl—the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl—the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbon ring or heterocycle—the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4, and where: (i) When ring X and its R x Substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 and Y 3 Not NH, NR w Or N; (ii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y 2 and Y 3 Each is CH, CR w CH2, CH(R) w ) or C(R w When )2, then Y 1 Not CH, CR w CH2, CH(R) w ) or C(R w )2 (iii) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is S, then ring Y is not a phenyl group or a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic group or heterocyclic group—the heterocyclic group has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; (iv) When ring X and its R x Substituents are X 1 It is N, and Y 1 It is NH, NR w Or when N, then Y 3 Not S; (v) When ring X and its R x Substituents are X 1 It is N, and Y 1 When it is O, then Y 2 Not NH, NR w Or N; (vi) When ring X and its R x Substituents are X 1 It is N, Y 1 It is NH, NR w Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w If z = 2, then z is neither 0 nor 1; (vii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, and Y 2 It is CH, CR w CH2, CH(R) w ) or C(R w When )2, then Y 2 and Y 3 Only one of them is O; (viii) When ring X and its R x Substituents are X 1 X 4 and X 5 Each is CH or CR w X 2 and X 3 Each is C, Y 1 It is O, NH, NR w Or N, and Y 2 and Y 3 It is CH, CR w CH2, CH(R) w ) or C(R w When z = 2, then z is neither 0 nor 1; and (ix) When ring X and its R x Substituents are X 5 It is N, and Y 1 It is NH, NR w Or when N, then Y 2 Not NH, NR w Or N, and The compound does not have a structure ABC as defined by the combination of structural units A, B, and C in the table below:

2. The compound of claim 1, wherein, Ring W and its R w The substituents are:

3. The compound of claim 1, wherein, Ring W and its R w The substituents are:

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

5. The compound of claim 4, wherein, Ring Y is 6. The compound according to any one of claims 1-5, wherein, the occurring R w is -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

7. The compound according to any one of claims 1-6, wherein, The R that appears w It is R B .

8. The compound according to any one of claims 1-7, wherein, The R that appears w It is a halogen (e.g., fluorine).

9. The compound according to any one of claims 1-8, wherein, This compound has formula Ia-1b or Ia-2b: Or its pharmaceutically acceptable salt, wherein: R w' is hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

10. The compound of claim 9, wherein, R w' It is optionally substituted with a ring selected from the following: phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

11. The compound according to any one of claims 1-10, wherein, The compound has the formula Ib-5, Ib-6, Ic-5, Ic-6, Id-5, Id-6, Ie-5, or Ie-6: Or its pharmaceutically acceptable salt, wherein: R w' is hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2, or -NRS(O)2R.

12. The compound according to any one of claims 1-11, wherein, R B Yes -L B -Cy B1 -H.

13. The compound according to any one of claims 1-11, wherein, R B is -L B -Cy B1 -Cy B2 .

14. The compound according to any one of claims 1-13, wherein, Cy B1 It is an 8-10 member saturated or partially unsaturated bicyclic heterocyclic group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

15. The compound according to any one of claims 1-13, wherein, Cy B1 It is a 3-7 member saturated or partially unsaturated heterocyclic group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

16. The compound according to any one of claims 1-11, wherein, R B yes 17. The compound according to any one of claims 1-16, wherein, Cy B2 It is a 5-6 membered monocyclic heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

18. The compound of claim 1, wherein: (i) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the optionally substituted ring is selected from the following: phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (ii) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the optionally substituted ring is selected from the following: phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group with 14 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the alternatively substituted ring is selected from the following: phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-10 membered monocyclic or bicyclic aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

19. The compound according to any one of claims 1-18, wherein, This compound is not selected from the compounds in Table B.

20. The compound of claim 1, wherein, The compound is selected from Table 1B, or a pharmaceutically acceptable salt thereof.

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

22. A pharmaceutical composition comprising a compound as described in any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or mediator.

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

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

25. A method for inhibiting STAT6, the method comprising contacting STAT6 with a compound having formula I: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are X 1 X 4 X 5 and X 6 Each is independently CH and CR w Or N; X 2 and X 3 Each is either C or N independently. Where X 1 X 2 X 3 X 4 X 5 At most one of X6 is N; Y 1 Y 2 and Y 3 Each is independently CH and CR w CH2, CH(R) w ), C(R w 2. NH, NR w N, O or S Where Y 2 and Y 3 At least one of them is CH, CR w CH2, CH(R) w ) or C(R w )2; Each Indicates a single bond or a double bond; Ring X and its R x Substituents are in Indicates the key with ring W, and Indicates the key with Lx; Ring Y is selected from the following rings: phenyl, naphthyl, 3-11 member saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic group—the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-10 member monocyclic or bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L x yes in Indicates the bond with ring Y; R w selected from hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R x and R y Independently selected from hydrogen, R A , Halogen, -CN, -NO2, -OR, -SR, NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR , -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R; R Z It is R A -OR or NR2; Each R A Independently, the optional substituted groups are selected from the following: C 1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle—the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R B Independently is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 ; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(NR)R-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 The ring is optionally substituted independently from the following: phenylene, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 5-10 membered monocyclic or bicyclic arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, arylene or heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Each Cy B2 The ring is independently optionally substituted from the following: phenyl, 3-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic rings—the heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; 5-10 membered monocyclic or bicyclic aryl or heteroaryl—the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 5-15 membered saturated or partially saturated monocyclic, bicyclic or tricyclic carbocyclic, heterocyclic, aryl or heteroaryl—the heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbon ring or heterocycle—the heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same or adjacent atoms may optionally form a 3-7 saturated or partially unsaturated ring together with the atom between them. This ring, in addition to the atoms to which the two R groups are attached or adjacent atoms, has 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur. w, x, y, and z are each independently 0, 1, 2, 3, or 4.

26. The method of claim 25, wherein, The compound has formula I′: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are and Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

27. The method of claim 25, wherein, The compound has formula II: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are and Ring Y is selected from the following rings: naphthyl, 5-10 saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 cyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

28. The method of claim 25, wherein, This compound has formula III: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic groups—the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 membered monocyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; naphthyl, 5-10 membered saturated or partially unsaturated bicyclic or bridged bicyclic carbocyclic or heterocyclic groups—the heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 membered bicyclic heteroaryl groups having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and L x yes in This indicates a bond with ring Y.

29. The method according to any one of claims 25-28, wherein, Ring W and its R w The substituents are:

30. The method according to any one of claims 25-28, wherein, Ring W and its R w The substituents are:

31. The method of claim 25, wherein, The compound has formula IV: Or its pharmaceutically acceptable salt, wherein: Ring W and its R w Substituents are and Ring Y is selected from the following rings: phenyl, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

32. The method of claim 25 or 31, wherein, Ring W and its R w The substituents are:

33. The method of claim 25 or 31, wherein, Ring W and its R w The substituents are:

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

35. The method of claim 34, wherein, Ring Y is 36. The method according to any one of claims 25-35, wherein, the occurring R w are -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

37. The method according to any one of claims 25-36, wherein, The R that appears w It is R B .

38. The method according to any one of claims 25-37, wherein, The R that appears w It is a halogen (e.g., fluorine).

39. The method according to any one of claims 25-38, wherein, The compound has the formula Ia-1b, Ia-2a, Ia-1b, or Ia-2b: Or its pharmaceutically acceptable salt, wherein: R w' is hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

40. The method of claim 39, wherein, R w' It is optionally substituted with a ring selected from the following: phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

41. The method according to any one of claims 25-40, wherein, The compound has formulas Ib-1 to Ib-6, Ic-1 to Ic-6, Id-1 to Id-6, or Ie-1 to Ie-6. Or its pharmaceutically acceptable salt, wherein: R w' is hydrogen, R A , R B , halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)R, -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)NROR, -OC(O)R, -OC(O)NR2, -P(O)R2, -P(O)(OR)2, -OP(O)R2, -OP(O)(OR)2, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R)2 and -NRS(O)2R.

42. The method according to any one of claims 25-41, wherein, R B Yes -L B -Cy B1 -H.

43. The method according to any one of claims 25-41, wherein, R B is -L B -Cy B1 - Cy B2 .

44. The method according to any one of claims 25-43, wherein, Cy B1 It is an 8-10 member saturated or partially unsaturated bicyclic heterocyclic group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

45. The method according to any one of claims 25-43, wherein, Cy B1 It is a 3-7 member saturated or partially unsaturated heterocyclic group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

46. ​​The method according to any one of claims 25-41, wherein, R B yes 47. The method according to any one of claims 25-46, wherein, Cy B2 It is a 5-6 membered monocyclic heteroaryl group with 1-4 independently substituted heteroatoms selected from nitrogen, oxygen and sulfur.

48. The method of claim 26, wherein: (i) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the optionally substituted ring is selected from the following: phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (ii) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the optionally substituted ring is selected from the following: phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-10 membered monocyclic or bicyclic aryl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or (iii) Ring W and its R w Substituents are Cycle Y is a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; z is 2; Each L B Independently, it is a covalent bond or C 1-3 A divalent straight-chain or branched saturated or unsaturated hydrocarbon chain, wherein one or two methylene units in the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CR2-, -CF2-, -CRF-, -CR(OR)-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)(NR)- or -CR=CR-; Each Cy B1 Independently, the optionally substituted ring is selected from the following: phenylene, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups—the heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-10 membered monocyclic or bicyclic arylene or heteroarylene—the heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each Cy B2 Independently, the alternatively substituted ring is selected from the following: phenyl, 3-7 membered saturated or partially unsaturated carbon ring or heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-10 membered monocyclic or bicyclic aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

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

50. The method according to any one of claims 25-49, wherein, This contact occurs in a patient or biological sample.

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