STAT6 modulators and methods of uses thereof

Abstract

The disclosure provides for compounds, compositions, and methods for modulating STAT6.

Description

STAT6 MODULATORS AND METHODS OF USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 662,078 filed 20-Jun-2024, U.S. Provisional Application Serial No.63 / 673,537 filed 19-Jul-2024, U.S. Provisional Application Serial No. 63 / 694,665 filed 13-Sep-2024, U.S. Provisional Application Serial No. 63 / 724,224 filed 22-Nov-2024, U.S. Provisional Application Serial No.63 / 765,019 filed 28-Feb-2025, U.S. Provisional Application Serial No. 63 / 774,384 filed 19-Mar-2025, and International Application No. PCT / US2025 / 025338 filed April 18, 2025; and is a continuation-in-part of International Application No. PCT / US2025 / 025338 filed April 18, 2025; which are hereby incorporated by reference in their entirety. BACKGROUND

[0002] The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play an essential role in the regulation of cell processes, such as proliferation, differentiation, apoptosis and angiogenesis. Seven STAT genes have been identified in the human genome: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

[0003] Activation of STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

[0004] STAT6 is implicated in driving Type 2 immunity, allergies. It may participate in IL-4 / IL-13- mediated allergic reaction, and play a vital role in the differentiation of T-helper type 2 (Th2) cells. STAT6 is a key node primarily activated in the Janus Kinase (JAK) pathway by inflammatory cytokines, interleukin-4 (IL4) and interleukin- 13 (IL13) and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Human STAT6 mutations have been associated with severe allergies such as asthma and eczema. There is a need to discover and develop STAT6 drugs, for example to treat allergic / inflammatory diseases and cancers. As such, small molecules that modulate STAT6 directly to target disease-associated proteins such as STAT6 hold promise as therapeutic agents. SUMMARY

[0005] Disclosed herein is a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IX) as disclosed herein.

[0006] Disclosed herein is a compound of Formula (IXa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IXa) as disclosed herein.

[0007] Disclosed herein is a compound of Formula (IXb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IXb) as disclosed herein.

[0008] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0009] Also disclosed herein is a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.

[0010] In some embodiments, the disorder in alopecia, aspergillus, asthma, atomic dermatitis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyposis, gastritis, inflammatory bowel disease, pemphigoid, prurigo nodularis, sinusitis, or urticaria.INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION Definitions

[0012] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0013] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0014] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0015] “Oxo” refers to =O.

[0016] “Amino” refers to -NH2.

[0017] “Hydroxy” refers to -OH.

[0018] “Carboxyl” refers to -COOH.

[0019] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “C1-C6alkyl,” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6alkyl, a C1- C5 alkyl, a C1-C4 alkyl, or a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0020] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6alkenyl,” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0021] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6alkynyl,” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

[0022] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, - OMe, -NH2, or -NO2. In some embodiments, the alkylene is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is independently optionally substituted with halogen.

[0023] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0024] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen.

[0025] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g.,C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0026] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro.

[0027] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0028] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0029] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0030] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0031] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. In some embodiments, the heteroalkyl is -CH2CH2OCH3. In some embodiments, the heteroalkyl is -CH2CH2OCH3wherein one, two, or three hydrogen has been replaced by a deuterium. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, - OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0032] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 8-membered partially or fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 6- membered partially or fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3- to 6- membered fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogenatom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.

[0033] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is a 5- to 10-membered ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted withone or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen.

[0034] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0035] The term “one or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent. In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.

[0036] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0037] “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0038] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0039] As used herein, a “disease or disorder associated with STAT6” or, alternatively, “a STAT6- mediated disease or disorder” means any disease or other deleterious condition in which STAT6, or a mutant thereof, is known or suspected to play a role. Compounds

[0040] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, useful in the treatment of a disease or disorder associated with STAT6.

[0041] Disclosed herein is a compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IX); wherein: R20is , -L-NR10C(=O)R11, -L-C(=O)NR12R13, -L-S(=O)2R11, -L-S(=O)(=NR10)R11, or - L-P(=O)(R11)2; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R1on the same carbon atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, or 6; R10is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; R11is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R12and R13are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R12and R13are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each Z is independently N or CR2; each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;U is C or N; T is C or N; provided that not both of U and T are N; X1is N or CR5; R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X2is N or CR6; R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R5and R6are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R6and R7are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; Ring F is a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, or a 6-membered heteroaryl; each R18is independently halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R18on the same atom form an oxo; v is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

[0042] In some embodiments of a compound of Formula (IX), X1is N. In some embodiments of a compound of Formula (IX), X1is CR5.

[0043] In some embodiments of a compound of Formula (IX), X2is N. In some embodiments of a compound of Formula (IX), X2is CR6.

[0044] In some embodiments of a compound of Formula (IX), X3is N. In some embodiments of a compound of Formula (IX), X3is CR7.

[0045] In some embodiments of a compound of Formula (IX), R5is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IX), R5is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R5is hydrogen.

[0046] In some embodiments of a compound of Formula (IX), R6is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IX), R6is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R6is hydrogen, halogen, or C1-C6haloalkyl.

[0047] In some embodiments of a compound of Formula (IX), R6is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R6is hydrogen, halogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R6is hydrogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R6is hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (IX), R6is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R6is C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R6is C1-C6alkyl. In some embodiments of a compound of Formula (IX), R6is halogen or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R6is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R6is -CH3or -CF3. In some embodiments of a compound of Formula (IX), R6is -CH3. In some embodiments of a compound of Formula (IX), R6is -CF3.

[0048] In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, C1-C6alkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R7is hydrogen.

[0049] In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IX), R7is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), R7is C1-C6haloalkyl.

[0050] In some embodiments of a compound of Formula (IX), Ring F is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (IX), Ring F is a 5-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0051] In some embodiments of a compound of Formula (IX), Ring F is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (IX), Ring F is a 6-membered heterocycloalkyl comprising one or two heteroatoms that are N.

[0052] In some embodiments of a compound of Formula (IX), Ring F is a 6-membered heteroaryl. In some embodiments of a compound of Formula (IX), Ring F is a 6-membered heteroaryl comprising one or two heteroatoms that are N.

[0053] In some embodiments of a compound of Formula (IX), each R18is independently halogen, -CN, - NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl,or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;

[0054] In some embodiments of a compound of Formula (IX), each R18is independently halogen, C1- C6alkyl, or C1-C6haloalkyl; and / or two R18on the same atom form an oxo. In some embodiments of a compound of Formula (IX), each R18is independently C1-C6alkyl or C1-C6haloalkyl; and / or two R18on the same atom form an oxo. In some embodiments of a compound of Formula (IX), each R18is independently C1-C6alkyl; and / or two R18on the same atom form an oxo.

[0055] In some embodiments of a compound of Formula (IX), v is 0, 1, 2, or 3. In some embodiments of a compound of Formula (IX), v is 0, 1, or 2. In some embodiments of a compound of Formula (IX), v is 1 or 2. In some embodiments of a compound of Formula (IX), v is 1. In some embodiments of a compound of Formula (IX), v is 2. In some embodiments of a compound of Formula (IX), v is 3. In some embodiments of a compound of Formula (IX), v is 1, 2, or 3. In some embodiments of a compound of Formula (IX), v is 2 or 3.

[0056] In some embodiments of a compound of Formulas

[0057] In some embodiments of a compound of Formula (IX), R20is.

[0058] In some embodiments of a compound of Formula (IX), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (IX), Ring A is 5- or 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (IX), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (IX), Ring A is 6-membered heterocycloalkyl.

[0059] In some embodiments of a compound of Formula (IX), each R1is independently halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; and / or two R1on the same carbon atom are taken together to form an oxo.

[0060] In some embodiments of a compound of Formula (IX), each R1is independently C1-C6alkyl; and / or two R1on the same carbon atom are taken together to form an oxo.

[0061] In some embodiments of a compound of Formula (IX), n is 2, 3, or 4. In some embodiments of a compound of Formula (IX), n is 3 or 4. In some embodiments of a compound of Formula (IX), n is 2. In some embodiments of a compound of Formula (IX), n is 3. In some embodiments of a compound of Formula (IX), n is 4.

[0062] In some embodiments of a compound of Formulawherein: R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-; R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0063] In some embodiments of a compound of Formula (IX), R30is hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl. In some embodiments of a compound of Formula (IX), R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -L-cycloalkyl, or -L- heterocycloalkyl. In some embodiments of a compound of Formula (IX), R30is hydrogen, C1-C6alkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IX), R30is C1-C6alkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (IX), R30is C1-C6alkyl.

[0064] In some embodiments of a compound of Formula (IX), R30is -CH3. In some embodiments of a compound of Formula (IX), R30is -CD3.

[0065] In some embodiments of a compound of Formula (IX), R31is hydrogen, halogen, -CN, -NO2, - OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl. In some embodiments of a compound of Formula (IX), R31is hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -L-cycloalkyl, or -L-heterocycloalkyl.

[0066] In some embodiments of a compound of Formula (IX), R31is hydrogen, -CN, C1-C6alkyl, C1- C6hydroxyalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IX), R31is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R31is -CN or C1-C6alkyl, In some embodiments of a compound of Formula (IX), R31is C1-C6alkyl.

[0067] In some embodiments of a compound of Formula (IX), X is -O-. In some embodiments of a compound of Formula (IX), X is -S-. In some embodiments of a compound of Formula (IX), X is -NR32-. In some embodiments of a compound of Formula (IX), X is -C(R33)2-.

[0068] In some embodiments of a compound of Formula (IX), R32is hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (IX), R32is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R32is hydrogen. In some embodiments of a compound of Formula (IX), R32is C1-C6alkyl. In some embodiments of a compound of Formula (IX), each R33is independently hydrogen, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), each R33is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), each R33is hydrogen.

[0069] In some embodiments of a compound of Formula (IX),,

[0070] In some embodiments of a compound of Formula (IX), R20is -NR10C(=O)R11.

[0071] In some embodiments of a compound of Formula (IX), R20is -L-S(=O)2R11, -L- S(=O)(=NR10)R11, or -L-P(=O)(R11)2.

[0072] In some embodiments of a compound of Formula (IX), R20is -L-S(=O)2R11.

[0073] In some embodiments of a compound of Formula (IX), R20is -S(=O)2R11. In some embodiments of a compound of Formula (IX), R20is -CH2-S(=O)2R11.

[0074] In some embodiments of a compound of Formula (IX), R20is -L-S(=O)(=NR10)R11. In some embodiments of a compound of Formula (IX), R20is -S(=O)(=NR10)R11. In some embodiments of a compound of Formula (IX), R20is -CH2-S(=O)(=NR10)R11.

[0075] In some embodiments of a compound of Formula (IX), R20is -L-P(=O)(R11)2. In some embodiments of a compound of Formula (IX), R20is -P(=O)(R11)2. In some embodiments of a compound of Formula (IX), R20is -CH2-P(=O)(R11)2.

[0076] In some embodiments of a compound of Formula (IX), R10is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IX), R10is C1-C6alkyl. In some embodiments of a compound of Formula (IX), R10is hydrogen.

[0077] In some embodiments of a compound of Formula (IX), R11is C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (IX), R11is C1-C6alkyl.

[0078] In some embodiments of a compound of Formula (IX), R20is -C(=O)NR12R13.

[0079] In some embodiments of a compound of Formula (IX), R12and R13are independently hydrogen or C1-C6alkyl.

[0080] Disclosed herein is a compound of Formula (IXa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-;R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Z is independently N or CR2; each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; RY1is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1- C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

[0081] Disclosed herein is a compound of Formula (IXb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-; R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Z is independently N or CR2; each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl,C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

[0082] In some embodiments of a compound of Formula (IXa) or (IXb), R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of acompound of Formula (IXa) or (IXb), R30is hydrogen, C1-C6alkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R30is C1-C6alkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R30is C1-C6alkyl.

[0083] In some embodiments of a compound of Formula (IXa) or (IXb), R30is -CH3. In some embodiments of a compound of Formula (IXa) or (IXb), R30is -CD3.

[0084] In some embodiments of a compound of Formula (IXa) or (IXb), X is -O-. In some embodiments of a compound of Formula (IXa) or (IXb), X is -S-. In some embodiments of a compound of Formula (IXa) or (IXb), X is -NR32-. In some embodiments of a compound of Formula (IXa) or (IXb), X is - C(R33)2-.

[0085] In some embodiments of a compound of Formula (IXa) or (IXb), R32is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R32is hydrogen or C1- C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R32is hydrogen. In some embodiments of a compound of Formula (IXa) or (IXb), R32is C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), each R33is independently hydrogen, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), each R33is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), each R33is hydrogen.

[0086] In some embodiments of a compound of Formula (,some embodiments of a compound of Formula (some embodiments of a compound of Formula (

[0087] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each Z is independently CR2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), one Z is N and the remaining Z are independently CR2.

[0088] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), is . In some embodiments of a compound of Formula (IX), (IXa), or (IXb),. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), is . In some embodiments of a compound of Formula (IX), (IXa), or (IXb),is . In some embodiments of a compound of Formula (IX), (IXa), or (IXb),is. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), is.

[0089] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is independently hydrogen, halogen, -CN, -OH, -ORa, C1-C6alkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is independently hydrogen, halogen, -CN, -ORa, or -L- cycloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is independently hydrogen, halogen, or -ORa. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is independently hydrogen or halogen. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R2is hydrogen.

[0090] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0091] In some embodiments of a compound of Formula (IXa), X3is N. In some embodiments of a compound of Formula (IXa), X3is CR7.

[0092] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0093] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0094] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0095] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0096] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0097] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0098] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0099] In some embodiments of a compound of Formula (IXb), X3is N. In some embodiments of a compound of Formula (IXb), X3is CR7.

[0100] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0101] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0102] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0103] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0104] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0105] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0106] In some embodiments of a compound of Formula (IXa) or (IXb), R31is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, -L-cycloalkyl, or -L- heterocycloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R31is hydrogen, -CN, C1-C6alkyl, C1-C6hydroxyalkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R31is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R31is -CN or C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R31is C1- C6alkyl.

[0107] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0108] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0109] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0110] In some embodiments, the compound of Formula (IX) or (IXa) has the following formula:.

[0111] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0112] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0113] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0114] In some embodiments, the compound of Formula (IX) or (IXb) has the following formula:.

[0115] In some embodiments of a compound of Formula (IXa), RY1is C1-C6heteroalkyl wherein one or more hydrogen is optionally replaced by a deuterium.

[0116] In some embodiments of a compound of Formula (IXa), RY1is C1-C6alkylene-O-cycloalkyl or C1-C6alkylene-O-heterocycloalkyl; wherein the alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0117] In some embodiments of a compound of Formula (IXa), RY1is C1-C6alkylene-O-cycloalkyl; wherein the alkylene and cycloalkyl is independently optionally substituted with one or more R.

[0118] In some embodiments of a compound of Formula (IXa), RY1is -C6alkylene-O-heterocycloalkyl; wherein the alkylene and heterocycloalkyl is independently optionally substituted with one or more R.

[0119] In some embodiments of a compound of Formula (IXa), RY1is -L-cycloalkyl or -L- heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0120] In some embodiments of a compound of Formula (IXa), RY1is -L-cycloalkyl; wherein the cycloalkyl is independently optionally substituted with one or more R.

[0121] In some embodiments of a compound of Formula (IXa), RY1is -L-heterocycloalkyl; wherein the heterocycloalkyl is independently optionally substituted with one or more R.

[0122] In some embodiments of a compound of Formula (IXa), RY1is hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0123] In some embodiments of a compound of Formula (IXa), RY1is hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (IXa), RY1is hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (IXa), RY1is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa), RY1is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IXa), RY1is hydrogen. In some embodiments of a compound of Formula (IXa), RY1is C1-C6alkyl independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IXa), RY1is C1-C6alkyl. In some embodiments of a compound of Formula (IXa), RY1is ethyl. In some embodiments of a compound of Formula (IXa), RY1is C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa), one or more hydrogen in RY1is replaced with a deuterium atom. In some embodiments of a compound of Formula (IXa), RY1is -CD2CD3or - CH2CH2OCD3. In some embodiments of a compound of Formula (IXa), RY1is -CD2CD3. In some embodiments of a compound of Formula (IXa), RY1is -CH2CH2OCD3.

[0124] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or C1-C6heteroalkyl wherein one or more hydrogen is optionally replaced by a deuterium.

[0125] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, C1- C6alkylene-O-cycloalkyl, or C1-C6alkylene-O-heterocycloalkyl; wherein the alkylene, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0126] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or C1-C6alkylene-O-cycloalkyl; wherein the alkylene and cycloalkyl is independently optionally substituted with one or more R.

[0127] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or - C6alkylene-O-heterocycloalkyl; wherein the alkylene and heterocycloalkyl is independently optionally substituted with one or more R.

[0128] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, -L- cycloalkyl, or -L-heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0129] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or - L-cycloalkyl; wherein the cycloalkyl is independently optionally substituted with one or more R.

[0130] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or - L-heterocycloalkyl; wherein the heterocycloalkyl is independently optionally substituted with one or more R.

[0131] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, ; wherein each alkyl is independently optionally substituted with one or more R.

[0132] In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IXb), each R3is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IXb), one R3is hydrogen and the other R3is C1-C6alkyl. In some embodiments of a compound of Formula (IXb), one R3is hydrogen and the other R3is ethyl. In some embodiments of a compound of Formula (IXa), each R3is independently hydrogen or -CH2CH2OCD3.

[0133] In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen, halogen, C1-C6alkyl, or C2- C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen.

[0134] In some embodiments of a compound of Formula (IXa) or (IXb), R7is hydrogen, halogen, C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R7is C1- C6haloalkyl.

[0135] In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, halogen, -CN, - OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, halogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, halogen, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, halogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C2-C6alkynyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is C1-C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is C1- C6alkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is halogen or C1- C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is C1-C6alkyl or C1- C6haloalkyl. In some embodiments of a compound of Formula (IXa) or (IXb), R6is -CH3or -CF3. In some embodiments of a compound of Formula (IXa) or (IXb), R6is -CH3. In some embodiments of a compound of Formula (IXa) or (IXb), R6is -CF3.

[0136] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is phenyl or 5- or 6-membered heteroaryl.

[0137] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is phenyl.

[0138] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is pyridinyl.

[0139] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), Ring B is 5-membered heteroaryl.

[0140] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, - L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, - CN, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or -L-heteroaryl; wherein each alkyl and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -CN, -C(=O)NRcRd, C1-C6alkyl, or -L- heteroaryl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -C(=O)NRcRd, C1-C6alkyl, or -L-heteroaryl.

[0141] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently -L-heteroaryl; wherein each heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen or heteroaryl; wherein each heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently heteroaryl; wherein each heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N, and S; wherein each heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently a 5-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of O, N, and S; wherein each heteroaryl is independently optionally substituted with one or more R.

[0142] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, - L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -CN, -OH, -ORa, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen, -CN, -ORa, -C(=O)NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (IX), (IXa),or (IXb), each R8is independently halogen, -CN, -C(=O)NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently -CN, -C(=O)NRcRd, or C1- C6alkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently C1-C6alkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently -C(=O)NRcRd. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen or -C(=O)NRcRd. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently halogen or -C(=O)NH(heteroaryl) wherein the heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), each R8is independently -C(=O)NH(heteroaryl) wherein the heteroaryl is independently optionally substituted with one or more R.

[0143] In some embodiments of a compound of Formula (IX), (IXa), or (IXb), m is 1, 2, or 3. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), m is 2 or 3. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), m is 1 or 2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), m is 0. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), m is 1. In some embodiments of a compound of Formula

[0144] In some embodiments of a compound of Formula (IX),

[0145] In some embodiments of a compound of Formula. , , ,. some embodiments of a compound of Formula (IX),some embodiments of a compound of Formula (IX),Ring H is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8ais hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and u is 0, 1, 2, 3, or 4.In some embodiments of a compound of Formula, w e e : Ring H is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8ais hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and u is 0, 1, 2, 3, or 4.

[0149] In some embodiments of a compound of Formula.

[0150] In some embodiments, Ring H is a heteroaryl. In some embodiments, Ring H is a 5-membered heteroaryl. In some embodiments, Ring H is a 5-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments, Ring H is a 5- membered heteroaryl comprising one or two heteroatoms selected from the group consisting of N and O. In some embodiments, Ring H is a 5-membered heteroaryl comprising one or two heteroatoms that are N.

[0151] In some embodiments, u is 0, 1, or 2. In some embodiments, u is 1 or 2. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2.

[0152] In some embodiments, R8ais hydrogen, halogen, or C1-C6alkyl. In some embodiments, R8ais hydrogen or halogen. In some embodiments, R8ais hydrogen, halogen, or C1-C6alkyl. In someembodiments, R8ais hydrogen. In some embodiments, R8ais hydrogen, halogen, or C1-C6alkyl. In some embodiments, R8ais halogen.

[0153] In some embodiments of a compound of Formula.

[0154] In some embodiments of a compound of Formula

[0156] In some embodiments of a compound of Formula.

[0158] In some embodiments of a compound disclosed herein, one or more hydrogen has been replaced by a deuterium.

[0159] In some embodiments of a compound disclosed herein, three hydrogens have been replaced by a deuterium.

[0160] In some embodiments of a compound disclosed herein, five hydrogens have been replaced by a deuterium.

[0161] In some embodiments of a compound disclosed herein, one or more hydrogen in R30has been replaced by a deuterium. In some embodiments of a compound disclosed herein, three hydrogens in R30have been replaced by a deuterium.

[0162] In some embodiments of a compound disclosed herein, one or more hydrogen in R31has been replaced by a deuterium. In some embodiments of a compound disclosed herein, three hydrogens in R31have been replaced by a deuterium.

[0163] In some embodiments of a compound disclosed herein, one or more hydrogen in RY1has been replaced by a deuterium. In some embodiments of a compound disclosed herein, three hydrogens in RY1have been replaced by a deuterium. In some embodiments of a compound disclosed herein, five hydrogens in RY1have been replaced by a deuterium.

[0164] In some embodiments of a compound disclosed herein, one or more hydrogen in R3has been replaced by a deuterium. In some embodiments of a compound disclosed herein, three hydrogens in R3have been replaced by a deuterium.

[0165] In some embodiments of a compound disclosed herein, one or more hydrogen in R8has been replaced by a deuterium. In some embodiments of a compound disclosed herein, three hydrogens in R8have been replaced by a deuterium.

[0166] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6haloalkyl.

[0167] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6haloalkyl.

[0168] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6haloalkyl.

[0169] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or heteroaryl independently optionally substituted with one or more R.

[0170] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0171] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C3alkylene independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C1-C3alkylene. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is - CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0172] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, - C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1- C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl; and / or two R on the same atom form an oxo. In some embodiments of acompound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1- C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1- C3alkoxy, or C1-C3haloalkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, C1-C3alkyl, or C1-C3haloalkyl; and / or two R on the same atom form an oxo.

[0173] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl. In some embodiments of a compound disclosed herein, each R is independently -CN, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each R is independently -CN, C1-C3alkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each R is independently -CN or C1-C3alkyl. In some embodiments of a compound disclosed herein, each R is independently C1-C3alkyl.

[0174] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0175] In some embodiments the compound disclosed herein, is selected from a compound found in table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Table 1Ex. Structure

[0176] In some embodiments the compound disclosed herein, is selected from a compound that is:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0177] In some embodiments the compound disclosed herein, is selected from a compound that is:, , ,pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0178] In some embodiments the compound disclosed herein, is selected from a compound that is:,acceptable salt, solvate, or stereoisomer thereof.

[0179] In some embodiments the compound disclosed herein, is selected from a compound that is:solvate, or stereoisomer thereof.

[0180] In some embodiments the compound disclosed herein, is selected from a compound that is:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0181] In some embodiments the compound disclosed herein, is selected from a compound that is:solvate, or stereoisomer thereof.

[0182] In some embodiments the compound disclosed herein, is selected from a compound that is:,

[0183] In some embodiments the compound disclosed herein, is selected from a compound that is:pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0184] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods providedherein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0185] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, one or more -CH3in a compound disclosed herein has been replaced by a -CD3.

[0186] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0187] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0188] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0189] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0190] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0191] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4 alkyl)4 hydroxide, and the like.

[0192] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0193] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0194] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Method of Treatment

[0195] Disclosed herein are methods of modulating STAT6 activity in a subject, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0196] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 include, but is not limited to, allergic disorder, atherosclerosis, autoimmune diseases such as lupus and rheumatoid arthritis, autoinflammatory syndromes, cancer, cardiovascular disorder, CNS disorder, condition associated with cell death, conditions associated with organ transplantation, destructive bone disorder, diabetes, gout and gouty arthritis, hereditary disorder, hormone-related disease, immunodeficiency disorder, infectious disease, inflammatory bowel disease, inflammatory disorder, liverdisease, metabolic disorder, neurodegenerative disorder, neurological disorder, osteoarthritis, pathologic immune conditions involving T cell activation, proliferative disorder, psoriasis, thrombin-induced platelet aggregation, viral disease, and Waldenstrom’s Macroglobulinemia.

[0197] Proliferative disorders, include, but are not limited to a benign or malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas (Hodgkin and non-Hodgkin), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-I driven disorder, an MyD88 driven disorder, smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[0198] In some embodiments, the cancer is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), and pancreatic cancer. In other embodiments, the cancer to be treated is cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non- small cell lung cancer (NSCLC) including EGFR-mutant NSCLC, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes.

[0199] In some embodiments, the cancer is solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia Such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL), or cutaneous B-cell lymphoma.

[0200] treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, asthmatic bronchitis, exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[0201] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is heteroimmune diseases including, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0202] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. Compounds, salts, and compositions described herein are also useful in the treatment of bronchitis including, but not limited to, acute, arachidic, catarrhal, croupous, chronic or phthinoid bronchitis. Compounds, salts, and compositions described herein are also useful in the treatment of pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0203] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita (EBA), acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0204] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is a disorder having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidneydisease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0205] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is cardiovascular diseases including, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

[0206] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is a neurodegenerative disease including, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.

[0207] In some embodiments, the disorder responsive to the modulation (e.g., inhibition) of STAT6 is alopecia, aspergillus, asthma, atomic dermatitis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyposis, gastritis, inflammatory bowel disease, pemphigoid, prurigo nodularis, sinusitis, or urticaria. Dosing

[0208] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose-escalation. Routes of Administration

[0209] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0210] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. Pharmaceutical Compositions / Formulations

[0211] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0212] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventionalmanner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. Combination

[0213] Disclosed herein are methods of treating a disease or disorder associated with STAT6 using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0214] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. EXAMPLES

[0215] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.Synthesis of Example 7

[0216] To a stirred mixture of 2-chloro-N-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3- nitropyridine-4-carboxamide (6 g, 15.4mmol) and Cs2CO3 (5.03 g, 15.4 mmol) in DMF (120 mL) was added CH3I (2.19 g, 15.4 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by trituration with water to afford 4-(4-(7- chloro-3-oxo-1H-pyrazolo[3,4-c]pyridin-2-ylphenyl)-2,5-dimethyl-1,2,4-triazol-3-one (5.1 g, 92.62% yield,) as a yellow solid. LCMS (ESI, m / z): 305 [M+H]+.

[0217] A mixture of tert-butyl N-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]carbamate (5.4 g, 17.7 mmol) in HCl (4.0 M in 1,4-dioxane, 60 mL) was stirred at room temperature for 2 h. The precipitated solids were collected by filtration and washed with DCM to afford 4-(4-aminophenyl)-2,5- dimethyl-1,2,4-triazol-3-one hydrochloride (4 g, 93.67% yield) as a yellow solid. LCMS (ESI, m / z): 205 [M+H]+.

[0218] To a stirred mixture of 4-(4-aminophenyl)-2,5-dimethyl-1,2,4-triazol-3-one hydrochloride (1 g, 4.16 mmol,) and 2-chloro-3-nitropyridine-4-carboxylic acid (0.84 g, 4.16 mmol) in pyridine (10 mL) was added (([3-(dimethylamino)propyl]iminomethylidene)(ethyl)amine (1.29 g, 8.31 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 2-chloro-N-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3-nitropyridine-4- carboxamide (1.2 g, 74.29% yield) as a yellow solid. LCMS (ESI, m / z): 389 / 391 [M+H]+.

[0219] To a stirred mixture of 2-chloro-N-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3- nitropyridine-4-carboxamide (1.2 g, 3.09 mmol) and B2(OH)4(1.38 g, 15.4 mmol) in methanol (38 mL) was added aqueous NaOH (38 mL, 10 equiv) dropwise at 0°C. The resulting mixture was stirred at 40 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified byflash chromatography to afford 4-(4-(7-chloro-3-oxo-1H-pyrazolo[3,4-c]pyridin-2-ylphenyl)-2,5- dimethyl-1,2,4-triazol-3-one (750 mg, 68.11% yield) as a yellow solid. LCMS (ESI, m / z): 357 / 359 [M+H]+.

[0220] To a stirred mixture of 4-(4-(7-chloro-3-oxo-1H-pyrazolo[3,4-c]pyridin-2-ylphenyl)-2,5- dimethyl-1,2,4-triazol-3-one (40 mg, 0.112 mmol) and K2CO3 (30 mg, 0.224 mmol) in MeCN (0.5 mL) was added iodoethane (35 mg, 0.224 mmol) dropwise. The resulting mixture was stirred at room temperature for 2h. The reaction was directly purified by flash chromatography to afford 4-(4-(7-chloro- 1-ethyl-3-oxopyrazolo[3,4-c]pyridin-2-ylphenyl)-2,5-dimethyl-1,2,4-triazol-3-one (30 mg, 69.53% yield, 92%purity) as a yellow oil. LCMS (ESI, m / z): 385 / 387 [M+H]+.

[0221] A mixture of 4-(4-(7-chloro-1-ethyl-3-oxopyrazolo[3,4-c]pyridin-2-ylphenyl)-2,5-dimethyl- 1,2,4-triazol-3-one (30 mg, 0.078 mmol), Pd(dtbpf)Cl2 (10 mg, 0.016 mmol) and Et3N (39 mg, 0.390 mmol) in methanol (0.5 mL) was stirred overnight under carbon dioxide atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford methyl 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxylate (20 mg, 62.81% yield) as a yellow solid. LCMS (ESI, m / z): 409 [M+H]+.

[0222] To a stirred solution of methyl 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxylate (20 mg, 0.049 mmol) in methanol (0.4 mL) and H2O (0.1 mL) was added NaOH (4 mg, 0.098 mmol). The resulting mixture was stirred for 2h at room temperature. The reaction was acidified to pH 4 with 1M HCl. The resulting mixture was extracted with EtOAc (3x3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 395 [M+H]+.

[0223] To a stirred mixture of 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxylic acid (20 mg, 0.051 mmol) and 3-aminobenzamide (6.90 mg, 0.051 mmol) in pyridine (0.5 mL) was added (([3- (dimethylamino)propyl]iminomethylidene)(ethyl)amine (16 mg, 0.101 mmol) at room temperature. The resulting mixture was stirred for 2h at room temperature. The reaction was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford N-(3-carbamoylphenyl)-2-[4-(1,3-dimethyl- 5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxamide (8.4 mg, 32.32% yield).1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H),7.99-7.96 (m, 2H) 7.80 (d, J = 8.8 Hz, 2H), 7.69-7.64 (m, 3H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 4.08 (q, J = 6.8 Hz, 2H), 3.36 (s, 3H), 2.15 (s, 3H), 0.62 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 513 [M+H]+. Synthesis of Example 25

[0224] Example 25 was prepared using Example 7 procedures.1H NMR (400 MHz, DMSO-d6) δ11.03 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 8.46-8.44 (m, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.03-7.95 (m, 2H),7.84-7.77 (m, 2H), 7.71-7.62 (m, 3H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 3.38 (s, 3H), 3.37 (s, 3H),2.15 (s, 3H). LCMS (ESI, m / z): 499 [M+H]+. Synthesis of Example 27

[0225] To a solution of 4-bromo-2,5-dimethylisoxazol-3(2H)-one (3.90 g, 20.3 mmol) and (4-((tert- butoxycarbonyl)amino)phenyl)boronic acid (5.78 g, 24.4 mmol) in 1,4-dioxane (390 mL) and H2O (39.0 mL) were added Pd(dppf)Cl2·CH2Cl2 (1.66 g, 2.03 mmol) and K2CO3 (8.42 g, 60.9 mmol) at room temperature. The resulting mixture was degassed three times with N2, and then was stirred for 3 h at 80 °C. The mixture was allowed to cool down to room temperature, and then was concentrated under reduced pressure. The residue was dissolved in DCM, filtered, and concentrated under reduced pressure, and then was purified by flash silica gel chromatography (with EtOAc / PE) to afford tert-butyl (4-(2,5- dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)carbamate (4.60 g, 74.4% yield) as a white solid. LCMS (ESI, m / z): 305 [M+H]+.

[0226] To a stirred solution of tert-butyl (4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)carbamate (4.40 g, 14.5 mmol) and 2,6-lutidine (6.20 g, 57.8 mmol) in DCM (50.0 mL) was added TMSOTf (9.64 g, 43.4 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to afford 4-(4-aminophenyl)-2,5-dimethylisoxazol-3(2H)-one (2.93 g, 99.3% yield) as a yellow solid. LCMS (ESI, m / z): 205 [M+H]+.

[0227] A mixture of 2-chloro-3-nitroisonicotinic acid (2.86 g, 14.1 mmol) and HATU (6.70 g, 17.6 mmol) in pyridine (55.0 mL) was stirred for 10 min at room temperature, followed by the addition of 4- (4-aminophenyl)-2,5-dimethylisoxazol-3(2H)-one (2.40 g, 11.8 mmol). The resulting mixture was stirred for 1 h at room temperature, and then was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (with EtOAc / PE) to afford 2-chloro-N-(4-(2,5-dimethyl-3- oxo-2,3-dihydroisoxazol-4-yl)phenyl)-3-nitroisonicotinamide (1.71 g, 37.4% yield) as a red solid. LCMS (ESI, m / z): 389 / 391 [M+H]+.

[0228] To a stirred solution of 2-chloro-N-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)- 3-nitroisonicotinamide (800 mg, 2.06 mmol) and tetrahydroxydiborane (922 mg, 10.3 mmol) in MeOH (26.0 mL) was added a solution of NaOH (823 mg, 20.6 mmol) in MeOH (26.0 mL) dropwise at 0 °C under nitrogen atmosphere. After addition, the resulting mixture was stirred for 3 h at 40 °C. The mixture was allowed to cool down to room temperature and then was concentrated under reduced pressure to remove most of the solvent. The residue was purified directly by reverse phase flash chromatography to afford 4-(4-(7-chloro-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)-2,5-dimethylisoxazol- 3(2H)-one (366 mg, 49.8% yield) as a yellow solid. LCMS (ESI, m / z): 357 / 359 [M+H]+.

[0229] To a stirred solution of 4-(4-(7-chloro-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-c]pyridin-2- yl)phenyl)-2,5-dimethylisoxazol-3(2H)-one (366 mg, 1.03 mmol) and EtI (480 mg, 3.08 mmol) in DMF (4.00 mL) was added K2CO3(425 mg, 3.08 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (5 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with EtOAc / PE) to afford 4-(4-(7-chloro-1-ethyl-3-oxo- 1,3-dihydro-2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)-2,5-dimethylisoxazol-3(2H)-one (230 mg, 58.2% yield) as a yellow solid. LCMS (ESI, m / z): 385 / 387 [M+H]+.

[0230] To a mixture of 4-(4-(7-chloro-1-ethyl-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-c]pyridin-2- yl)phenyl)-2,5-dimethylisoxazol-3(2H)-one (260 mg, 0.68 mmol) and TEA (342 mg, 3.38 mmol) in MeOH (20.0 mL) was added Pd(dppf)Cl2·CH2Cl2(110 mg, 0.14 mmol) in a autoclave. The mixture was pressurized with carbon monoxide gas to 3 MPa, and then stirred for 3 h at 90 °C. The resulting mixture was cooled to room temperature and then was concentrated under reduced pressure. The residue was purified by silica gel chromatography (with EtOAc / PE) to afford methyl 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (120 mg, 43.5% yield) as a yellow solid. LCMS (ESI, m / z): 409 [M+H]+.

[0231] To a solution of methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3- oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (100 mg, 0.25 mmol) in MeOH (5.00 mL) and H2O (5.00 mL) was added LiOH·H2O (21 mg, 0.49 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was acidified to pH 3 with 0.5 N HCl (aq.). Theresidue was purified directly by reverse phase flash chromatography to afford 2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (80 mg, 82.8% yield) as a yellow solid. LCMS (ESI, m / z): 395 [M+H]+.

[0232] A mixture of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3- dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (30 mg, 0.08 mmol) and HATU (58 mg, 0.15 mmol) in pyridine (1.00 mL) was stirred for 10 min at room temperature. To the above mixture was added 3-aminobenzamide (16 mg, 0.11 mmol) at room temperature. After stirring for additional 1 h at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to afford N-(3-carbamoylphenyl)-2-(4-(2,5-dimethyl-3- oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxamide (16.5 mg, 42.3% yield).1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.70 (d, J = 4.8 Hz, 1H), 8.41 (t, J = 2.0 Hz, 1H), 8.13 (d, J = 4.8 Hz, 1H), 7.98 (dd, J = 8.0, 2.0 Hz, 2H), 7.83 (t, J = 8.4 Hz, 2H), 7.71 (t, J = 8.4 Hz, 2H), 7.65 (dt, J = 8.0, 1.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.49 (s, 3H), 2.49 (s, 3H), 0.60 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 513 [M+H]+. Synthesis of Example 35

[0233] To a stirred mixture of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxylic acid (160 mg, 0.41 mmol) in H2O (5.00 mL) were added conc. H2SO4 (14 µL, 0.27 mmol) and AcOH (31 µL, 0.54 mmol) at 0 °C. To the above mixture was added a solution of Br2 (130 mg, 0.81 mmol) in AcOH (1.00 mL) dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature. The reaction solution was purified directly by reverse phase flash chromatography to afford 5-bromo-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl- 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (25 mg, 13.0% yield) as a yellow solid. LCMS (ESI, m / z): 473 / 475 [M+H]+.

[0234] To a stirred mixture of 5-bromo-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1- ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (15 mg, 0.03 mmol) and 3-amino- N-methylbenzamide (6 mg, 0.04 mmol) in DMF (0.30 mL) were added NMI (10 mg, 0.13 mmol) and TCFH (18 mg, 0.06 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, and then was purified directly by reversed phase flash chromatography to afford 5-bromo-2-(4- (2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(3-(methylcarbamoyl)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (2.3 mg, 12.0% yield).1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.49-8.48 (m, 1H), 8.35-8.34 (m, 1H), 8.30 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.49 (s, 3H), 2.80 (d, J = 4.4 Hz, 3H), 2.48 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 605 / 607 [M+H]+. Synthesis of Example 43

[0235] To a stirred solution of 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine (20 g, 82.0 mmol) in THF (200 mL) was added dropwise LDA (2 M in THF, 82.0 mL, 164 mmol) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -50 °C for 40 mins. Then the resulting mixture was degassed with CO2gas, and stirred at -60 °C for 30 min under CO2atmosphere. The reaction was poured into sat. NH4Cl (aq.) at 0 °C, and then the mixture was extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 2-bromo-3- fluoro-6-(trifluoromethyl)pyridine-4-carboxylic acid (10.5 g, 44.48% yield) as an off-white solid. LCMS (ESI, m / z): 286, 288 [M-H]-.

[0236] A solution of 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxylic acid (10.5 g, 36.5 mmol) in SOCl2(100 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL) and stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure and diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedpressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 302, 304 [M+H]+.

[0237] To a stirred solution of methyl 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine-4-carboxylate (10.0 g, 33.1 mmol) and hydrazine hydrochloride (6.80 g, 99.3 mmol) in DMSO (100 mL) was added DIEA (42.8 g, 331 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 4 h. The reaction mixture was cooled to room temperature and purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 7-bromo-5- (trifluoromethyl)-1H,2H-pyrazolo[3,4-c]pyridin-3-one (5.50 g, 58.9% yield) as a white solid. LCMS (ESI, m / z): 269, 271 [M+H]+.

[0238] To a stirred solution of 7-bromo-5-(trifluoromethyl)-1H,2H-pyrazolo[3,4-c]pyridin-3-one (5.40 g, 19.1 mmol) in DMF (80 mL) was added NaH (2.29 g, 57.3 mmol, 60% dispersion in mineral oil) at 0 °C. After stirring at 0 °C for 20 mins, ethyl iodide (3.29 g, 21.0 mmol) was added and the mixture was stirred at 0 °C for another 20 mins. The reaction mixture was quenched by sat. NH4Cl (aq.) and extracted with EA (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 7-bromo-1-ethyl-5-(trifluoromethyl)-2H-pyrazolo[3,4-c]pyridin-3-one (4.20 g, 70.74% yield) as an off-white solid. LCMS (ESI, m / z): 310, 312 [M+H]+.

[0239] To a stirred mixture of 7-bromo-1-ethyl-5-(trifluoromethyl)-2H-pyrazolo[3,4-c]pyridin-3-one (3.00 g, 9.68 mmol) and TEA (4.90 g, 48.4 mmol) in methanol (100 mL) was added Pd(dppf)Cl2.CH2Cl2(1.58 g, 1.94 mmol) at room temperature. The resulting mixture was stirred at 100 °C overnight under CO atmosphere (30 atm). The resulting mixture was concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford methyl 1-ethyl-3-oxo-5-(trifluoromethyl)-2H- pyrazolo[3,4-c]pyridine-7-carboxylate (1.48 g, 52.89% yield) as a yellow solid. LCMS (ESI, m / z): 290 [M+H]+.

[0240] To a stirred solution of methyl 1-ethyl-3-oxo-5-(trifluoromethyl)-2H-pyrazolo[3,4-c]pyridine- 7-carboxylate (130 mg, 0.45 mmol) and 4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenylboronic acid (126 mg, 0.54 mmol) in THF (3 mL) were added pyridine (178 mg, 2.25 mmol) and Cu(OAc)2(163 mg, 0.90 mmol) at room temperature. The mixture was degassed three times with O2, and then was stirred at 60 °C overnight. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford methyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylate (80 mg, 37.36% yield) as a yellow solid. LCMS (ESI, m / z): 477 [M+H]+.

[0241] To a stirred solution of methyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3- oxo-5-(trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylate (80 mg, 0.17 mmol) in methanol (1.00 mL) was added a solution of NaOH (20 mg, 0.50 mmol) in water (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The mixture was acidified to pH 7 with FA. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-1-ethyl-3-oxo-5-(trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylic acid (45 mg, 57.96% yield) as a white solid. LCMS (ESI, m / z): 463 [M+H]+.

[0242] To a stirred solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylic acid (25 mg, 0.05 mmol) and 3-amino-N- methylbenzamide (12 mg, 0.08 mmol) in pyridine (1.00 mL) was added HATU (41 mg, 0.11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC. The product- containing fraction was collected and concentrated under vacuum to afford 2-[4-(2,5-dimethyl-3-oxo-1,2- oxazol-4-yl)phenyl]-1-ethyl-N-[3-(methylcarbamoyl)phenyl]-3-oxo-5-(trifluoromethyl)pyrazolo[3,4- c]pyridine-7-carboxamide (18.5 mg, 57.55% yield, 98.9% purity).1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.55 (s, 1H), 8.49 (q, J = 4.4 Hz, 1H), 8.27 (t, J = 2.0 Hz, 1H), 7.97-7.94 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.63 (dt, J = 8.0, 1.2 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 3.49 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H), 2.50 (s, 3H), 0.74 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 595 [M+H]+. Synthesis of Example 50

[0243] To a stirred solution of 2-bromo-3-fluoro-6-methylpyridine (5.00 g, 26.3 mmol) in THF (50.0 mL) was added LDA (2.0 M solution in THF, 19.7 mL, 39.5 mmol) dropwise at -50 °C under nitrogen atmosphere. After stirring for 30 min at -50 °C, the reaction was cooled to -70°C, and then was degassed with CO2. After stirring for additional 1 h at -60 °C, the reaction was slowly poured into sat. NH4Cl (aq.) at 0 °C, and then was concentrated to remove the THF. The resulting mixture was acidified to pH 2 with 1 N HCl (aq.). The precipitated solids were collected by filtration and washed with water (5x100 mL) and dried under reduced pressure to afford 2-bromo-3-fluoro-6-methylisonicotinic acid (3.00 g, 48.7% yield) as a white solid. LCMS (ESI, m / z): 234 / 236 [M+H]+.

[0244] To a stirred solution of 2-bromo-3-fluoro-6-methylisonicotinic acid (2.00 g, 8.55 mmol) in DCM (21.0 mL) and MeOH (7.00 mL) was added TMSCHN2(2.0 M solution in hexane, 12.8 mL, 25.6 mmol) dropwise at 0 °C under nitrogen atmosphere. After stirring for 1 h at 0 °C, the reaction was quenched with AcOH (1.50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (with EtOAc / PE) to afford methyl 2-bromo- 3-fluoro-6-methylisonicotinate (1.90 g, 89.6% yield) as a white solid. LCMS (ESI, m / z): 248 / 250 [M+H]+.

[0245] To a stirred solution of methyl 2-bromo-3-fluoro-6-methylisonicotinate (1.80 g, 7.26 mmol) and hydrazine monohydrochloride (1.49 g, 21.8 mmol) in DMSO (20.0 mL) was added DIEA (9.38 g, 72.6 mmol) at room temperature. After stirring for 1 h at 100 °C, the reaction was allowed to cool down to room temperature. The resulting mixture was diluted with water (100 mL), acidified to pH 3 with 1 N HCl (aq.), and then was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (with MeOH / DCM) to afford 7-bromo-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (900 mg, 54.4% yield) as a white solid. LCMS (ESI, m / z): 228 / 230 [M+H]+.

[0246] To a stirred solution of 7-bromo-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (600 mg, 2.63 mmol) in DMF (6.00 mL) was added NaH (60% dispersion in mineral oil, 210 mg, 5.26 mmol) at 0 °C. The resulting mixture was degassed three times with N2, and then was stirred for 15 min at 0 °C. To the above mixture was added EtI (410 mg, 2.63 mmol) at 0 °C. After stirring for additional 30 min at 0 °C, the reaction was poured into sat. NH4Cl (aq.) at 0 °C. The resulting mixture was acidified to pH 3with 1 N HCl (aq.), and then was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (with EtOAc / PE) to afford 7-bromo-1-ethyl-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (440 mg, 65.3% yield) as a light yellow solid. LCMS (ESI, m / z): 256 / 258 [M+H]+.

[0247] To a mixture of 7-bromo-1-ethyl-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (390 mg, 1.52 mmol) and TEA (770 mg, 7.62 mmol) in MeOH (20.0 mL) was added Pd(dppf)Cl2.cH2Cl2 (249 mg, 0.31 mmol) in an autoclave. The mixture was pressurized with carbon monoxide gas to 3 MPa, and then stirred for 24 h at 90 °C. The resulting mixture was cooled to room temperature and then was concentrated under reduced pressure. The residue was purified by silica gel chromatography (with EtOAc / PE) to afford methyl 1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxylate (190 mg, 53.0% yield) as a yellow solid. LCMS (ESI, m / z): 236 [M+H]+.

[0248] To a mixture of methyl 1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxylate (140 mg, 0.60 mmol) and (4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)boronic acid (139 mg, 0.60 mmol) in THF (5.00 mL) were added pyridine (235 mg, 2.98 mmol) and Cu(OAc)2(216 mg, 1.19 mmol) at room temperature. The resulting mixture was degassed three times with O2, and then was stirred for 16 h at 60 °C. The reaction was allowed to cool down to room temperature, and then was concentrated under reduced pressure. The residue was dissolved in DCM and filtered; the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (with EtOAc / PE) to afford methyl 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxylate (140 mg, 55.7% yield) as a yellow solid. LCMS (ESI, m / z): 423 [M+H]+.

[0249] To a solution of methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5- methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (120 mg, 0.28 mmol) in MeOH (1.50 mL) was added a solution of LiOH·H2O (24 mg, 0.57 mmol) in H2O (1.50 mL) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was acidified to pH 3 with 1 N HCl (aq.) and purified by reverse phase flash chromatography to afford 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxylic acid (100 mg, 86.2% yield) as a yellow solid. LCMS (ESI, m / z): 409 [M+H]+.

[0250] To a stirred solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5- methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (15 mg, 0.037 mmol) and 3- aminobenzamide (6 mg, 0.044 mmol) in DMF (0.50 mL) were added NMI (12 mg, 0.15 mmol) and TCFH (21 mg, 0.074 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was dissolved in DMSO. The resulting solution was purified by reverse phase flash chromatography to afford N-(3-carbamoylphenyl)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (8.8 mg, 45.5% yield).1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.36 (t, J = 2.0 Hz, 1H), 8.02-7.98 (m, 3H), 7.82-7.80 (m, 2H), 7.71-7.69 (m, 2H), 7.65 (dt, J = 8.0, 1.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.41(s, 1H), 4.04 (q, J = 7.2 Hz 2H), 3.48 (s, 3H), 2.73 (s, 3H), 2.48 (s, 3H), 0.57 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 527 [M+H]+. Synthesis of Example 51

[0251] Example 51 was prepared using Example 50 procedures and 3-amino-2-fluorobenzamide as starting material.1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.18 (td, J = 8.0, 1.6 Hz, 1H), 8.04 (s, 3H), 7.84-7.80 (m, 3H), 7.72-7.69 (m, 2H), 7.50-7.46 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 4.11 (q, J = 6.8 Hz 2H), 3.48 (s, 3H), 2.73 (s, 3H), 2.48 (s, 3H), 0.57 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 545 [M+H]+. Synthesis of Example 53

[0252] Example 53 was prepared using Example 50 procedures and 5-amino-2-fluorobenzamide as starting material.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.23 (dd, J = 6.4, 2.8 Hz, 1H), 8.01- 7.97 (m, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H), 7.74-7.69 (m, 3H), 7.33 (dd, J = 10.0, 8.8 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 3.50 (s, 3H), 2.73 (s, 3H), 2.49 (s, 3H), 0.57 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 545 [M+H]+. Synthesis of Example 54

[0253] Example 54 was prepared using Example 50 procedures and 3-(1H-imidazol-2-yl)aniline as starting material.1H NMR (400 MHz, DMSO-d6) δ 14.15 (s, 1H), 11.00 (s, 1H), 8.59 (t, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.93-7.91 (m, 1H), 7.83-7.81 (m, 2H), 7.75 (dt, J = 8.0, 1.2 Hz, 1H), 7.71-7.69 (m, 2H), 7.63-7.58 (m, 3H), 4.05 (q, J = 6.8 Hz, 1H), 3.49 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H), 0.59 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 550 [M+H]+. Synthesis of Example 55

[0254] To a stirred solution of 2,6-dichloro-3-fluoropyridine (15.0 g, 90.4 mmol) in THF (200 mL) was added n-BuLi (2.5 M in hexane, 44 mL, 110.0 mmol) dropwise at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for 1 h. Then the resulting mixture was degassed with CO2gas and stirred at -78 °C for another 2 h under CO2atmosphere. The reaction was poured into sat. NH4Cl (aq.) at0 °C, and then the mixture was extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 2,6-dichloro-3-fluoropyridine-4-carboxylic acid (11.0 g, 57.96% yield) as a yellow solid. LCMS (ESI, m / z): 208, 210 [M-H]-.

[0255] To a stirred solution of 2,6-dichloro-3-fluoropyridine-4-carboxylic acid (10.0 g, 47.6 mmol) in DCM (120 mL) and MeOH (40.0 mL) was added (Trimethylsilyl)diazomethane (2 M in hexanes, 71.0 mL, 142 mmol) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at 0 °C for 1h. The reaction was quenched with HOAc (10 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EA (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2,6-dichloro-3-fluoropyridine-4-carboxylate (10.0 g) as an off-white solid. LCMS (ESI, m / z): 224, 226 [M+H]+.

[0256] To a stirred solution of methyl 2,6-dichloro-3-fluoropyridine-4-carboxylate (10.0 g, 44.6 mmol) and hydrazine monohydrochloride (6.12 g, 89.3 mmol) in DMSO (150 mL) was added DIEA (28.9 g, 223 mmol) at room temperature. After stirring at 80 °C for 4 h, the reaction mixture was cooled down to room temperature. The reaction was quenched by 0.1 M HCl (aq.). The resulting mixture was extracted with EA (3x500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 5,7- dichloro-1H,2H-pyrazolo[3,4-c]pyridin-3-one (8.50 g, 93.33% yield) as an off-white solid. LCMS (ESI, m / z): 204, 206 [M+H]+.

[0257] To a solution of 5,7-dichloro-1H,2H-pyrazolo[3,4-c]pyridin-3-one (8.50 g, 41.7 mmol,) in DMF (250 mL) was added NaH (5.00 g, 125 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 20 mins. Then iodoethane (7.15 g, 45.8 mmol) was added and the mixture was stirred at 0°C for additional 20 mins. The reaction mixture was quenched by sat. NH4Cl (aq.) and extracted with EA (3x200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with toluene (30 mL) to afford 5,7-dichloro-1-ethyl-2H-pyrazolo[3,4- c]pyridin-3-one (7.00 g, 72.40% yield) as an off-white solid. LCMS (ESI, m / z): 232, 234 [M+H]+.

[0258] To a stirred solution of 5,7-dichloro-1-ethyl-2H-pyrazolo[3,4-c]pyridin-3-one (6.00 g, 25.7 mmol) and TEA (13.1 g, 129 mmol) in MeOH(160 mL) was added Pd(dppf)Cl2.CH2Cl2(4.22 g, 5.17 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 3 days under CO atmosphere (15 atm). The resulting mixture was cooled down to room temperature and then was concentrated under reduced pressure. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford methyl 5-chloro-1-ethyl-3-oxo- 2H-pyrazolo[3,4-c]pyridine-7-carboxylate (4.00 g, 60.5% yield) as an off-white solid. LCMS (ESI, m / z): 256 [M+H]+.

[0259] To a stirred solution of methyl 5-chloro-1-ethyl-3-oxo-2H-pyrazolo[3,4-c]pyridine-7- carboxylate (100 mg, 0.39 mmol) and 4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenylboronic acid (137 mg, 0.59 mmol) in THF (5.00 mL) were added pyridine (155 mg, 1.95 mmol) and Cu(OAc)2(142 mg, 0.78 mmol) at room temperature. The mixture was degassed three times with O2, and then was stirred at 60 °C overnight. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 5-chloro-2-[4-(2,5- dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxylate (100 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 443 [M+H]+.

[0260] To a stirred solution of methyl 5-chloro-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1- ethyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxylate (100 mg, crude) in methanol (1.00 mL) was added a solution of NaOH (18 mg, 0.46 mmol) in water (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 7 with FA. The residue was purified via reverse phase chromatography. The product-containing fraction was collected and concentrated under reduced pressure to afford 5-chloro-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-1-ethyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxylic acid (40 mg, 41.31 % yield) as a white solid. LCMS (ESI, m / z): 429 [M+H]+.

[0261] To a stirred mixture of 5-chloro-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxylic acid (20 mg, 0.05 mmol) and 3-amino-N-methylbenzamide (11 mg, 0.07 mmol) in pyridine (1.00 mL) was added HATU (35 mg, 0.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure, and then was diluted with water and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC. The product-containing fraction was collected and concentrated under reduced pressure to afford 5-chloro-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-1-ethyl-N-[3-(methylcarbamoyl)phenyl]-3-oxopyrazolo[3,4-c]pyridine-7-carboxamide (14.5 mg, 55.42% yield, 99.7%purity).1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.47 (q, J = 4.4 Hz, 3H), 8.31 (t, J = 2.0 Hz, 1H), 8.25 (s, 1H), 7.98-7.95 (m, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.61 (dt, J = 8.0, 1.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.48 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H), 2.49 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 561 [M+H]+. Synthesis of Example 56

[0262] Example 56 was prepared using example 43 procedure and 5-amino-2-fluorobenzamide as starting material.1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.55 (s, 1H), 8.14 (dd, J = 6.4, 2.8 Hz, 1H), 7.96-7.92 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.35 (dd, J = 10.0, 8.8 Hz, 1H), 3.99 (q, J = 7.2 Hz, 2H), 3.49 (s, 3H), 2.50 (s, 3H), 0.73 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 599 [M+H]+. Synthesis of Example 57

[0263] Example 57 was prepared using example 43 procedure and 5-amino-2-fluorobenzamide as starting material.1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.54 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, J = 8.0, 2.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.69-7.67 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.50 (s, 3H), 2.50 (s, 3H), 0.74 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 581 [M+H]+. Synthesis of Example 58

[0264] To a stirred mixture of methyl 1-ethyl-3-oxo-5-(trifluoromethyl)-2H-pyrazolo[3,4-c]pyridine- 7-carboxylate (500 mg, 1.73 mmol) and 4-bromophenylboric acid (521 mg, 2.59 mmol) in THF (20.0 mL) were added pyridine (684 mg, 8.65 mmol) and Cu(OAc)2(628 mg, 3.46 mmol) at room temperature. The mixture was degassed three times with O2, and then was stirred at 60 °C for 3 h. The reaction mixture was allowed to cool down to room temperature, and then was poured into water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-(4-bromophenyl)-1-ethyl-3-oxo-5-(trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylate (600 mg, crude). The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 444, 446 [M+H]+.

[0265] To a stirred mixture of methyl 2-(4-bromophenyl)-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylate (600 mg, crude) in MeOH (10.0 mL) was added a solution of NaOH (216 mg, 5.40 mmol) in H2O (10.0 mL) at room temperature. After stirring at room temperature for 4 h, the mixture was acidified to pH 5 with 1 M HCl (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by trituration with ACN (10 mL) to afford 2-(4-bromophenyl)-1-ethyl-3-oxo-5-(trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylic acid (400 mg, 68.84% yield) as a yellow solid. LCMS (ESI, m / z): 430, 432 [M+H]+.

[0266] To a stirred solution of 2-(4-bromophenyl)-1-ethyl-3-oxo-5-(trifluoromethyl)pyrazolo[3,4- c]pyridine-7-carboxylic acid (200 mg, 0.47 mmol) and 5-amino-2-fluorobenzamide (86 mg, 0.56 mmol) in DMF (5.00 mL) were added 1-methyl-1H-imidazole (153 mg, 1.86 mmol) and TCFH (261 mg, 0.93 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was poured into water (20.0 mL) at room temperature. The precipitated solids were collected by filtration and washed with ACN to afford 2-(4-bromophenyl)-N-(3-carbamoyl-4-fluorophenyl)-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxamide (180 mg, 68.37% yield) as a yellow solid. LCMS (ESI, m / z): 566, 568 [M+H]+.

[0267] To a stirred mixture of 2-(4-bromophenyl)-N-(3-carbamoyl-4-fluorophenyl)-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxamide (150 mg, 0.27 mmol) and bis(pinacolato)diboron (81 mg, 0.32 mmol) in dioxane (5.00 mL) were added AcOK (78 mg, 0.80 mmol) and Pd(dppf)Cl2.CH2Cl2(43 mg, 0.05 mmol) at room temperature. The mixture was degassed three times with N2, and then was stirred for 4 h at 100 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was used directly in the next step without further purification. LCMS (ESI, m / z): 614 [M+H]+.

[0268] To the mixture of step 4 were added 4-bromo-2-methyl-3-oxo-1,2-oxazole-5-carbonitrile (74 mg, 0.37 mmol), K2CO3(84 mg, 0.61 mmol), H2O(1.00 mL) and Pd(dppf)Cl2(40 mg, 0.05 mmol) at room temperature. The mixture was degassed three times with N2, and then was stirred for 3 h at 100 °C. The mixture was acidified to pH 7 with FA and purified by reverse phase chromatography to afford crude product (100 mg). The crude product was repurified by Prep-HPLC to afford N-(3-carbamoyl-4- fluorophenyl)-2-[4-(5-cyano-2-methyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxamide (32.6 mg, 21.87% yield, 90.5% purity).1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.57 (s, 1H), 8.20-8.11 (m, 3H), 7.96-7.92 (m, 1H), 7.87- 7.82 (m, 2H), 7.76-7.72 (m, 2H), 7.36 (dd, J = 10.0, 9.2 Hz, 1H), 4.02 (q, J = 6.8 Hz, 2H), 3.65 (s, 3H), 0.72 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 610 [M+H]+. Synthesis of Example 59

[0269] Example 59 was prepared using example 58 procedures.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.57 (s, 1H), 8.49 (q, J = 4.4 Hz, 1H), 8.28 (t, J = 2.0 Hz, 1H), 8.16-8.10 (m, 2H), 7.99- 7.94 (m, 1H), 7.87-7.81 (m, 2H), 7.67-7.62 (m, 1H), 7.51 (t, J = 8.0 Hz, 1H), 4.02 (q, J = 6.8 Hz, 2H), 3.66 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H), 0.73 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+. Synthesis of Example 60

[0270] Example 60 was prepared using example 55 procedures.1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.25 (s, 1H), 8.19 (dd, J = 6.4, 2.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.83-7.81 (m, 2H), 7.73- 7.67 (m, 4H), 7.34 (dd, J = 10.0, 9.2 Hz, 1H), 3.96 (q, J = 6.8 Hz, 2H), 3.48 (s, 3H), 2.07 (s, 3H), 0.64 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 565 [M+H]+. Synthesis of Example 62

[0271] To a stirred mixture of 3-[(tert-butoxycarbonyl)amino]benzoic acid (1.00 g, 4.22 mmol) and 1- methylpyrazol-3-amine (410 mg, 4.22 mmol) in ACN (10.0 mL) were added NMI (1.38 g, 16.8 mmol) and TCFH (2.37 g, 8.43 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1h and concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford tert-butyl (3-((1-methyl-1H-pyrazol-3- yl)carbamoyl)phenyl)carbamate (1.00 g, 74.9% yield) as a yellow solid. LCMS (ESI, m / z): 317 [M+H]+.

[0272] A solution of tert-butyl (3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamate (1.00 g, 3.16 mmol) and 4M HCl in dioxane (5.00 mL, 20.0 mmol) in DCM (10.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford 3-amino-N-(1- methyl-1H-pyrazol-3-yl)benzamide HCl salt (800 mg crude). The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 217 [M+H]+.

[0273] To a stirred mixture of 3-amino-N-(1-methylpyrazol-3-yl)benzamide HCl salt (8 mg, 0.03 mmol) and 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-5-methyl-3-oxopyrazolo[3,4- c]pyridine-7-carboxylic acid (15 mg, 0.04 mmol) in DMF (0.50 mL) were added TCFH (21 mg, 0.06 mmol) and NMI (9 mg, 0.11 mmol) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was purified by Prep-HPLC to afford 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-1-ethyl-5-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-3-oxopyrazolo[3,4- c]pyridine-7-carboxamide (5.5 mg, 24.31% yield).1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.83 (s, 1H), 8.46 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.82-7.78 (m, 3H), 7.71 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 4.04 (q, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.48 (s, 3H), 2.74 (s, 3H), 2.49 (s, 3H), 0.58 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 607 [M+H]+. Synthesis of Example 63

[0274] To a solution of methyl 5-chloro-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7- carboxylate (330 mg, 1.29 mmol) and (4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)boronic acid (602 mg, 2.58 mmol) in THF (10.0 mL) were added Py (511 mg, 6.46 mmol) and Cu(OAc)2(469 mg, 2.58 mmol) at room temperature. The resulting mixture was degassed three times with O2, and then was stirred for 16 h at 60 °C. The reaction was allowed to cool down to room temperature, and then was concentrated under reduced pressure. The residue was dissolved in DCM and filtered; the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (with EtOAc / PE) to afford methyl 5-chloro-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (200 mg, 35.0% yield) as a yellow solid. LCMS (ESI, m / z): 443 [M+H]+.

[0275] To a solution of methyl 5-chloro-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)- 1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (160 mg, 0.36 mmol) and (tributylstannyl)methanol (348 mg, 1.08 mmol) in DMF (3.00 mL) was added Pd(PPh3)4(42 mg, 36.1 μmol) at room temperature. The resulting mixture was degassed three times with N2, and then was stirred for 1 h at 100 °C. The reaction was allowed to cool to room temperature, and then was purified by reverse phase flash chromatography to afford methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-1-ethyl-5-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (83 mg, 52.40% yield) as a yellow solid. LCMS (ESI, m / z): 439 [M+H]+.

[0276] To a stirred solution of methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1- ethyl-5-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (73 mg, 0.17 mmol) in DCM (3.00 mL) was added Dess-Martin periodinane (141 mg, 0.33 mmol) at roomtemperature. After stirring for 2 h at room temperature, the resulting mixture was diluted with water (5 mL), and then was extracted with DCM (3 x 5 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 437 [M+H]+.

[0277] To a stirred solution of methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1- ethyl-5-(hydroxymethyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (73 mg, 0.17 mmol) in DCM (0.50 mL) was added DAST (135 mg, 0.84 mmol) at room temperature. After stirring for 16 h at room temperature, the resulting mixture was added to water at 0 °C. The resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (with EtOAc / PE) to afford methyl 5-(difluoromethyl)-2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (60 mg, 78.25% yield) as a yellow solid. LCMS (ESI, m / z): 459 [M+H]+.

[0278] To a solution of methyl 5-(difluoromethyl)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (60 mg, 0.13 mmol) in MeOH (1.00 mL) was added a solution of LiOH.H2O (11 mg, 0.26 mmol) in H2O (1.00 mL) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was acidified to pH 3 with 1 N HCl (aq.), and then was purified by reverse phase flash chromatography to afford 5-(difluoromethyl)- 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4- c]pyridine-7-carboxylic acid (50 mg, 86.0% yield) as a yellow solid.

[0279] LCMS (ESI, m / z): 445 [M+H]+. To a solution of 5-(difluoromethyl)-2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (25 mg, 56.3 μmol) and 5-amino-2-fluorobenzamide (10 mg, 67.6 μmol) in DMF (0.50 mL) were added NMI (18 mg, 0.22 mmol) and TCFH (32 mg, 0.11 mmol) at room temperature. After stirring for 1 h at room temperature, the resulting mixture was dissolved in DMSO and purified by reverse phase flash chromatography to afford N-(3-carbamoyl-4-fluorophenyl)-5-(difluoromethyl)-2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (27.1 mg, 83.0% yield).1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.33 (s, 1H), 8.17 (dd, J = 6.4, 2.8 Hz, 1H), 7.98-7.94 (m, 1H), 7.84-7.82 (m, 2H), 7.76-7.68 (m, 4H), 7.35 (t, J = 9.6 Hz, 1H), 7.19 (t, J = 54.8 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.49 (s, 3H), 2.49 (s, 3H), 0.68 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 581 [M+H]+. Synthesis of Example 64

[0280] Example 64 was prepared using example 63 procedures.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.33-8.32 (m, 2H), 8.02-7.97 (m, 2H), 7.85-7.83 (m, 2H), 7.70-7.67 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.21 (t, J = 54.8 Hz, 1H), 4.05 (q, J = 6.8 Hz, 2H), 3.49 (s, 3H), 2.49 (s, 3H), 0.69 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 563 [M+H]+. Synthesis of Example 66

[0281] Example 66 was prepared using example 55 procedures.1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.28 (s, 1H), 8.03 (t, J = 7.2 Hz, 1H), 7.84-7.82 (m, 3H), 7.69-7.67 (m, 3H), 7.52-7.49 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.48 (s, 3H), 2.49 (s, 3H), 0.66 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 565 / 567 [M+H]+. Synthesis of example 75

[0282] To a solution of 2,4-dichloro-6-methylpyridine-3-carbaldehyde (1.0 g, 5.26 mmol) and tert- butanesulfinamide (956 mg, 7.89 mmol) in THF (20 mL) was added tetrakis(propan-2-yloxy)titanium (4.5 g, 15.79 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 16 h under nitrogen atmosphere. LCMS showed the reaction was completed. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (4:1) to give N-[(1E)-(2,4-dichloro-6- methylpyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide (1.2 g, 77.77% yield, 90%purity) as an off-white solid. LCMS (ESI, m / z): 293, 295 [M+H]+.

[0283] To a solution of N-[(1E)-(2,4-dichloro-6-methylpyridin-3-yl)methylidene]-2-methylpropane-2- sulfinamide (1.0 g, 3.44 mmol) in THF (30 mL) was added ethylmagnesium bromide(1.0 M in THF)(20.4 mL). The resulting mixture was stirred for 2h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic extracts were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:1) to give N-[1-(2,4-dichloro- 6-methylpyridin-3-yl)propyl]-2-methylpropane-2-sulfinamide (1000 mg, 90.70% yield, 80%purity) as a yellow oil. LCMS (ESI, m / z): 323, 325 [M+H]+.

[0284] To a solution of N-[1-(2,4-dichloro-6-methylpyridin-3-yl)propyl]-2-methylpropane-2- sulfinamide (1.0 g, 3.09 mmol) in dioxane (10 mL) was added HCl in 1,4-dioxane (4.0 M, 0.5 mL). The resulting mixture was stirred for 1h under a nitrogen atmosphere. The resulting solution was concentrated under reduce pressure to give 1-(2,4-dichloro-6-methylpyridin-3-yl)propan-1-amine (600 mg) as a yellow oil. LCMS (ESI, m / z): 219, 221 [M+H]+.

[0285] To a solution of 1-(2,4-dichloro-6-methylpyridin-3-yl)propan-1-amine (600 mg, 2.74 mmol) in EtOH (10 mL) was added Et3N (831 mg, 8.21 mmol) and Pd(dppf)Cl2(223 mg, 0.27 mmol) in a pressure tank. The reaction mixture was stirred at 140 °C under carbon monoxide (20 atm) for 48h. LCMS showed the reaction was completed. The resulting solution was quenched with water (200 mL) and extracted with ethyl acetate (3x200 mL). The combined organic extracts were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The resulting mixture was directly purified by reverse flash chromatography to give ethyl 3-ethyl-6-methyl-1-oxo- 2H,3H-pyrrolo[3,4-c]pyridine-4-carboxylate (80 mg, 11.77% yield, 80%purity) as a yellow oil. LCMS (ESI, m / z): 249 [M+H]+.

[0286] To a solution of ethyl 3-ethyl-6-methyl-1-oxo-2H,3H-pyrrolo[3,4-c]pyridine-4-carboxylate (65 mg, 0.26 mmol) and 4-(4-bromophenyl)-2,5-dimethyl-1,2-oxazol-3-one (140 mg, 0.52 mmol) in dioxane (5 mL) was added Pd2(dba)3(27 mg, 0.03 mmol) RuPhos (24 mg, 0.05 mmol) and K2CO3(108 mg, 0.79 mmol). The resulting mixture was stirred at 90°C for 16h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was quenched with water (40 mL) and extracted with ethyl acetate (3x40 mL). The combined organic extracts were washed with brine (2x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by reverse flash chromatography to give ethyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6- methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (50 mg, 43.86% yield, 90%purity) as a yellow solid. LCMS (ESI, m / z): 422 [M+H]+.

[0287] To a solution of ethyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (50 mg, 0.12 mmol) in methanol (4 mL) and water (1 mL) was added NaOH (9 mg, 0.23 mmol). The resulting mixture was stirred for 2 h at 50°C under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was directly purified by reverse flash chromatography give 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl- 1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (40 mg, 85.51% yield, 90%purity) as a yellow solid. LCMS (ESI, m / z): 408 [M+H]+.

[0288] To a solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo- 3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (30 mg, 0.07 mmol) and 5-amino-2-fluorobenzamide (15 mg, 0.10 mmol) in DMF (3 mL) was added TCFH (41 mg, 0.15 mmol) and 1-methyl-1H-imidazole (36 mg, 0.44 mmol). The resulting mixture was stirred for 2h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was directly purified by reverse flash chromatography to give N-(3-carbamoyl-4-fluorophenyl)-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6- methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (30 mg, 74.96% yield, 99.8%purity) as a yellow solid. LCMS (ESI, m / z): 544 [M+H]+.

[0289] The racemate (30 mg) was separated by chiral-HPLC to afford rel-(3R)-N-(3-carbamoyl-4- fluorophenyl)-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxamide (9.6 mg, 32.00% yield, the first eluting peak). The first peak was arbitrarily assigned as R-isomer.1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.29 (dd, J = 6.4, 2.8 Hz, 1H), 8.05- 8.01 (m, 1H), 7.96 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.73-7.71 (m, 4H), 7.33 (dd, J = 10.0, 8.8 Hz, 1H), 6.16 (s, 1H), 3.48 (s, 3H), 2.79 (s, 3H), 2.47 (s, 3H), 2.45-2.42 (m, 1H),1.95-1.84 (m, 1H), 0.22 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 544 [M+H]+. Synthesis of example 77

[0290] To a stirred solution of 2-fluoro-3-nitrobenzaldehyde (1.00 g, 5.91 mmol) in i-PrOH (5.00 mL) and H2O (5.00 mL) were added NH4OAc (4.10 g, 53.2 mmol) and aqueous oxalaldehyde (40%, 7.72 g, 53.2 mmol) at room temperature. After stirring for 16 h at room temperature, the resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with EtOAc / PE) to afford 2-(2-fluoro-3-nitrophenyl)-1H- imidazole (130 mg, 10.6% yield) as a yellow solid. LCMS (ESI, m / z): 208 [M+H]+.

[0291] To a stirred solution of 2-(2-fluoro-3-nitrophenyl)-1H-imidazole (130 mg, 0.63 mmol) in MeOH (5.00 mL) was added Pd / C (13 mg, 10% w / w) at room temperature. The reaction mixture was degassed three times with H2and stirred for 16 h at room temperature under H2atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was dissolved in ACN and H2O, and then was lyophilized to afford 2-fluoro-3-(1H-imidazol-2-yl)aniline (100 mg, crude) as a yellow solid, which was used in the next step directly without further purification.

[0292] To a solution of 2-fluoro-3-(1H-imidazol-2-yl)aniline (21 mg, 0.12 mmol) and 2-(4-(2,5- dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4- c]pyridine-7-carboxylic acid (40 mg, 98 μmol) in DMF (0.50 mL) were added NMI (32 mg, 0.39 mmol) and TCFH (55 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature and then was dissolved in DMSO. The resulting solution was purified directly by prep- HPLC to afford 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(2-fluoro-3-(1H- imidazol-2-yl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (34.9 mg, 62.8% yield).1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 10.77 (s, 1H), 8.10-8.05 (m, 2H), 7.88- 7.81 (m, 3H), 7.73-7.71 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.29 (dd, J = 2.0, 1.2 Hz,1H), 7.13 (d, J = 1.2 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 3.49 (s, 3H), 2.74 (s, 3H), 2.49 (s, 3H), 0.59 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 568 [M+H]+. Synthesis of Example 78

[0293] To a stirred solution of isoxazol-3-amine (3 g, 35.7 mmol) and 3-((tert- butoxycarbonyl)amino)benzoic acid (8.47 g, 35.7 mmol) in ACN (30 mL) were added and NMI (5.86 g, 71.4 mmol) and TCFH (20 g, 71.4 mmol) in portions at room temperature. After stirring for 16 h at room temperature, the resulting mixture was diluted with H2O (100 mL) and extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (with EtOAc / PE) to afford tert-butyl (3-(isoxazol-3- ylcarbamoyl)phenyl)carbamate (8.5 g, 78.5% yield) as a yellow solid. LCMS (ESI, m / z): 304 [M+H]+.

[0294] To a stirred solution of tert-butyl (3-(isoxazol-3-ylcarbamoyl)phenyl)carbamate (8 g, 26.4 mmol) in DCM (40 mL) was added 4 M HCl solution in 1,4-dioxane (40 mL) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford 3-amino-N-(isoxazol-3-yl)benzamide HCl salt (6 g, crude) as a white solid, which was used in the next step directly without further purification. LCMS (ESI, m / z): 204 [M+H]+.

[0295] To a mixture of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl- 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (50 mg, 0.12 mmol) and 3-amino-N- (isoxazol-3-yl)benzamide HCl salt (29 mg, 0.12 mmol) in Py (2 mL) was added HATU (70 mg, 0.18 mmol) at room temperature. After stirring for 2 h at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-HPLC to afford 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(3-(isoxazol-3- ylcarbamoyl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (19.5 mg, 28.3% yield).1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.00 (s, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.52 (t, J = 2.0 Hz, 1H), 8.12-8.09 (m, 1H), 8.00 (s, 1H), 7.83-7.80 (m, 3H), 7.72-7.69 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 4.04 (q, J = 6.8 Hz, 2H), 3.48 (s, 3H), 2.74 (s, 3H), 2.49 (s, 3H), 0.58 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 594 [M+H]+. Synthesis of Example 80

[0296] To a stirred solution of 2-fluoro-5-nitrobenzoic acid (5 g, 27 mmol) and 1-methy-1H-pyrazol- 3-amine (3.14 g, 32 mmol) in MeCN (50 mL) were added NMI (8.86 g, 108 mmol) and TCFH (15.1 g, 54 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-5- nitrobenzamide (5.10 g, crude). The crude product was used in the next step directly without further purification.

[0297] To a stirred solution of 2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-5-nitrobenzamide (5.1 g, 19.3 mmol) in MeOH (51 mL) was added Pd / C (5% w / w, 2.50 g) at room temperature. The mixture was degassed three times with H2, and then was stirred for 4 h at room temperature. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to offered 5-amino-2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide (4.32 g, crude). LCMS (ESI, m / z): 235 [M+H]+.

[0298] To a stirred solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5- methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (50 mg, 0.12 mmol) and 5-amino-2-fluoro-N-(1-methy-1H-lpyrazol-3-yl)benzamide (33 mg, 0.14 mmol) in DMF (1 mL) was added NMI (39 mg, 0.48 mmol) and TCFH (67 mg, 0.196 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by Prep-HPLC. The product-containing fraction was collected and concentrated under reduced pressure to afford 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(4-fluoro-3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)-5- methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (38.8 mg, 63.4% yield, 99.9%purity ).1NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.79 (s, 1H), 8.22 (dd, J = 6.4, 2.8 Hz, 1H), 8.03-7.99 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.37 (t, J = 9.2 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.49 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H), 0.57 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 625 [M+H]+. Synthesis of Example 81

[0299] To a stirred solution of 2-fluoro-3-nitrobenzoic acid (5 g, 27.0 mmol) and 1-methy-1H- pyrazol-3-amine (3.14 g, 32.4 mmol) in MeCN (50 mL) were added NMI (8.86 g, 108 mmol) and TCFH (15.1 g, 54.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-3- nitrobenzamide (6.0 g, crude). The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 264.95 [M+H]+.

[0300] To a stirred solution of 2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-3-nitrobenzamide (6.10 g, 19.3 mmol) in MeOH (51.0 mL) was added Pd / C (5% w / w, 3.05 g) at room temperature. The mixture was degassed three times with H2, and then was stirred for 4 h at room temperature. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to offer 3-amino-2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide (5.13 g, crude). The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 235.05 [M+H]+.

[0301] To a stirred solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5- methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (50 mg, 0.12 mmol) and 3- amino-2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide (33 mg, 0.14 mmol) in DMF (1.00 mL) wereadded NMI (39 mg, 0.48 mmol) and TCFH (67 mg, 0.196 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by Prep-HPLC. The product- containing fraction was collected and concentrated under reduced pressure to afford 2-(4-(2,5-dimethyl- 3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(2-fluoro-3-((1-methyl-1H-pyrazol-3- yl)carbamoyl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (29.1 mg, 47.6% yield, 99.8%purity)).1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.74 (s, 1H), 8.22 (td, J = 7.6, 2.0 Hz, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.48-7.43 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.49 (s, 3H), 2.74 (s, 3H), 2.49 (s, 3H), 0.59 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 625 [M+H]+. Synthesis of Example 86

[0302] To a solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo- 3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (50 mg, 0.123 mmol), 3-aminobenzamide (33 mg, 0.246 mmol) and 1-methyl-1H-imidazole (30 mg, 0.369 mmol) in DMF (2 mL) was added TCFH (51 mg, 0.184 mmol). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was purified directly by reverse flash chromatography to give N-(3- carbamoylphenyl)-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxamide (45 mg, 76.7% yield) as an off-white solid. LCMS (ESI, m / z): 526 [M+H]+.

[0303] The racemate (45 mg) was separated by chiral-HPLC to afford (3R)-N-(3-carbamoylphenyl)-2- [4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4- carboxamide (the first eluting peak, 20.9 mg, 46.4% yield).1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.0, 2.4 Hz, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.41 (s, 1H), 6.17 (s, 1H), 3.48 (s, 3H), 2.79 (s, 3H), 2.51-2.48 (m, 1H), 2.47 (s, 3H), 1.93-1.86 (m, 1H), 0.22 (t, J = 7.6 Hz, 3H). LCMS (ESI, m / z): 526 [M+H]+. Synthesis of Example 87

[0304] To a solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo- 3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (45 mg, 0.110 mmol), 3-amino-N-(1-methylpyrazol-3- yl)benzamide (35 mg, 0.165 mmol) and 1-methyl-1H-imidazole (27 mg, 0.330 mmol) in DMF (3 mL) was added TCFH (47 mg, 0.165 mmol). The resulting mixture was stirred at room temperature for 2h under a nitrogen atmosphere. The resulting mixture was purified directly by reverse flash chromatography to give 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3-[(1- methylpyrazol-3-yl)carbamoyl]phenyl}-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (35 mg, 52.31% yield) as an off-white solid. LCMS (ESI, m / z): 606 [M+H]+.

[0305] The racemate (35 mg) was separated by chiral-HPLC to afford (3R)-2-[4-(2,5-dimethyl-3-oxo- 1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl] phenyl}-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxamide. The first and second eluting peaks were obtained. Structures were arbitrarily assigned.1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.82 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.11-8.08 (m, 1H), 7.97 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79 (dt, J = 8.0, 1.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.17 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 2.81 (s, 3H), 2.51-2.48 (m, 1H), 2.47 (s, 3H), 1.93-1.87 (m, 1H), 0.22 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+. Synthesis of Example 92

[0306] To a solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl- 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (40 mg, 0.09 mmol) and DIEA (64 mg, 0.49 mmol) in DMF (1 mL) was added HATU (56 mg, 0.14 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 10 minutes. Then to the above resulting mixture was added 3-amino-N-(1-methyl-1H-imidazol-4-yl)benzamide (43 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was purified by Prep-HPLC. The pure fractions were combined and concentrated under vacuum to remove organic solvents. The residual aqueous solution was lyophilized overnight to afford 2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-5-methyl-N-(3-((1-methyl-1H-imidazol-4- yl)carbamoyl)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (23.7 mg, 39.8%yield).1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.78 (s, 1H), 8.46 (s, 1H), 8.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.99 (s, 1H), 7.82-7.72 (m, 3H), 7.71 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 4.05 (q, J = 6.8 Hz, 2H), 3.68 (s, 3H), 3.48 (s, 3H), 2.74 (s, 3H), 2.48 (s, 3H), 0.58 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 607 [M+H]+. Synthesis of Example 93

[0307] To a stirred solution of 5-chloro-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1- ethyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (70 mg, 0.16 mmol) and 5-amino- 2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide (45 mg, 0.19 mmol) in ACN (1 mL) were added NMI (52 mg, 0.64 mmol) and TCFH (90 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by Prep-HPLC. The product-containing fraction was collected and concentrated under reduced pressure to afford 5-chloro-2-(4-(2,5-dimethyl-3- oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-ethyl-N-(4-fluoro-3-((1-methyl-1H-pyrazol-3- yl)carbamoyl)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (29.6 mg, 39.3% yield, 99.6%purity)).1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.80 (s, 1H), 8.25 (s, 1H), 8.17 (dd, J = 6.4, 2.8 Hz,1H), 7.98-7.94 (m, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 3.97 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.49 (s, 3H), 2.48 (s, 3H), 0.65 (t, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 645, 647 [M+H]+. Synthesis of Example 97a and 97b

[0308] To a solution of ethyl 3-ethyl-6-methyl-1-oxo-2H,3H-pyrrolo[3,4-c]pyridine-4-carboxylate (200 mg, 0.80 mmol), 4-(4-bromophenyl)-2,5-dimethyl-1,2,4-triazol-3-one (432 mg, 1.61 mmol), RuPhos (75 mg, 0.16 mmol) and K2CO3(334 mg, 2.42 mmol) in dioxane (5 mL) was added Pd2(dba)3(74 mg, 0.08 mmol). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The resulting solution was directly purified by flash chromatography to give ethyl 2-[4-(1,3-dimethyl-5- oxo-1,2,4-triazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (150 mg, 42% yield) as a white solid. LCMS (ESI, m / z): 436 [M+H]+.

[0309] To a solution of ethyl 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3-ethyl-6-methyl-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (140 mg, 0.32 mmol) in methanol (4 mL) and H2O (0.8 mL) was added NaOH (26 mg, 0.64 mmol). The resulting mixture was stirred at 50 °C for 2 h. The resulting solution was directly purified by flash chromatography to give 2-[4-(1,3-dimethyl-5-oxo-1,2,4- triazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 76% yield) as a white solid. LCMS (ESI, m / z): 408 [M+H]+.

[0310] To a solution of 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo- 3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 0.24 mmol), 3-amino-N-(1-methylpyrazol-3- yl)benzamide (106 mg, 0.48 mmol) in DMF (2 mL) were added TCFH (138 mg, 0.48 mmol) and 1- methyl-1H-imidazole (60 mg, 0.72 mmol). The resulting solution was stirred for 2 h at room temperature. L The resulting solution was directly purified by flash chromatography to give 2-[4-(1,3-dimethyl-5-oxo- 1,2,4-triazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxamide (90 mg, 60% yield) as a white solid. LCMS (ESI, m / z): 606 [M+H]+.

[0311] The racemate of 2-[4-(1,3-dimethyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3- [(1-methylpyrazol-3-yl)carbamoyl]phenyl}-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (90 mg) was resolved by prep-chiral-HPLC to obtain first eluting peak, 33.3 mg, 37% and the second eluting peak, 30 mg, 33%. Structures were arbitrarily assigned.

[0312] Peak-11H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.81 (s, 1H), 8.51 (t, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.0, 2.4 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.22 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.36 (s, 3H), 2.81 (s, 3H), 2.53-2.52 (m, 1H), 2.08 (s, 3H), 1.96-1.89 (m, 1H), 0.25 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+.

[0313] Peak-21H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.82 (s, 1H), 8.51 (t, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.0, 2.4 Hz, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.22 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.36 (s, 3H), 2.80 (s, 3H), 2.53-2.52 (m, 1H), 2.13 (s, 3H), 1.96-1.89 (m, 1H), 0.24 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+.Synthesis of Example 99

[0314] To a solution of 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (10.0 g, 52.4 mmol) and tert-butanesulfinamide (6.3 g, 52.4 mmol) in THF (100 mL) was added titanium ion tetrakis(ethanolate) (17.9 g, 78.5 mmol). The resulting mixture was stirred at 60 °C overnight under a nitrogen atmosphere. The resulting mixture was directly purified by column chromatography with petroleum ether / ethyl acetate (3:1) to give N-[(1E)-(4,6-dichloro-2-methylpyrimidin-5-yl)methylidene]-2-methylpropane-2- sulfinamide (12 g, 77.91% yield) as a yellow solid. LCMS (ESI, m / z): 294, 296, 298 [M+H]+.

[0315] To a solution of N-[(1E)-(4,6-dichloro-2-methylpyrimidin-5-yl)methylidene]-2-methylpropane- 2-sulfinamide (12 g, 40.8 mmol) in THF (125 mL) was added dropwise ethyl magnesium bromide (1M in THF, 82 mL, 81.6 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The resulting mixture was quenched with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (3x100 mL). The combined organic layers were with washed brine (2x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate (1:3) to give N-[1-(4,6-dichloro-2-methylpyrimidin-5-yl)propyl]-2-methylpropane-2- sulfinamide (4.9 g, 37.05% yield) as a yellow solid. LCMS (ESI, m / z): 324, 326, 328 [M+H]+.

[0316] To a solution of N-[1-(4,6-dichloro-2-methylpyrimidin-5-yl)propyl]-2-methylpropane-2- sulfinamide (4.5 g, 13.89 mmol) in dioxane (25 mL) was added dropwise HCl (4.0 M in 1,4-dioxane, 5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give crude 1- (4,6-dichloro-2-methylpyrimidin-5-yl)propan-1-amine (3.5 g, 98.18% yield) as a red solid. The crude product was used directly for the next step without further purification. LCMS (ESI, m / z): 220, 222, 224 [M+H]+.

[0317] To a solution of 1-(4,6-dichloro-2-methylpyrimidin-5-yl)propan-1-amine (3.1 g, 14.1 mmol) and Et3N (4.2 g, 42.3 mmol) in methanol (60 mL) was added Pd(dppf)Cl2 (1.1 g, 1.41 mmol). The resulting mixture was stirred at 100 °C overnight under a 2 MPa carbon monoxide atmospheres. The resulting mixture was concentrated under reduce pressure and the residue was purified by column chromatography on silica gel with dichloromethane / methanol (10:1) to give 1 g crude product. The crude product was purified by reverse flash chromatography to afford methyl 5-ethyl-2-methyl-7-oxo-5H,6H- pyrrolo[3,4-d]pyrimidine-4-carboxylate (530 mg, 16.00% yield) as an off-white solid. LCMS (ESI, m / z): 236 [M+H]+.

[0318] To a solution of methyl 5-ethyl-2-methyl-7-oxo-5H,6H-pyrrolo[3,4-d]pyrimidine-4- carboxylate (530 mg, 2.26 mmol), 4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenylboronic acid (1.1 g, 4.51 mmol) and Cu(OAc)2(818 mg, 4.51 mmol) in DCM (8 mL) was added Et3N (683 mg, 6.78 mmol). The resulting mixture was stirred at 30 °C for 3 h under an oxygen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with ethyl acetate to give crude methyl 6-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-5-ethyl-2- methyl-7-oxo-5H-pyrrolo[3,4-d]pyrimidine-4-carboxylate (510 mg, 30.57% yield) as a yellow solid. LCMS (ESI, m / z): 423 [M+H]+.

[0319] To a solution of methyl 6-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-5-ethyl-2-methyl-7- oxo-5H-pyrrolo[3,4-d]pyrimidine-4-carboxylate (510 mg, 1.21 mmol) in THF (5 mL) and H2O (1 mL) was added LiOH·H2O (75 mg, 1.81 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting was diluted with water (10 mL) and extracted with ethyl acetate (2x20 mL). The aqueous layer was lyophilized to give crude 6-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-5-ethyl-2-methyl- 7-oxo-5H-pyrrolo[3,4-d]pyrimidine-4-carboxylic acid (300 mg, 60.84% yield) as a yellow solid. LCMS (ESI, m / z): 409 [M+H]+.

[0320] To a solution of 6-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-5-ethyl-2-methyl-7-oxo- 5H-pyrrolo[3,4-d]pyrimidine-4-carboxylic acid (70 mg, 0.17 mmol), 3-amino-N-(1-methylpyrazol-3- yl)benzamide (74 mg, 0.34 mmol) and DIEA (66 mg, 0.51 mmol in DMF (1 mL) was added HATU (97 mg, 0.26 mmol). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was purified directly by reverse flash chromatography to give 6-[4- (2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-5-ethyl-2-methyl-N-{3-[(1-methylpyrazol-3- yl)carbamoyl]phenyl}-7-oxo-5H-pyrrolo[3,4-d]pyrimidine-4-carboxamide (30 mg, 28.85% yield) as a yellow solid. LCMS (ESI, m / z): 607 [M+H]+.

[0321] The racemate (30 mg) was separated by chiral-HPLC to afford (5R)-6-[4-(2,5-dimethyl-3-oxo- 1,2-oxazol-4-yl)phenyl]-5-ethyl-2-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-7-oxo-5H- pyrrolo[3,4-d]pyrimidine-4-carboxamide (the first eluting peak, 2.9 mg, 9.67% yield). The structure was arbitrarily assigned. LCMS (ESI, m / z): 607 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.84 (s, 1H), 8.52 (t, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.0, 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H),6.13 (t, J = 3.2 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 2.97 (s, 3H), 2.52-2.49 (m, 1H), 2.48 (s, 3H), 1.98- 1.87 (m, 1H), 0.27 (t, J = 6.8 Hz, 3H). Synthesis of Example 100a and 100b

[0322] To a solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo- 3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 0.24 mmol), 3-amino-N-(1-methylimidazol-4- yl)benzamide (106 mg, 0.49 mmol) in DMF (2 mL) were added TCFH (103 mg, 0.37 mmol) and 1- methyl-1H-imidazole (30 mg, 0.37 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting solution was directly purified by flash chromatography to give 2-[4-(2,5-dimethyl-3-oxo- 1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3-[(1-methylimidazol-4-yl)carbamoyl]phenyl}-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxamide (100 mg, 67% yield). LCMS (ESI, m / z): 606 [M+H]+.

[0323] The racemate of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-{3-[(1- methylimidazol-4-yl)carbamoyl]phenyl}-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (100 mg) was resolved by prep-chiral-HPLC to obtain the first eluting peak, 35.5 mg, 35% and the second eluting peak, 34.7 mg, 34% both as off-white solid. Structures were arbitrarily assigned.

[0324] Peak 1:1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.72 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.11-8.08 (m, 1H), 7.96 (s, 1H), 7.85-7.79 (m, 3H), 7.74-7.71 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H), 6.18 (t, J = 3.6 Hz, 1H), 3.67 (s, 3H), 3.47 (s, 3H), 2.80 (s, 3H), 2.52-2.50 (m, 1H), 2.47 (s, 3H), 1.93 – 1.87 (m, 1H), 0.23 (t, J = 7.6 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+.

[0325] Peak 2:1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.72 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.96 (s, 1H), 7.85-7.79 (m, 3H), 7.74-7.71 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H), 6.18 (t, J = 3.6 Hz, 1H), 3.67 (s, 3H), 3.47 (s, 3H), 2.80 (s, 3H), 2.52-2.50 (m, 1H), 2.47 (s, 3H), 1.93-1.87 (m, 1H), 0.23 (t, J = 7.6 Hz, 3H). LCMS (ESI, m / z): 606 [M+H]+.Synthesis of Example 101

[0326] A mixture of 2-(methoxy- d3)ethyl methanesulfonate (700 mg, 4.45 mmol) and NaI (1.33 g, 8.91 mmol) in acetone (7.00 mL) was stirred for 48 h at room temperature. The resulting mixture was filtered, the filter cake was washed with acetone. The filtrate was concentrated under reduced pressure to afford 1-iodo-2-(methoxy- d3)ethane (600 mg, crude) as a yellow solid, which was used in the next step directly without further purification.

[0327] To a stirred solution of 7-bromo-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (800 mg, 3.51 mmol) in DMF (8.00 mL) was added NaH (60% dispersion in mineral oil, 281 mg, 7.02 mmol) at room temperature. The resulting mixture was degassed three times with N2, and then was stirred for 30 min at 0 °C. To the above mixture was added a solution of 1-iodo-2-(methoxy-d3)ethane (600 mg, 3.16 mmol) in DMF (1.00 mL) at 0 °C. After stirring for 1 h at 0 °C, the reaction was quenched with sat. NH4Cl (aq.) and acidified to pH 2 with 1 N HCl (aq.). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford 7-bromo-1-(2-(methoxy-d3)ethyl)-5-methyl-1,2-dihydro-3H-pyrazolo[3,4- c]pyridin-3-one (100 mg, 9.86% yield) as a white solid. LCMS (ESI, m / z): 289 / 291 [M+H]+.

[0328] To a solution of 7-bromo-1-(2-(methoxy-d3)ethyl)-5-methyl-1,2-dihydro-3H-pyrazolo[3,4- c]pyridin-3-one (100 mg, 0.35 mmol) and TEA (175 mg, 1.73 mmol) in MeOH (10.0 mL) was added Pd(dppf)Cl2·CH2Cl2 (56 mg, 68.5 μmol). The mixture was stirred for 16 h at 100 °C under carbon monoxide atmosphere (3 MPa). The reaction was cooled to room temperature and filtered. The filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (with EtOAc / PE) to afford methyl 1-(2-(methoxy-d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (80 mg, 86.2% yield) as an orange solid. LCMS (ESI, m / z): 269 [M+H]+.

[0329] To a mixture of methyl 1-(2-(methoxy-d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H- pyrazolo[3,4-c]pyridine-7-carboxylate (80 mg, 0.30 mmol) and (4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)boronic acid (83 mg, 0.36 mmol) in THF (10.0 mL) were added Py (118 mg, 1.49 mmol) and Cu(OAc)2(108 mg, 0.60 mmol) at room temperature. The resulting mixture was degassed three times with O2, and then was stirred for 16 h at 60 °C. The mixture was allowed to cool down to room temperature and filtered. The filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE to afford methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-(2-(methoxy- d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (70 mg, 51.5% yield) as a yellow solid. LCMS (ESI, m / z): 456 [M+H]+.

[0330] To a solution of methyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-(2- (methoxy-d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (70 mg, 0.15 mmol) in MeOH (1.50 mL) was added a solution of LiOH·H2O (13 mg, 0.31 mmol) in H2O (1.50 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was acidified to pH 2 with 1 N HCl (aq.). The resulting mixture was concentrated under reduced pressure to remove the MeOH. The residue was purified by flash column chromatography to afford 2-(4-(2,5-dimethyl-3- oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-(2-(methoxy-d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H- pyrazolo[3,4-c]pyridine-7-carboxylic acid (55 mg, 81.1% yield) as a yellow solid. LCMS (ESI, m / z): 442 [M+H]+.

[0331] To a stirred solution of 2-fluoro-3-(1H-imidazol-2-yl)aniline hydrochloride (20 mg, 92.0 μmol) and 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-(2-(methoxy-d3)ethyl)-5-methyl-3- oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (27 mg, 61.2 μmol) in DMF (0.50 mL) were added NMI (35 mg, 0.43 mmol) and TCFH (34 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature, and then was diluted with DMSO (1 mL). The resulting solution was purified by flash column chromatography to afford 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-N-[2-fluoro-3-(1H-imidazol-2-yl)phenyl]-1-[2-(2H3)methoxyethyl]-5-methyl-3- oxopyrazolo[3,4-c]pyridine-7-carboxamide (21.2 mg, 57.7% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.71 (s, 1H), 8.11-8.07 (m, 1H), 8.02 (s, 1H), 7.87-7.80 (m, 3H), 7.69 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.49 (s, 3H), 3.16 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.48 (s, 3H). LCMS (ESI, m / z): 601 [M+H]+.Synthesis of Example 102

[0332] To a stirred solution of 4-(3-cyano-1-methyl-5-oxo-1,2,4-triazol-4-yl)phenylboronic acid (600 mg, 2.46 mmol) and methyl 1-ethyl-5-methyl-3-oxo-2H-pyrazolo[3,4-c]pyridine-7-carboxylate (578 mg, 2.46 mmol) in THF (60 mL) were added Cu(OAc)2(893 mg, 4.92 mmol) and pyridine (972 mg, 12.3 mmol) at room temperature. The resulting mixture was stirred at 60°C overnight under oxygen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (2x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) to afford methyl 2-[4-(3-cyano-1-methyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-5-methyl-3-oxopyrazolo[3,4- c]pyridine-7-carboxylate (500 mg, 46% yield) as a yellow solid. LCMS (ESI, m / z): 434 [M+H]+.

[0333] To a stirred solution of methyl 2-[4-(3-cyano-1-methyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1- ethyl-5-methyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxylate (85 mg, 0.19 mmol) in DCE (1 mL) was added trimethylstannanol (71 mg, 0.37 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2h. The resulting mixture was concentrated under reduced pressure at room temperature. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 420 [M+H]+.

[0334] To a stirred solution of 2-[4-(3-cyano-1-methyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1-ethyl-5- methyl-3-oxopyrazolo[3,4-c]pyridine-7-carboxylic acid (80 mg, 0.191 mmol) and 3-amino-N-(1- methylpyrazol-3-yl)benzamide hydrochloride (96 mg, 0.382 mmol) in DMF (2 mL) were added 1- methyl-1H-imidazole (46 mg, 0.573 mmol) and TCFH (160 mg, 0.573 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1h. The solid was removed by filtration and the filtrate purified by Prep-HPLC to afford 2-[4-(3-cyano-1-methyl-5-oxo-1,2,4-triazol-4-yl)phenyl]-1- ethyl-5-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-3-oxopyrazolo[3,4-c]pyridine-7- carboxamide (60.2 mg, 51% yield over two steps). LCMS (ESI, m / z): 618 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.84 (s, 1H), 8.47 (t, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.90-7.88 (m, 2H), 7.84-7.78 (m, 3H), 7.62 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.54 (s, 3H), 2.75 (s, 3H), 0.60 (t, J = 6.8 Hz, 3H).Synthesis of Example 103

[0335] To a solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-1-(2-(methoxy- d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (30 mg, 68.0 μmol) and 5-amino-2-fluoro-N-(1-methyl-1H-pyrazol-3-yl)benzamide (24 mg, 0.10 mmol) in DMF (1.00 mL) were added NMI (39 mg, 0.48 mmol) and TCFH (38 mg, 0.14 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature, and then was diluted with DMSO (1 mL). The mixture was purified by flash column chromatography to afford 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-N-(4-fluoro-3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)-1-(2- (methoxy-d3)ethyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (25.7 mg, 57.5% yield).1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.79 (s, 1H), 8.25 (dd, J = 6.4, 2.8 Hz, 1H), 8.06-8.02 (m, 1H), 7.95 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.24 (t, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.49 (s, 3H), 3.14 (t, J = 4.8 Hz, 2H), 2.73 (s, 3H), 2.48 (s, 3H). LCMS (ESI, m / z): 658 [M+H]+. Synthesis of Examples 105a and 105b

[0336] To a stirred solution of 4-bromo-2,6-dichloropyridine (25 g, 110 mmol) and bis[(4- methoxyphenyl)methyl]amine (31 g, 121 mmol) in DMSO (150 mL) was added DIEA (28 g, 220 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 3 days under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (500 mL) and extracted with EtOAc (1 L). The organic layer was washed with water (2x1 L) and brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6:1) to afford 4-bromo-6-chloro-N,N- bis[(4-methoxyphenyl)methyl]pyridin-2-amine (12 g, 24.3% yield ) as a light yellow solid. LCMS (ESI, m / z): 447, 449 [M+H]+.

[0337] To a solution of 4-bromo-6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (10 g, 22 mmol) in THF (200 mL) was added LDA (2.0 M in THF, 10 mL, 20.1 mmol) in portions at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h under nitrogen atmosphere. To the above mixture was added DMF (8 g, 111 mmol) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding aqueous NH4Cl (200 mL) at -78 °C, extracted with ethyl acetate (2x300 mL). The combined organic extracts were washed with brine (600 mL), dried over anhydrous sodium sulfate, concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to afford 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-2- chloropyridine-3-carbaldehyde (10 g, 94% yield) as a light yellow solid. LCMS (ESI, m / z): 475, 477 [M+H]+.

[0338] To a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-2-chloropyridine-3- carbaldehyde (10 g, 21.0 mmol) in THF (200 mL) was added tetrakis(propan-2-yloxy)titanium (18 g, 63.1 mmol). The resulting mixture was stirred at 60 °C for overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to afford N-[(1E)-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-2-chloropyridin-3-yl)methylidene]-2- methylpropane-2-sulfinamide (12 g, 98.6% yield) as a yellow oil. LCMS (ESI, m / z): 578580 [M+H]+.

[0339] To a solution of N-[(1E)-(6-{bis[(4-methoxyphenyl)methyl]amino}-4-bromo-2-chloropyridin- 3-yl)methylidene]-2-methylpropane-2-sulfinamide (4 g, 6.90 mmol) in THF (70 mL) was added Ethylmagnesium bromide(2.0 M in THF, 17 mL, 34.5 mmol) in portions at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding aqueous NH4Cl (100 mL) at -78 °C, extracted with ethyl acetate (2x100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to afford N-[1-(6-{bis[(4- methoxyphenyl)methyl]amino}-4-bromo-2-chloropyridin-3-yl)propyl]-2-methylpropane-2-sulfinamide (900 mg, 21.4% yield) as a light yellow oil. LCMS (ESI, m / z): 608610 [M+H]+.

[0340] To a solution of HCl in 1,4-dioxane (4.0 M, 100 mL) was added N-[1-(6-{bis[(4- methoxyphenyl)methyl]amino}-4-bromo-2-chloropyridin-3-yl)propyl]-2-methylpropane-2-sulfinamide (6 g, 9.85 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The reaction was concentrated under vacuum to afford 5-(1-aminopropyl)-4- bromo-6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (6 g) as a yellow solid. LCMS (ESI, m / z): 504, 506 [M+H]+.

[0341] To a solution of 5-(1-aminopropyl)-4-bromo-6-chloro-N,N-bis[(4- methoxyphenyl)methyl]pyridin-2-amine (6 g, 11.8 mmol) and Et3N (6 g, 59.4 mmol) in EtOH (150 mL) was added Pd(dppf)Cl2(1.8 g, 2.37 mmol) under nitrogen atmosphere. The mixture was recharged with carbon monoxide gas three times and the resulting mixture was stirred under carbon monoxide atmospheres (20 atm) at 100 °C for 16 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate) to afford 6-{bis[(4-methoxyphenyl)methyl]amino}-4-chloro-3-ethyl-2H,3H-pyrrolo[3,4- c]pyridin-1-one (2 g, 37.2% yield) as a yellow solid. LCMS (ESI, m / z): 452, 454 [M+H]

[0342] To a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-4-chloro-3-ethyl-2H,3H- pyrrolo[3,4-c]pyridin-1-one (2 g, 4.42 mmol) and Et3N (2.2 g, 22.1 mmol) in EtOH (150 mL) was added Pd(dppf)Cl2CH2Cl2(723 mg, 0.885 mmol) under nitrogen atmosphere. The mixture was recharged with carbon monoxide gas three times and the resulting mixture was stirred under carbon monoxide atmospheres (20 atm) at 100 °C for 16 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate) to afford ethyl 6-{bis[(4-methoxyphenyl)methyl]amino}-3-ethyl-1-oxo-2H,3H- pyrrolo[3,4-c]pyridine-4-carboxylate (1.8 g, 83.1% yield) as a yellow solid. LCMS (ESI, m / z): 490 [M+H]+.

[0343] To a solution of ethyl 6-{bis[(4-methoxyphenyl)methyl]amino}-3-ethyl-1-oxo-2H,3H- pyrrolo[3,4-c]pyridine-4-carboxylate (900 mg, 1.83 mmol), 4-(4-bromophenyl)-2,5-dimethyl-1,2-oxazol- 3-one (739 mg, 2.75 mmol) and K2CO3 (1 g, 7.35 mmol) in dioxane (50 mL) was added RuPhos (343mg, 0.735 mmol) and Pd2(dba)3 (336 mg, 0.368 mmol) under nitrogen atmosphere. The resulting mixture were stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by flash column chromatography on C18 silica with water (0.5% TFA) / MeCN to afford ethyl 6-{bis[(4-methoxyphenyl)methyl]amino}-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-3-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (1.2 g, 96.4%yield) as a yellow solid. LCMS (ESI, m / z): 677 [M+H]+.

[0344] To a solution of ethyl 6-{bis[(4-methoxyphenyl)methyl]amino}-2-[4-(2,5-dimethyl-3-oxo-1,2- oxazol-4-yl)phenyl]-3-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (1.2 g, 1.77 mmol) in DCM (15 mL) was added TFA (5 mL) under nitrogen atmosphere. The resulting mixture were stirred at 50 °C overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica with water (0.5% TFA) / MeCN to afford ethyl 6-amino-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-3-ethyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (600 mg, 77.5% yield) as a light yellow solid. LCMS (ESI, m / z): 437 [M+H]+.

[0345] To a solution of ethyl 6-amino-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (200 mg, 0.46 mmol) in pyridine hydrofluoride (6 mL) was added NaNO2(47 mg, 0.69 mmol) at 0 °C. The resulting mixture was stirred for 4 h at 0 °C. The reaction was monitored by LCMS. The crude product was purified by flash column chromatography on C18 silica with water (0.5% TFA) / MeCN to afford ethyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl- 6-fluoro-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (140 mg, 69.5% yield) as a yellow solid. LCMS (ESI, m / z): 440 [M+H]+.

[0346] To a solution of ethyl 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-fluoro-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (140 mg, 0.32 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (23 mg, 0.96 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The crude product was purified by flash column chromatography on C18 silica with water (0.5% TFA) / MeCN to afford 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3- ethyl-6-fluoro-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 76.3% yield) as a light yellow solid. LCMS (ESI, m / z): 412 [M+H]+.

[0347] To a solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-fluoro-1-oxo-3H- pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 0.24 mmol) and HATU (138 mg, 0.36 mmol) in DMF (3 mL), were added DIEA (125 mg, 0.97 mmol) and 3-amino-N-(1-methylpyrazol-3-yl)benzamide (78 mg, 0.36 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The crude product was purified by flash column chromatography on C18 silica with water (0.5% FA) / MeCN and further purified by Prep-Chiral-HPLC. The pure fractions were combined and concentrated under vacuum to remove organic solvents. The residual aqueous solution was lyophilized overnight to afford (R)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-3-ethyl-6-fluoro-N-(3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (24.8 mg, the first eluting peak, 16.7% yield) and (S)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-3-ethyl-6-fluoro-N-(3-((1-methyl-1H-pyrazol-3- yl)carbamoyl)phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (23.7 mg, the second eluting peak, 15.99%yield). The stereochemistry of the molecules was arbitrarily assigned.1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.82 (s, 1H), 8.53 (t, J = 2.0 Hz, 1H), 8.06-8.03 (m, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.0, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.20 (t, J = 3.6 Hz, 1H), 3.79 (s, 3H), 3.48 (s, 3H), 2.48 (s, 3H), 2.45-2.42 (m, 1H), 1.93-1.87 (m, 1H), 0.28 (t, J = 7.6 Hz, 3H). LCMS (ESI, m / z): 610 [M+H]+(same NMR data for both compounds). Synthesis of Examples 106a and 106b

[0348] To a solution of 3-nitro-1H-pyrazole (25 g, 221 mmol) in DMF (300 mL) were added K2CO3 (91.67 g, 663 mmol) and iodo(2H3)methane (64.10 g, 442 mmol,). The resulting mixture was stirred at 50 °C for 3h. The solid was removed by filtration and washed with ethyl acetate (200 mL). The filtrate was diluted with water (600 mL) and extracted with ethyl acetate (3x600 mL). The combined organic layers were washed with brine (3x400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1:3) to afford 1-(2H3)methyl-3-nitropyrazole (21 g, 73.00%yield) as a light yellow solid. LCMS (ESI, m / z): 131 [M+H]+.

[0349] To a solution of 1-(2H3)methyl-3-nitropyrazole (21 g, 161 mmol) in MeOH (400 mL) was added Pd / C (4.29 g, 8.07 mmol). The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere. LCMS showed the reaction was completed. The solid was filtered out through a Celite pad. The filtrate was concentrated under reduced pressure to afford crude product 1-(2H3)methylpyrazol-3-amine (16 g) as a light yellow solid. The crude product was used for the next step directly without further purification. LCMS (ESI, m / z): 101 [M+H]+.

[0350] To a solution of 1-(2H3)methylpyrazol-3-amine (16 g, 159 mmol), 1-methyl-1H-imidazole (39.36 g, 479 mmol) and tert-butyl N-(3-carbamoylphenyl)carbamate (37.75 g, 159 mmol) in DMF (200 mL) was added TCFH (67.25 g, 239 mmol). The resulting mixture was stirred for 3h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was quenched with water (1000 mL) and extracted with ethyl acetate (3x1000 mL). The combined organic extracts were washed with brine (3x500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with ethyl acetate / petroleum ether (1:1) to give tert-butyl N-(3-{[1-(2H3)methylpyrazol-3-yl]carbamoyl}phenyl)carbamate (34.8 g, 68.20%yield) as a yellow solid. LCMS (ESI, m / z): 320 [M+H]+.

[0351] To a solution of tert-butyl N-(3-{[1-(2H3)methylpyrazol-3-yl]carbamoyl}phenyl)carbamate (260 mg, 0.814 mmol) in dioxane (3 mL) was added HCl in 1,4-dioxane (4.0 M, 1 mL). The resulting mixture was stirred for 2h at 50°C under a nitrogen atmosphere. The resulting solution was concentrated under reduce pressure to give 3-amino-N-[1-(2H3)methylpyrazol-3-yl]benzamide (260 mg) as a yellow solid. LCMS (ESI, m / z): 220 [M+H]+.

[0352] To a solution of 3-amino-N-[1-(2H3)methylpyrazol-3-yl]benzamide (260 mg, 1.19 mmol) and 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4- carboxylic acid (966 mg, 2.37 mmol) in DMF (5 mL) was added TCFH (665 mg, 2.37 mmol) and 1- methyl-1H-imidazole (584 mg, 7.12 mmol). The resulting mixture was stirred for 2 h under a nitrogen atmosphere. The reaction was quenched by water (60 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with dichloromethane / methanol (15:1) to give 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl- 6-methyl-N-(3-{[1-(2H3)methylpyrazol-3-yl]carbamoyl}phenyl)-1-oxo-3H-pyrrolo[3,4-c]pyridine-4- carboxamide (190 mg, 26.32%yield) as a yellow solid. LCMS (ESI, m / z): 609 [M+H]+.

[0353] 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-(3-{[1- (2H3)methylpyrazol-3-yl]carbamoyl}phenyl)-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (190 mg, 0.312 mmol) was separated by chiral-HPLC to afford both chiral isomers rel-(3R)-2-[4-(2,5-dimethyl-3- oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-(3-{[1-(2H3)methylpyrazol-3-yl]carbamoyl}phenyl)-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (29 mg, the first eluting peak, 15.26%yield) and rel-(3S)- 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-3-ethyl-6-methyl-N-(3-{[1-(2H3)methylpyrazol-3- yl]carbamoyl}phenyl)-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (23 mg, the second eluting peak). The stereochemistry of the molecules was arbitrarily assigned.1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.82 (s, 1H), 8.51 (t, J = 2.0 Hz, 1H), 8.12-8.08 (m, 1H), 7.97 (s, 1H), 7.88-7.81 (m, 2H), 7.81-7.76 (m, 1H), 7.76-7.69 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.18 (t, J = 3.6 Hz, 1H), 3.48 (s, 3H), 2.81 (s, 3H), 2.57-2.52 (m, 1H), 2.48 (s, 3H), 1.97-1.84 (m, 1H), 0.23 (t, J = 7.6 Hz, 3H). LCMS (ESI, m / z): 609 [M+H]+(same NMR data for both compounds).Synthesis of Examples 111a and 111b

[0354] To a solution of N-[(1E)-(4-bromo-2-chloro-6-methylpyridin-3-yl)methylidene]-2- methylpropane-2-sulfinamide (2 g, 5.92 mmol) in THF (30 mL) was added dropwise 1M bromo(cyclopropyl)magnesium in THF (11.8 mL, 11.83 mmol) at -60 °C under a nitrogen atmosphere. The resulting mixture was stirred at -60 °C for 5 minutes under a nitrogen atmosphere. The resulting mixture was quenched with saturated aqueous ammonium chloride (120 mL) and extracted with ethyl acetate (3x60 mL). The combined organic layers were washed with brine (2x40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:3) to give N-[(4-bromo-2- chloro-6-methylpyridin-3-yl)(cyclopropyl)methyl]-2-methylpropane-2-sulfinamide (2.2 g, 97.81%yield) an off-white solid. LCMS (ESI, m / z): 381, 379 [M+H].

[0355] To a solution of N-[(4-bromo-2-chloro-6-methylpyridin-3-yl)(cyclopropyl)methyl]-2- methylpropane-2-sulfinamide (2.0 g, 5.2 mmol) in dioxane (20 mL) was added HCl in 1,4-dioxane (4M, 0.2 mL, ) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 1 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The resulting solution was diluted with 250 ml of 2-methoxy-2-methylpropane. The solid was collected by filtration and was dried in the oven to give 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-1-cyclopropylmethanamine (1.5 g, 97.34%yield) as an off- white solid. LCMS (ESI, m / z): 275, 277[M+H+]+.

[0356] To a solution of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-1-cyclopropylmethanamine (500 mg, 1.8 mmol) and TEA (550 mg, 5.4 mmol) in EtOH (20 mL) was added Pd(dppf)Cl2·CH2Cl2 (148 mg, 0.1 mmol). The mixture was stirred overnight under carbon monoxide (20 atm) at 100°C. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether / ethyl acetate (1:1) to give ethyl 3- cyclopropyl-6-methyl-1-oxo-2H,3H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 57.17%yield) as an off-white solid.

[0357] LCMS (ESI, m / z): 261 [M+H+]+. To a solution of ethyl 3-cyclopropyl-6-methyl-1-oxo- 2H,3H-pyrrolo[3,4-c]pyridine-4-carboxylate (150 mg, 0.5 mmol), 4-(4-bromophenyl)-2,5-dimethyl-1,2- oxazol-3-one (309 mg, 1.1 mmol) and K2CO3(238 mg, 1.7 mmol) in dioxane (1.5 mL) were added Pd2(dba)3(52 mg, 0.1 mmol) and RuPhos (53 mg, 0.1 mmol). The resulting mixture was stirred at 90°C overnight under a nitrogen atmosphere. The mixture was concentrated and purified by flash chromatography on C18 silica with water (10 mmol NH4HCO3) / MeCN (2:1) to give ethyl 3-cyclopropyl- 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4- carboxylate (250 mg, 75% purity) as a yellow solid. LCMS (ESI, m / z): 448 [M+H+]+.

[0358] To a solution of ethyl 3-cyclopropyl-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-6- methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylate (230 mg, 0.5 mmol) in THF (2.5 mL) and H2O (0.5 mL) was added LiOH·H2O (32 mg, 0.7 mmol). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was neutralized with 1M HCl. The mixture was extracted with ethyl acetate (2x20 mL) and the organic layers were concentrated under vacuum to afford 3-cyclopropyl-2-[4-(2,5-dimethyl-3-oxo-1,2- oxazol-4-yl)phenyl]-6-methyl-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (200 mg, 92.76%yield) as a yellow solid. LCMS (ESI, m / z): 420 [M+H]+.

[0359] To a solution of 3-cyclopropyl-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-6-methyl-1- oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (100 mg, 0.2 mmol), 3-amino-N-(1-methylpyrazol-3- yl)benzamide (61 mg, 0.2 mmol) and 1-methyl-1H-imidazole (58 mg, 0.7 mmol) in DMF (0.5 mL) was added TCFH (100 mg, 0.3 mmol) . The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was purified directly by flash chromatography on C18 silica with water (0.1% TFA) / MeCN (1:1) to give 3-cyclopropyl-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4- yl)phenyl]-6-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-1-oxo-3H-pyrrolo[3,4-c]pyridine- 4-carboxamide (60 mg, 40.74%yield) as a light-yellow solid. LCMS (ESI, m / z): 618 [M+H+]+.

[0360] The racemate (60 mg) was separated by chiral-HPLC to afford rel-(3R)-3-cyclopropyl-2-[4- (2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-6-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}- 1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (15.2 mg, the first eluting peak) and rel-(3S)-3- cyclopropyl-2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-6-methyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-1-oxo-3H-pyrrolo[3,4-c]pyridine-4-carboxamide (14mg, The second eluting peak). LCMS (ESI, m / z): 618 [M+H]+. The stereochemistry of the molecules was assigned arbitrarily.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.83 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 8.11-8.08 (m, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.08 (d, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 2.78 (s, 3H), 2.47 (s, 3H), 1.48-1.35 (m, 1H), 0.32-0.21 (m, 2H), 0.11-0.06 (m, 2H) (same NMR data for both compounds). Synthesis of Example 112

[0361] To a stirred solution of 7-bromo-5-methyl-1,2-dihydro-3H-pyrazolo[3,4-c]pyridin-3-one (5.00 g, 21.9 mmol) and SEMCl (5.48 g, 32.9 mmol) in DCM (100 mL) was added TEA (11.1 g, 110 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature, and then was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica to afford 7-bromo-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H- pyrazolo[3,4-c]pyridine (4.30 g, 46.9% yield) as a yellow solid. LCMS (ESI, m / z): 358 / 360 [M+H]+.

[0362] To a stirred solution of 7-bromo-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H- pyrazolo[3,4-c]pyridine (500 mg, 1.40 mmol) and cyclopropylboronic acid (600 mg, 6.98 mmol) in THF (20.0 mL) were added Py (553 mg, 7.00 mmol) and Cu(OAc)2(510 mg, 2.80 mmol) at room temperature. The resulting mixture was degassed three times with O2, and then was stirred for 16 h at 60 °C. The resulting mixture was allowed to cool down to room temperature and filtered; the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (with EtOAc / PE) to afford 7-bromo-1-cyclopropyl-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazolo[3,4-c]pyridine (300 mg, 54.0% yield) as a white solid. LCMS (ESI, m / z): 398 / 400 [M+H]+.

[0363] To a mixture of 7-bromo-1-cyclopropyl-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H- pyrazolo[3,4-c]pyridine (300 mg, 0.75 mmol) and TEA (229 mg, 2.26 mmol) in MeOH (10.0 mL) was added Pd(dppf)Cl2·CH2Cl2 (62 mg, 76 μmol,). The resulting mixture was pressurized with carbon monoxide gas to 3 MPa and stirred for 16 h at 80 ℃. The resulting mixture was cooled to room temperature, and then was filtered. The filter cake was washed with MeOH; the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (with EtOAc / PE) to afford methyl 1-cyclopropyl-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazolo[3,4- c]pyridine-7-carboxylate (220 mg, 77.4 % yield) as a white solid. LCMS (ESI, m / z): 378 [M+H]+.

[0364] To a solution of methyl 1-cyclopropyl-5-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H- pyrazolo[3,4-c]pyridine-7-carboxylate (220 mg, 0.58 mmol) in MeOH (10 mL) was added TFA (2 mL) at room temperature. The mixture was stirred for 1 h at room temperature, and then was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 silica with water (10 mmol / L NH4HCO3)-ACN to afford methyl 1-cyclopropyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4- c]pyridine-7-carboxylate (120 mg, 81% yield) as a white solid. LCMS (ESI, m / z): 248 [M+H]+.

[0365] To a stirred solution of methyl 1-cyclopropyl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4- c]pyridine-7-carboxylate (120 mg, 0.49 mmol) and (4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)boronic acid (137 mg, 0.59 mmol) in THF (15.0 mL) were added Py (194 mg, 2.45 mmol) and Cu(OAc)2(178 mg, 0.98 mmol) at room temperature. The resulting mixture was degassed three times with O2, and then was stirred for 16 h at 60 °C. The resulting mixture was allowed to cool down to room temperature, and then was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (with EtOAc / PE) to afford methyl 1-cyclopropyl-2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (107 mg, 53.0% yield) as a white solid. LCMS (ESI, m / z): 435 [M+H]+.

[0366] To a stirred solution of methyl 1-cyclopropyl-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylate (107 mg, 0.25 mmol) in THF (5.00 mL) was added a solution LiOH (12 mg, 0.49 mmol) in H2O (5.00 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to remove the MeOH. The residue was diluted with H2O (2.00 mL) and acidified to pH 3 with 1 N HCl (aq.). The resulting mixture was purified by flash chromatography on C18 silica with water (0.1% FA)-ACN to afford 1-cyclopropyl-2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (80 mg, 77.3% yield) as a red solid. LCMS (ESI, m / z): 421 [M+H]+.

[0367] To a stirred solution of 1-cyclopropyl-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-5-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (40 mg, 0.10 mmol) and 3-amino-N-(1-methyl-1H-pyrazol-3-yl)benzamide HCl salt (30 mg, 0.12 mmol) in MeCN (0.50 mL) were added NMI (33 mg, 0.40 mmol) and TCFH (56 mg, 0.20 mmol) at room temperature.The resulting mixture was stirred for 2 h at room temperature, and then was purified by prep-HPLC. The product-containing fraction was collected and concentrated under reduced pressure to afford 1- cyclopropyl-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-5-methyl-N-(3-((1-methyl-1H- pyrazol-3-yl)carbamoyl)phenyl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-c]pyridine-7-carboxamide (20.3 mg, 34.5% yield, 98.5% purity).1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 10.83 (s, 1H), 8.44 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82-7.75 (m, 5H), 7.63 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H), 3.49 (s, 3H), 3.47-3.43 (m, 1H), 2.71 (s, 3H), 2.49 (s, 3H), 0.63-0.60 (m, 2H), 0.51-0.50 (m, 2H). LCMS (ESI, m / z): 619 [M+H]+. Synthesis of Example 117:

[0368] To a stirred solution of 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]-1-ethyl-3-oxo-5- (trifluoromethyl)pyrazolo[3,4-c]pyridine-7-carboxylic acid (50 mg, 0.11 mmol) and 3-amino-N-(1- methylpyrazol-3-yl)benzamide hydrochloride (33 mg, 0.13 mmol) in DMF (1.00 mL) were added 1- methyl-1H-imidazole (36 mg, 0.43 mmol) and TCFH (61 mg, 0.22 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by Prep-HPLC (Column: C18 silica gel; Mobile phase, A: water (containing 0.05% TFA) and B: CH3CN; Gradient: 5% to 95% B in 40 min; Detector: 254 / 220 nm) to afford 2-[4-(2,5-dimethyl-3-oxo-1,2-oxazol-4-yl)phenyl]- 1-ethyl-N-{3-[(1-methylpyrazol-3-yl)carbamoyl]phenyl}-3-oxo-5-(trifluoromethyl)pyrazolo[3,4- c]pyridine-7-carboxamide (24.7 mg, 34.58% yield, 97.5% purity).1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.88 (s, 1H), 8.56 (s, 1H), 8.40 (t, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.0, 2.0 Hz, 1H), 7.90- 7.79 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 4.05-4.02 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.49 (s, 3H), 2.50 (s, 3H), 0.75 (t, J = 7.2 Hz, 3H). LCMS (ESI, m / z): 661.2 [M+H]+. Synthesis of Example 118a and 118b

[0369] To a solution of 4-bromo-2-chloro-6-methylpyridine (20 g, 96.8 mmol) in THF (200 mL) was added dropwise LDA (2 M in heptane, 96.87 mL, 193.7 mmol) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 30 min. Then a solution of 3-((tert-butyldimethylsilyl) oxy) propanal (21.8 g, 116.2 mmol) was added dropwise and the mixture was stirred for another 30 min. The reaction was quenched with sat. NH4Cl (100 mL), and was extracted with ethyl acetate (3x300 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:10) to give 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-((tert- butyldimethylsilyl) oxy) propan-1-ol (15 g, 39.22%yield) as a yellow oil.

[0370] To a stirred mixture of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-[(tert-butyldimethylsilyl) oxy] propan-1-ol (13 g, 32.9 mmol) in DCM (150 mL) was added DMP (27.9 g, 65.8 mmol) at room temperature. The resulting mixture was stirred for 2h at room temperature. The reaction was filtered and the filter cake was washed with DCM (150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (3:1) to afford 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-((tert-butyldimethylsilyl) oxy) propan-1-one (9.5 g, 73.45%yield) as a yellow oil. LCMS (ESI, m / z): 392.0, 394.0 [M+H]+.

[0371] A mixture of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-((tert-butyldimethylsilyl) oxy) propan-1-one (12 g, 30.551 mmol) in HCl in dioxane (100 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (1:1) to afford 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-hydroxypropan-1-one (5 g, 58.76%yield) as a yellow oil. LCMS (ESI, m / z): 277.9, 279.9 [M+H]+.

[0372] To a solution of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-2-hydroxyethanone (5 g, 18.0 mmol) and Ag2O (12.4 g, 54.1 mmol) in DCM (100 mL) was added CD3I (30.7 g, 212 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:2) to give 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy- d3) propan-1-one (3 g, 56.6%yield) as a white solid. LCMS (ESI, m / z): 294,9, 296.9 [M+H]+.

[0373] To a solution of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy-d3) propan-1-one (3 g, 10.2 mmol) in MeOH (50 mL) was added NaBH4 (1.5 g, 40.8 mmol) in portions under an ice bath. The mixture was stirred at room temperature overnight. The resulting mixture was quenched with water (100 mL) and extracted with dichloromethane (3x100mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (1:5) to give 1-(4- bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy-d3) propan-1-ol (2.6 g, 86%yield) as an orange oil. LCMS (ESI, m / z): 295.9, 298.9 [M+H]+.

[0374] To a solution of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy-d3) propan-1-ol (2.6 g, 6.95 mmol) and TEA (2.1 g, 20.8 mmol) in DCM (40 mL) was added Ms2O (1.8 g, 10.4 mmol). The mixture was stirred at 40 °C for 1 h. The resulting mixture was quenched with water (200 mL) and extracted with dichloromethane (3x200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was used directly without further purification. LCMS (ESI, m / z): 375.0, 377.0 [M+H]+.

[0375] To a stirred mixture of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy-d3) propyl methanesulfonate (3.6 g, 9.5 mmol) in DMSO (30 mL) was added NaN3(1.87 g, 28.7 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was used for the next step directly without further purification. LCMS (ESI, m / z): 322.0, 324.0 [M+H]+.

[0376] To a stirred mixture of 3-(1-azido-3-(methoxy-d3) propyl)-4-bromo-2-chloro-6-methylpyridine (3 g, 9.2 mmol) in THF (30 mL) was added PPh3(7.32 g, 27.8 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then H2O (5 mL) was added. The resulting mixture was stirred at 50 °C for 4 h. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford 1-(4-bromo-2-chloro-6-methylpyridin-3- yl)-3-(methoxy-d3) propan-1-amine (1 g, 36.26%yield) as a yellow solid. LCMS (ESI, m / z): 296.0, 298.0 [M+H]+.

[0377] To a solution of 1-(4-bromo-2-chloro-6-methylpyridin-3-yl)-3-(methoxy-d3) propan-1-amine (1 g, 3.3 mmol) and TEA (1 g, 10.1 mmol) in EtOH (10 mL) was added Pd(dppf)Cl2CH2Cl2 (282 mg, 0.3 mmol) in a pressure tank. The mixture was purged with nitrogen for 1 min and then was pressurized to 20 atm with carbon monoxide at 100 °C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with dichloromethane / methanol (95:5) to give ethyl 3-(2-(methoxy-d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylate (700 mg, 71.5%yield) as an orange solid. LCMS (ESI, m / z): 282.1 [M+H]+.

[0378] To a solution of ethyl 3-(2-(methoxy-d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylate (700 mg, 2.48 mmol), 4-(4-bromophenyl)-2,5-dimethyl-1,2-oxazol-3-one (662.7 mg, 2.48 mmol) and K2CO3 (952 mg, 7.44 mmol) in dioxane (5 mL) were added Pd2(dba)3 (681 mg, 0.7 mmol) and RuPhos (693 mg, 1.4 mmol). The mixture was stirred at 90 °C under N2 atmosphere. The resulting mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with ethyl acetate / petroleum ether (2:1) to give ethyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylate (900 mg, 77.5%yield) as an orange solid. LCMS (ESI, m / z): 469.2 [M+H]+.

[0379] To a solution of ethyl 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2- (methoxy-d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylate (900 mg, 1.91 mmol) in THF (5 mL) and water (0.5 mL) was added LiOH.H2O (153 mg, 3.83 mmol). The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with H2O (3x5 mL) to afford 2-(4-(2,5- dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylic acid (600 mg,71.0%yield) as a yellow solid. LCMS (ESI, m / z): 483.3 [M+H]+.

[0380] To a solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy- d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylic acid (100 mg, 0.25 mmol) and 3-Amino-N-(1-methyl-1H-pyrazol-3-yl) benzamide (54 mg, 0.25 mmol) in DMF (2 mL) were added TCFH (112 mg, 0.4 mmol) add 1-methyl-1H-imidazole (61 mg, 0.75 mmol). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting solution was purified by reverse flash chromatography with water (0.1% FA) / MeCN (8:3) to give 2-(4-(2,5-dimethyl-3-oxo-2,3- dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6-Methyl-N-(3-((1-methyl-1H-pyrazol-3-yl) carbamoyl) phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (120 mg, 82.7%yield) as yellow solid. LCMS (ESI, m / z): 639.5 [M+H]+.

[0381] 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6- Methyl-N-(3-((1-methyl-1H-pyrazol-3-yl) carbamoyl) phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (120 mg racemate) was separated by chiral-HPLC (Column: CHIRAL ART Cellulose-SA, 5 μm, 20*250 mm; Mobile Phase A: EtOH: DCM=1: 1, Mobile Phase B: Hex (with 0.5%NH3 (2 M in MeOH)); to give rel-(R)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-3-(2- (methoxy-d3)ethyl)-6-methyl-N-(3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (18.9 mg, the first eluting peak, 15.7%yield, 97.5%purity) and rel-(S)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-3-(2-(methoxy-d3)ethyl)-6-methyl-N- (3-((1-methyl-1H-pyrazol-3-yl)carbamoyl)phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (21.4 mg, the second eluting peak, 17.8%yield, 99.2% purity). Stereochemistry of the products have been arbitrarily assigned. LCMS (ESI, m / z): 639.5 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 10.82 (s, 2H), 8.52 (t, J = 2.0 Hz, 1H), 8.13 – 8.10 (m, 1H), 7.94 (s, 1H), 7.85 – 7.77 (m, 4H), 7.72 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.19 (t, J = 4.0 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H), 2.95 – 2.86 (m, 1H), 2.85 – 2.66 (m, 5H), 2.48 (s, 3H), 2.20 – 2.04 (m, 1H). Synthesis of Example 119a and 119b

[0382] To a solution of 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy- d3) ethyl)-6-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxylic acid (100 mg, 0.25 mmol) and 3-Amino-N-(1-methyl-1H-imidazol-4-yl) benzamide (54 mg, 0.25 mmol) in DMF (2 mL) were added TCFH (112 mg, 0.4 mmol) add 1-methyl-1H-imidazole (61 mg, 0.75 mmol). The mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting solution was purified by reverse flash chromatography with water (0.1% FA) / MeCN (6:3) to give2-(4-(2,5-dimethyl-3-oxo- 2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6-methyl-N-(3-((1-methyl-1H-imidazol-4- yl) carbamoyl) phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (100 mg, 68.9%yield) as yellow solid. LCMS (ESI, m / z): 639.5 [M+H]+.

[0383] 2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl) phenyl)-3-(2-(methoxy-d3) ethyl)-6- Methyl-N-(3-((1-methyl-1H-pyrazol-3-yl) carbamoyl) phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (100 mg racemate) was separated by chiral-HPLC (Column: Column: CHIRAL ART Cellulose-SA, 5 μm, 20*250 mm; Mobile Phase A: EtOH: DCM=1: 1, Mobile Phase B: Hex (with 0.5% NH3 (2 M in MeOH)); Flow rate: 20 mL / min; Gradient (B%): isocratic 40% B; Wave Length: 220 / 254 nm; RT1(min): 5.16; RT2(min): 6.79) to give rel-(R)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4-yl)phenyl)-3-(2-(methoxy-d3)ethyl)-6-methyl-N-(3-((1-methyl-1H-pyrazol-3- yl)carbamoyl)phenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (27.7 mg, the first eluting peak, 27.7%yield, 98.3%purity) and rel-(S)-2-(4-(2,5-dimethyl-3-oxo-2,3-dihydroisoxazol-4- yl)phenyl)-3-(2-(methoxy-d3)ethyl)-6-methyl-N-(3-((1-methyl-1H-imidazol-4-yl)carbamoyl)phenyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (18.7 mg, the second eluting peak, 18.7% yield, 98.3% purity). Stereochemistry of the products have been assigned arbitrarily. LCMS (ESI, m / z): 639.5 [M+H]+.1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 10.72 (s, 1H), 8.50 (t, J = 2.0 Hz, 1H), 8.12 – 8.08 (m, 1H), 7.94 (s, 1H), 7.86 – 7.77 (m, 3H), 7.73 – 7.68 (m, 2H), 7.52 – 7.47 (m, 2H), 7.40 (d, J = 1.6 Hz, 1H), 6.18 (t, J = 4.0 Hz, 1H), 3.67 (s, 3H), 3.48 (s, 3H), 2.93 – 2.76 (m, 6H), 2.47 (s, 3H), 2.13 – 2.06 (m, 1H).

[0384] The following examples were synthesized as described above. Stereochemistry has been assigned arbitrarily.Example A: STAT6 activity reporter assay using HEK-BlueTMIL-4 / IL-13 cell

[0385] The potency of compounds was examined in HEK-BlueTMIL-4 / IL-13 cells (Invivogen, Cat# hkb-il413). HEK-Blue™ IL-4 / IL-13 cells were generated by stable transfection of the HEK 293 cell line with the human STAT6 gene to obtain a fully active STAT6 pathway plus a STAT6-inducible SEAP reporter gene. The cells produce SEAP in response to IL-4 or IL-13 stimulation, The compound inhibits STAT6 activity and prevents the production of SEAP in the cells. The levels of SEAP in the supernatant can be easily determined using QUANTI-Blue™ Solution (Invivogen, cat# rep-qbs) by reading the OD at 620-655 nm.

[0386] HEK-BlueTMIL-4 / IL-13 cells were cultured in DMEM supplemented with 10% in activated FBS, 100µ / mL Pen-Strep, 100 µg / mL normocin, 10µg / mL blasticidin, and 100 µg / mL zeocin. The culture was maintained in culture incubator with 5% CO2at 37°C. When used for assay, the cells were gently rinsed twice with pre-warmed phosphate buffered saline (PBS) and detached in presence of PBS by tapping the flask or by using a cell scraper. The cells were spun to remove PBS and resuspended in fresh, pre-warmed test medium (DMEM supplemented with 10% in activated FBS, 100µ / mL Pen-Strep). A serial dilution of work solution of tested compound was made in DMSO with 1000X of final concentration, and 50 nL of compound DMSO solution was transferred into 384-well plates (Corning 3764) by Echo655 and incubated with 40uL of HEK-Blu IL-4 / IL-13 cell suspension to assay plate (10000 cells per well) at 37°C in a 5% CO2incubator for 1 h. The cells were stimulated with 10 µL of recombinant human IL-4 protein (R&D, 204-IL-050 / CF) with final concentration at 0.4 ng / mL for 16h at 37°C in a 5% CO2incubator.

[0387] After incubation, 5 μL of induced cell supernatant was transferred to a new 384-well plate well (Coring 3764) to mix with 45 μL of QUANTI-Blue Solution. After 1 h incubation at 37°C, the plate was read using a spectrophotometer at 620 nm.

[0388] The percentage of inhibition was calculated by the following formula: % inhibition = (positive control-Sample) / (positive control-negative control) *100 Positive control: OD620 reading of cells with IL-4 stimulation. Negative control: OD620 reading of cells without IL-4 stimulation. Sample: OD620 reading of cells with compound at specific concentration and IL-4 stimulation

[0389] The % inhibition was plotted against compound concentration in logarithmic scale and the IC50was rendered using 4-parameter nonlinear regression (GraphPad Prism).Example B: STAT6 TR-FRET binding assay

[0390] The binding potency of inhibitors was examined in STAT6 / IL-4R interaction in competitive mode using TR-FRET technology. His-tagged STAT6 (AA123-658) (Biortus) can bind Biotinylated ASSGEEG{pTYR}KPFQDLI peptide (pIL-4R peptide, Genscript); anti-His6-Tb cryptate Gold can detect STAT6 and function as a donor, and SA-XL665 detecting pIL-4R functions as an acceptor. STAT6 binding to pIL-4R produces a FRET signal, and when the binding is competed by an inhibitor, the FRET signal deceases in a dose-dependent manner.

[0391] A serial dilution of work solution of tested compound was made in DMSO with 1000X of final concentration, and 20 nL of compound DMSO solution was transferred into OptiPlate-384 plates (Perkin Elmer, 6007290) by Echo655 and incubated with 5 µL STAT6 (123-658) at final concentration of 25 nM for 1 minutes. Five µL biotinylated pIL-4R was transferred to each well at final concentration of 400 nM and incubated for 30 minutes at room temperature. Finally, 5ul of each anti-His6-Tb cryptate Gold donor (0.5 nM final) and SA-XL665 acceptor (50 nM final) were added into the well and incubated at room temperature for 2 hours in the dark. The FRET signal was then recorded with EnVison2105 microplate reader (Perkin Elmer).

[0392] The percentage of inhibition was calculated by the following formula: % inhibition = (positive control-Sample) / (positive control-negative control) *100 Positive control: FRET reading of control cells with both STAT6 and pIL-4R without compound. Negative control: FRET reading of control cells without pIL-4R and compounds. Sample: FRET reading of cells with compound at specific concentration and STAT6 and pIL-4R

[0393] The % inhibition was plotted against compound concentration in logarithmic scale and the IC50was rendered using 4-parameter nonlinear regression (GraphPad Prism).

[0394] The data from example A and B is shown in table 2. Table 2A: 0 < IC50 ≤ 500nM B: IC50 >500nM NT: Not tested

[0395] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1is independently halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R1on the same carbon atom are taken together to form an oxo; n is 0, 1, 2, 3, 4, 5, or 6; R10is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; R11is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R12and R13are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R12and R13are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; each Z is independently N or CR2;each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; U is C or N; T is C or N; provided that not both of U and T are N; X1is N or CR5; R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X2is N or CR6; R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R5and R6are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R6and R7are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4;Ring F is a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, or a 6-membered heteroaryl; each R18is independently halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, - L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R18on the same atom form an oxo; v is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring F is a 5-membered heterocycloalkyl comprising one or two heteroatoms that are N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R18is independently halogen, C1-C6alkyl, or C1-C6haloalkyl; and / or two R18on the same atom form an oxo.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R18is independently C1-C6alkyl or C1-C6haloalkyl; and / or two R18on the same atom form an oxo.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R18is independently C1-C6alkyl; and / or two R18on the same atom form an oxo.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: v is 0, 1, 2, or 3.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: v is 2 or 3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: U is C.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: T is C.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X1is N.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X1is CR5.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X2is N.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X2is CR6.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X3is N.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X3is CR7.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: Ring A is heterocycloalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: each R1is independently C1-C6alkyl; and / or two R1on the same carbon atom are taken together to form an oxo.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: n is 2, 3, or 4.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-; R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

23. The compound of claim 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R30is C1-C6alkyl.

24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R31is hydrogen, -CN, C1-C6alkyl, C1-C6hydroxyalkyl, or -L-cycloalkyl.

25. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R31is C1-C6alkyl.

26. The compound of any one of claims 22-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: X is -O-.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:.

28. A compound of Formula (IXa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (IXa); wherein: R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-; R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Z is independently N or CR2; each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; RY1is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1- C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2,C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

29. The compound of claim 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: RY1is C1-C6alkyl.

30. The compound of claim 28 or 29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: RY1is ethyl.

31. A compound of Formula (IXb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: R30is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R31is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, - L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X is -O-, -S-, -NR32-, or -C(R33)2-; R32is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R33is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Z is independently N or CR2; each R2is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R3is independently hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkylene-O-cycloalkyl, C1-C6alkylene-O-heterocycloalkyl, C2- C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; X3is N or CR7; R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SF5, -SH, -SRa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R8is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=NRb)(=O)Rb, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -P(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; m is 0, 1, 2, 3, or 4; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3alkylene independently optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen, -CN, -OH, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom form an oxo.

32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R3is independently hydrogen or C1-C6alkyl.

33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: one R3is hydrogen and the other R3is ethyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: X3is N.

35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: X3is CR7.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R30is C1-C6alkyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R31is hydrogen, -CN, C1-C6alkyl, C1-C6hydroxyalkyl, or -L-cycloalkyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R31is -CN or C1-C6alkyl.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R31is C1-C6alkyl.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:.

42. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: Z is CR2.

43. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: Z is N.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R2is independently hydrogen or halogen.

45. The compound of any one of claims 1-42 or 44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R2is hydrogen.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R7is hydrogen, halogen, or C1-C6alkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R7is hydrogen.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R6is hydrogen, halogen, or C1-C6haloalkyl.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R6is C1-C6alkyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R6is C1-C6haloalkyl.

51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: Ring B is phenyl.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R8is independently halogen or -C(=O)NRcRd.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R8is independently -C(=O)NRcRd.

54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R8is independently halogen or -C(=O)NH(heteroaryl); wherein the heteroaryl is independently optionally substituted with one or more R.

55. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R8is independently halogen or heteroaryl; wherein each heteroaryl is independently optionally substituted with one or more R.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: m is 1 or 2.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: m is 1.

58. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:

59. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:, wherein: Ring H is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8ais hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and u is 0, 1, 2, 3, or 4.

60. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:, wherein: Ring H is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R8ais hydrogen, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; each R is independently halogen, -CN, -OH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, - S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -C(=O)C1- C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C3-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and u is 0, 1, 2, 3, or 4.

61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: Ring H is a 5-membered heteroaryl.

62. The compound of any one of claims 59-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R8ais hydrogen, halogen, or C1-C6alkyl.

63. The compound of any one of claims 59-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: R8ais halogen.

64. The compound of any one of claims 59-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:each R is independently halogen, -CN, -OH, -NH2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C3- C6cycloalkyl, or 3- to 6-membered heterocycloalkyl.

65. The compound of any one of claims 59-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R is independently -CN, C1-C3alkyl, or C3-C6cycloalkyl.

66. The compound of any one of claims 59-65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: each R is independently C1-C3alkyl.

67. The compound of any one of claims 59-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein: u is 1 or 2.

68. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:

69. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:

70. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein:.

71. A compound selected from a compound found in table 1 or in the specification, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

72. A pharmaceutical composition comprising a compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

73. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or the pharmaceutical composition of claim 72.

74. The method of claim 73, wherein the disorder in alopecia, aspergillus, asthma, atomic dermatitis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyposis, gastritis, inflammatory bowel disease, pemphigoid, prurigo nodularis, sinusitis, or urticaria.

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