Heterocyclic compounds as KIT kinase inhibitors

Abstract

Described herein are compounds of Formula I that are inhibitors of wild-type and oncogenic mutant c-KIT kinase, and their use in the treatment of disorders such as cancer. TIFF2024546477000398.tif2961

Description

Related Applications

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 287,857, filed December 9, 2021, and U.S. Provisional Patent Application No. 63 / 329,674, filed April 11, 2022, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

[0002] Gain-of-function mutations in the type III receptor tyrosine kinases KIT and PDGFRA are present in many cancers and myeloproliferative disorders. For example, gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT (~80%) and PDGFRA (~5-10%). Mutations in KIT drive more than 90% of cases of systemic mastocytosis (SM) and mast cell leukemia (MCL), as well as a small but significant proportion of acute myeloid leukemia (AML), germ cell tumors, and melanomas. PDGFRA mutations or gene rearrangements are also observed in cancers such as eosinophilic leukemia and glioblastoma. KIT and / or PDGFRA gene amplifications are also likely to be oncogenic in gliomas and lung cancers.

[0003] Most primary and secondary resistance mutations in KIT and PDGFRA are located within switch regions present within the intracellular kinase domain. KIT and PDGFRA have been named "dual switch kinases" based on the observation that they each incorporate a) an autoinhibitory switch within the intracellular juxtamembrane domain (JMD), and b) a major activation loop (AL) switch within the kinase domain. Several studies have shown that this dual switch mechanism regulates KIT and PDGFRA cellular kinase activity by controlling kinase conformation. Indeed, phosphorylation of one or more amino acids induces a conformational change that leads to activation of the kinase from an inactive (or "off") state to an active (or "on") state. Disruption of one or more of these switch control mechanisms can cause the kinase to abnormally adopt an active type I conformation. In approximately 70% of GIST patients, the primary activating mutation is found in KIT exon 11, which encodes the JMD inhibitory switch, which results in a loss of function in the inhibitory switch, shifting the conformational equilibrium toward the active type I form. A small proportion of primary activating mutations and nearly all secondary resistance mutations in GISTs are mutations located either in the major AL switch found in exons 17 and 18 of KIT and exon 18 of PDGFRA, respectively, or in exons 13 and 14 of KIT and exons 14 and 15 of PDGFRA in the switch pocket region adjacent to the ATP-binding pocket. These gain-of-function mutations similarly stabilize the active type I conformation. Specifically, the D816 switch residue of KIT (exon 17) and the analogous D842 residue of PDGFRA (exon 18) are essential for the AL switch to exist in the type II off state. Mutation of these aspartic acid residues to valine (KIT D816V and PDGFRA D842V mutants) results in a change in protein conformation, resulting in the transition of the kinase from an inactive state (type II conformation) to an active state (type I conformation). Diseases caused by mast cell proliferation, such as systemic mastocytosis (SM) and mantle cell lymphoma (MCL), as well as a small proportion of acute myeloid leukemias (AML), are driven by primary mutations in the major AL switch of KIT (e.g., D816V or N822K).Similarly, the D842V mutation within the major AL switch of PDGFRA is the most common primary mutation observed within a small subset of PDGFRA mutant GISTs.

[0004] The treatment of metastatic GIST was revolutionized by the advent of tyrosine kinase inhibitors (TKIs), led by imatinib, a potent inhibitor of the primary exon 11 JMD KIT mutation, which was approved in 2002 as a first-line therapy for advanced GIST. Although the majority of GIST patients responded well to imatinib treatment, approximately 10-14% of treated patients were found to be insensitive to imatinib therapy. In addition, more than half of the initial imatinib treatment responders showed drug resistance within 2 years of imatinib therapy. This resistance was mainly due to the formation of secondary mutations within KIT (e.g., exon 13 V654A within the switch pocket region or various exon 17 mutations in the AL switch). Subsequently, sunitinib and regorafenib were approved as second- and third-line therapies for imatinib-resistant GIST. Sunitinib preferentially inhibits secondary KIT mutations in exons 13 and 14, but does not inhibit secondary mutations in exon 17 / 18 AL switch. Conversely, regorafenib inhibits a subset of secondary mutations primarily in exon 17, but only weakly inhibits secondary mutations in KIT exons 13 and 14.

[0005] Examination of individual GIST patient biopsies obtained from different ongoing metastases indicates that a complex heterogeneous array of primary and multiple secondary KIT mutations can exist within the same patient and within different metastatic lesions. This observation further complicates the selection of an appropriate TKI-based therapy. Furthermore, the off-target kinase activity of sunitinib and regorafenib poses tolerability issues, which require significant clinical treatment management (e.g., drug holidays, dose reductions). The necessary adjustments of the therapy treatment schedule may also exacerbate the development of additional secondary resistance mutations. From a safety perspective, the use of avapritinib has also been limited by central nervous system (CNS) adverse events that have led to black box label restrictions.

[0006] There is a clear unmet need for tyrosine kinase inhibitors with potent inhibitory activity against a broad range of clinically relevant KIT and PDGFRA mutations, as well as an improved safety and tolerability profile compared to currently available GIST treatments. Summary of the Invention

[0007] Described in part herein are compounds that are inhibitors of wild-type and oncogenic mutant c-KIT kinase, and methods of their use, e.g., for the treatment of cancers driven by c-KIT kinase mutations, e.g., primary (KIT exons 9 or 11) and secondary (exons 13, 14, 17, and 18) c-KIT mutations.

[0008] In one embodiment, the compound represented by formula I:

[0009] [ka]

[0010] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, Q is,

[0011] [ka]

[0012] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 )m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0013] [ka]

[0014] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0015] [ka]

[0016] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3; However, the compound is

[0017] [ka]

[0018] Provided that: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019]

[0009] The features and other details of the present disclosure are described more specifically here. The specific terms employed in the specification, examples and the appended claims are summarized here. These definitions should be read in light of the remaining parts of this disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0020] definition

[0010] The definitions set forth in this application are intended to clarify terms used throughout this application.

[0021]

[0011] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this subject belongs. When used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth to facilitate understanding of this disclosure.

[0022]

[0012] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The terms "comprise," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0023]

[0013] As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th Ed. 1994. In addition, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Smith, MB and March, J., eds. John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0024]

[0014] As used in this specification, the term "herein" means the entire application.

[0015] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs as well as cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl may be substituted and also cases where the alkyl is not substituted.

[0025]

[0016] It is understood that the substituents and substitution patterns on the compounds of the present disclosure can be selected by those skilled in the art to produce chemically stable compounds that can be easily synthesized from readily available starting materials by techniques known in the art, as well as the methods described below.When a substituent itself is substituted with two or more groups, it is understood that these multiple groups can be on the same carbon or different carbons, as long as a stable structural result is obtained.

[0026] As used herein, the term "optionally substituted" includes any of the following: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, alkoxy, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, and -OC(=O)-CH 2 Refers to the replacement of 1-6 hydrogen atoms in a given structure with the radical of a specified substituent, including but not limited to -Oalkyl. Preferably, "optionally substituted" refers to the replacement of 1-4 hydrogen radicals in a given structure with a substituent as described above. More preferably, 1-3 hydrogen radicals are replaced by a substituent as described above. It is understood that the substituents may be further substituted.

[0027]

[0018] As used herein, the term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It should be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, as well as the implicit proviso that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more of the same or different substituents for appropriate organic compounds. For purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom.

[0028]

[0019] The substituents can include any of the substituents described herein, for example, such substituents can include, unless otherwise specified, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, alkoxy, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety. Those skilled in the art will understand that the substituents themselves can be substituted where appropriate. For example, substituents of substituted alkyl include substituted and unsubstituted amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN, etc. Unless specifically described as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0029]

[0020] As used herein, the term "alkyl" refers to a completely saturated straight or branched chain non-aromatic hydrocarbon. Typically, a straight or branched chain alkyl group has from 1 to about 20, preferably from 1 to about 10, carbon atoms, e.g., C, unless otherwise defined. 1 -C 6 Alkyl, or e.g. C 1 -C 6It may be alkyl. Examples of straight chain and branched alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. Furthermore, the term "alkyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone. An "alkyl" group may be optionally substituted.

[0030] When used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, or alkoxy, "C x -C y " is meant to include groups containing x to y carbons in the chain. For example, "C x -C y The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. 0 Alkyl represents a hydrogen when the group is in a terminal position and a bond when it is internal.

[0031]

[0022] As used herein, the terms "amine" and "amino" refer to both unsubstituted and substituted amines and their salts, e.g., moieties represented by the formula:

[0032] [ka]

[0033] In the formula, R zeach independently represents hydrogen or a hydrocarbyl group, or R z The groups, together with the N atom to which they are attached, complete a heterocyclyl having 4 to 8 atoms in the ring structure.

[0034]

[0023] As used herein, the terms "amide" and "amido" are represented by the formula:

[0035] [ka]

[0036] In the formula, R x , R y , and R z each independently represents hydrogen or a hydrocarbyl group, or R y and R z together with the N atom to which they are attached complete a heterocyclyl having 4 to 8 atoms in the ring structure.

[0037]

[0024] As used herein, the term "alkoxy" refers to a straight or branched chain saturated aliphatic (alkyl) hydrocarbon radical bonded to an oxygen atom attached to a core structure. The alkoxy group preferably has 1 to 6 carbon atoms, i.e., C 1 -C 6 It may be alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, etc. As used herein, the term "alkoxy" may be optionally substituted as defined above.

[0038]

[0025] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogens. Monohaloalkyl radicals can have, for example, a chlorine, bromine, iodine, or fluorine atom. Dihalo and polyhaloalkyl radicals can have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and the like.

[0039]

[0026] As used herein, the term "haloalkoxy" refers to a radical in which one or more of the hydrogen atoms of an alkoxy group has been replaced with one or more halogens. Representative examples of "haloalkoxy" groups include difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), or trifluoroethoxy (-OCH 2 CF 3 ), but are not limited to these.

[0040]

[0027] As used herein, the term "hydrocarbyl" refers to an aliphatic hydrocarbon group. The hydrocarbyl moiety may be a "saturated alkyl" group, meaning that it does not contain any alkene or alkyne moieties. The hydrocarbyl moiety may also be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a straight or branched hydrocarbon chain group consisting of 2-8 carbon atoms and at least one carbon-carbon double bond, which is attached to the remainder of the molecule by a single bond, such as ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. An "alkyne" moiety refers to a straight or branched hydrocarbon chain group consisting of 2-8 carbon atoms and at least one carbon-carbon triple bond, which is attached to the remainder of the molecule by a single bond. The hydrocarbyl moiety may be branched or straight, whether saturated or unsaturated.

[0041] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group. As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0042]

[0030] As used herein, the term "cycloalkyl", alone or in combination with other terms, refers to a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic, bicyclic, and tricyclic rings. Typically, monocyclic cycloalkyl groups, unless otherwise defined, have from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms (e.g., C 3 -C 10 Cycloalkyl, or for example, C 3 -C 6Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The second ring of a bicyclic cycloalkyl, or the second or third ring of a tricyclic cycloalkyl, may be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic and tricyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic or tricyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl, or the second or third ring of a fused tricyclic cycloalkyl, may be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyl includes alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF 3 , -CN, and the like. Cycloalkyl may alternatively be polycyclic having three or more rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls. As used herein, the term "cycloalkyl" may be optionally substituted as defined above.

[0043]

[0031] As used herein, the term "cycloalkyloxy" refers to a cycloalkyl group bonded to an oxygen atom attached to a core structure. Exemplary cycloalkyloxy groups include those described herein as C 3 -C 6 Examples of cycloalkyloxy groups include, but are not limited to, cycloalkyloxy groups of 3 to 6 carbon atoms, referred to as cycloalkyloxy groups. Exemplary cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutoyloxy, cyclohexyloxy, and the like.

[0044] As used herein, the term "cyano" refers to the group --CN. As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0045]

[0034] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean chloro, fluoro, bromo, and iodo.

[0035] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen (N), oxygen (O), sulfur (S), and silicon (Si).

[0046] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocyclyl," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures that include monocyclic, polycyclic (e.g., bicyclic, tricyclic), bridged or fused ring structures, preferably 3-10 membered rings, more preferably 3-7 membered rings, whose ring structures contain at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Attachment of a heterocyclyl substituent can occur via either a carbon atom or a heteroatom. Examples of "heterocyclyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl, lactone, lactam, and the like, and N-oxides thereof. Heterocyclyl groups may be optionally substituted with one or more suitable groups. Examples of "heterocyclyl" include, but are not limited to, morpholine mimetics. Examples of morpholine mimetics include the following:

[0047] [ka]

[0048] These include, but are not limited to:

[0037] As used herein, the term "heterocyclyloxy" refers to a heterocyclyl group bonded to an oxygen atom attached to a core structure. Exemplary heterocyclyloxy groups include those described herein as C 3 -C 10 Examples of heterocyclyloxy groups include, but are not limited to, 3- to 10-membered heterocyclyloxy rings, referred to as heterocyclyloxy groups. Exemplary heterocyclyloxy groups include, but are not limited to, oxetanyloxy, azetidinyloxy, tetrahydrofuranyloxy, piperidinyloxy, piperazinyloxy, and the like.

[0049]

[0038] "Combination therapy" is treatment that involves the administration of two or more therapeutic agents, for example, a compound of the disclosure and a MAPK pathway inhibitor, to a patient in need thereof.

[0039] "Disease," "disorder," and "condition" are used interchangeably herein.

[0050]

[0040] "Individual", "patient", or "subject" are used interchangeably herein and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. The compounds described herein may be administered to mammals, such as humans, but also to other mammals, such as animals requiring veterinary care, for example, companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0051]

[0041] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0052]

[0042] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonicity agents, absorption retardants, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also include other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0053]

[0043] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of an acidic or basic group that may be present in the compound used in the present composition. The compounds included in the present composition that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharma- ceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts with pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds contained in the present composition that are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, specifically calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds contained in the present composition that contain a basic or acidic moiety can also form pharma-ceutically acceptable salts with various amino acids. Compounds of the present disclosure may contain both acidic and basic groups, for example, one amino group and one carboxylic acid group. In such cases, the compounds may exist as acid addition salts, zwitterions, or base salts.

[0054]

[0044] The compounds of the present disclosure may contain one or more chiral centers and therefore may exist as stereoisomers. As used herein, the term "stereoisomer" consists of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S" depending on the configuration of the substituents around the stereogenic carbon atom, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center. The compounds described herein include all stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the nomenclature "(±)", but those skilled in the art will recognize that the structure may implicitly indicate a chiral center.

[0055]

[0045] As used herein, the term "therapeutically effective amount" refers to an amount of the subject compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

[0056]

[0046] "Treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., for example, amelioration, alleviation, modulation, or elimination.

[0047] The present disclosure also encompasses isotopically labeled compounds that are identical to those enumerated herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36Cl. For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0057]

[0048] Individual enantiomers and diastereomers of the compounds of the present disclosure may be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary, (2) salt formation with an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers in a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods such as chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, which is a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis encompasses both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. See, e.g., Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0058]

[0049] As used herein, "compounds of the disclosure" include compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE, formula IF, formula IG, formula IH, formula II, formula IJ, formula IK, formula IL, formula IM, formula IN, formula IO, and formula IP, formula IQ, formula IR, formula IS, formula IT, formula IU, formula IV, formula IW, formula IX, formula IY, formula IZ, formula I-AA, formula I-AB, and formula I-AC, or pharma- ceutically acceptable salts, enantiomers, stereoisomers, or tautomers thereof.

[0059] compound Compounds of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF In one embodiment, the compound represented by formula I:

[0060] [ka]

[0061] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, Q is,

[0062] [ka]

[0063] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0064] [ka]

[0065] If L is R 7 , and L and R 7together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0066] [ka]

[0067] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3; However, the compound is

[0068] [ka]

[0069] Provided that: In one embodiment, the compound represented by formula IA:

[0070] [ka]

[0071] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0072] [ka]

[0073] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0074] [ka]

[0075] If L is R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, alkoxy, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0076] [ka]

[0077] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 H, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3; However, the compound is

[0078] [ka]

[0079] Provided that: In one embodiment, the compound represented by formula IB:

[0080] [ka]

[0081] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0082] [ka]

[0083] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6alkyl, or Q is selected from the group consisting of

[0084] [ka]

[0085] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0086] [ka]

[0087] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3.

[0088] In one embodiment, the compound represented by formula IC:

[0089] [ka]

[0090] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0091] [ka]

[0092] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0093] [ka]

[0094] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0095] [ka]

[0096] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3.

[0097] In one embodiment, the compound represented by formula ID:

[0098] [ka]

[0099] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0100] [ka]

[0101] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0102] [ka]

[0103] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0104] [ka]

[0105] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 6 is an optionally substituted C 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and cycloalkyl, or R 1When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3.

[0106] In one embodiment, the compound represented by formula IE:

[0107] [ka]

[0108] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0109] [ka]

[0110] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0111] [ka]

[0112] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0113] [ka]

[0114] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 6 is an optionally substituted C 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and cycloalkyl, or R 5When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 R is independently selected from the group consisting of alkyl and halogen; 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3.

[0115] In one embodiment, the compound represented by formula IF:

[0116] [ka]

[0117] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; Q is,

[0118] [ka]

[0119] wherein s1 is a moiety covalently attached to the ring and s2 is a moiety covalently attached to L; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or Q is selected from the group consisting of

[0120] [ka]

[0121] If L is R 7 , and L and R 7 together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or QLE together,

[0122] [ka]

[0123] is selected from the group consisting of E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3; However, the compound is

[0124] [ka]

[0125] Provided that: In some embodiments, R1 is H, haloalkyl, optionally substituted C 1 -C 6 Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6alkyl.

[0126] In some embodiments, R 1 H,

[0127] [ka]

[0128] is selected from the group consisting of: In some embodiments, R 1 H,

[0129] [ka]

[0130] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6 Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen.1 -C 6 Heterocyclyl, optionally substituted C 1 -C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0131] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 , C.F. 2 CF 3 ,

[0132] [ka]

[0133] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0134] [ka]

[0135] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C 1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6is independently selected from the group consisting of alkyl and halogen.

[0136] In some embodiments, R 2 H,

[0137] [ka]

[0138] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 1 and R 2 Together,

[0139] [ka]

[0140] and forming a ring structure selected from the group consisting of: In some embodiments, R 2 and R 5 Together,

[0141] [ka]

[0142] wherein s3 is a site covalently bonded to the bicyclic ring structure and s4 is a site covalently bonded to the oxygen atom. In some embodiments, R 6 is an optionally substituted C 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, and cycloalkyl.

[0143] In some embodiments, R 6 is methyl and

[0144] [ka]

[0145] is selected from the group consisting of: In some embodiments, R 1 and R 6 Together,

[0146] [ka]

[0147] wherein s3 is a site covalently bonded to the bicyclic ring structure and s4 is a site covalently bonded to the oxygen atom. In some embodiments, R 5 and R 6 Together,

[0148] [ka]

[0149] and forming a ring structure selected from the group consisting of: In some embodiments, R 3 is F or alkoxy. In some embodiments, R 3 is F.

[0150] In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy. In some embodiments, R 4 is H.

[0151] In some embodiments, X 1 , X 2 , X 3 , and X 4 are independently CH or N, with the proviso that X 3 and X 4 The condition is that at most one of is N. In some embodiments, X 1 is CH and X 2 is CH.

[0152] In some embodiments, X 1 is CH and X 2 is N. In some embodiments, X 3 is CH and X 4 is N. In some embodiments, X 1 is N and X 2 is CH and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is N and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is N and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is CH and X 4 is either N or X 1 is N and X 2 is N and X 3 is CH and X 4 is CH or X 1 is N and X 2 is N and X 3 is N and X 4 is CH or X 1 is N and X 2is N and X 3 is CH and X 4 is N.

[0153] In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl. In some embodiments,

[0154] [ka]

[0155] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0156] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro. In some embodiments,

[0157] [ka]

[0158] is selected from the group consisting of: In some embodiments, E is H;C 1 -C 6 Alkenyl; Cyano; Haloalkoxy; Haloalkyl; Optionally substituted C 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are 1 -C 6Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 1 -C 6 Alkyl; optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted, at each occurrence, is selected from the group consisting of C 1 -C 6 Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 3 -C 6 cycloalkyl; optionally substituted heterocyclyl, each of which is optionally substituted, at each occurrence, C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl.

[0159] In some embodiments, E is H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0160] [ka]

[0161] is selected from the group consisting of: In some embodiments,

[0162] [ka]

[0163] is selected from the group consisting of: In some embodiments,

[0164] [ka]

[0165] is selected from the group consisting of: In some embodiments, L is not a direct bond and E is H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0166] [ka]

[0167] is selected from the group consisting of: In some embodiments, L is not a direct bond and E is H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0168] [ka]

[0169] is selected from the group consisting of: In some embodiments,

[0170] [ka]

[0171] teeth,

[0172] [ka]

[0173] is selected from the group consisting of: In some embodiments, when L is a direct bond,

[0174] [ka]

[0175] teeth,

[0176] [ka]

[0177] is selected from the group consisting of: In some embodiments, R 7 is H, alkyl, or haloalkyl. In some embodiments, R 7 is H.

[0178] In some embodiments,

[0179] [ka]

[0180] It is. In some embodiments,

[0181] [ka]

[0182] It is. In some embodiments, E is selected from the group consisting of H, fluoro, methoxy, and cyano.

[0183] In some embodiments,

[0184] [ka]

[0185] teeth,

[0186] [ka]

[0187] is selected from the group consisting of:

[0100] In some embodiments,

[0188] [ka]

[0189] teeth,

[0190] [ka]

[0191] is selected from the group consisting of:

[0101] In some embodiments,

[0192] [ka]

[0193] teeth,

[0194] [ka]

[0195] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0196] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro. In some embodiments, E is H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0197] [ka]

[0198] is selected from the group consisting of: In some embodiments, E is H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0199] [ka]

[0200] is selected from the group consisting of:

[0106] In some embodiments,

[0201] [ka]

[0202] teeth,

[0203] [ka]

[0204] is selected from the group consisting of: In some embodiments, R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; R 10 is selected from the group consisting of H and alkyl.

[0205] In some embodiments, R 8 teeth,

[0206] [ka]

[0207] R 10 is selected from the group consisting of H, methyl, ethyl, and isopropyl. In some embodiments, R 8 is R 10 , and R 8 and R 10 Together with the N atom to which it is attached,

[0208] [ka]

[0209] and forming a ring structure selected from the group consisting of: In some embodiments, L is a direct bond and R 8 teeth,

[0210] [ka]

[0211] R 10 is H. In some embodiments, R 9 teeth,

[0212] [ka]

[0213] is selected from the group consisting of: In some embodiments, R 11 H and C1 -C 6 alkyl.

[0214] In some embodiments, R 11 is selected from the group consisting of H and methyl. In some embodiments, R 11 is R 9 and together with the atoms to which they are each attached form an optionally substituted ring structure, the substituents, at each occurrence, are independently selected from the group consisting of alkyl, haloalkyl, and cycloalkyl.

[0215] In some embodiments, R 11 is R 9 and each of them together with the atom to which they are attached form an optionally substituted ring, and in the case of two occurrences of substituents, together with the atom to which they are attached form a 4- to 6-membered ring.

[0216] In some embodiments, R 11 is R 9 and together with the atoms to which they are each attached,

[0217] [ka]

[0218] and forming an optionally substituted ring selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0219] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro. Compounds of formula IG, IH, II, IJ, IK, IL, and IM In one embodiment, the compound represented by formula IG:

[0220] [ka]

[0221] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0222] In one embodiment, the compound represented by formula IH:

[0223] [ka]

[0224] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5is an optionally substituted alkyl group, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0225] In one embodiment, the compound represented by formula II:

[0226] [ka]

[0227] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X2 are each independently selected from the group consisting of N, CH, and CF; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0228] In one embodiment, the compound represented by formula IJ:

[0229] [ka]

[0230] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0231] In one embodiment, the compound represented by formula IK:

[0232] [ka]

[0233] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0234] In one embodiment, the compound represented by formula IL:

[0235] [ka]

[0236] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 7 is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0237] In one embodiment, the compound represented by formula IM:

[0238] [ka]

[0239] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl, or R 7 , and L and R 7 when taken together with the N atom to which it is attached, forms an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. wherein the substituents of the optionally substituted amide are independently, at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 7is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; each occurrence of m is independently 0, 1, 2, 3, or 4; However, the compound is

[0240] [ka]

[0241] Provided that: In some embodiments, R 1 is H, haloalkyl, optionally substituted C 1 -C 6 Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6Alkoxy, C 1 -C 6 Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6 alkyl.

[0242] In some embodiments, R 1 H,

[0243] [ka]

[0244] is selected from the group consisting of: In some embodiments, R 1 H,

[0245] [ka]

[0246] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6 Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 Heterocyclyl, optionally substituted C 1 -C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0247] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 , C.F. 2 CF 3 ,

[0248] [ka]

[0249] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0250] [ka]

[0251] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C 1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 is independently selected from the group consisting of alkyl and halogen.

[0252] In some embodiments, R 2 H,

[0253] [ka]

[0254] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 3 is F or alkoxy.

[0255] In some embodiments, R 3 is F. In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy.

[0256] In some embodiments, R 4 is H. In some embodiments, X 1 , X 2 , X 3 , and X 4are independently CH or N, with the proviso that X 3 and X 4 The condition is that at most one of is N.

[0257] In some embodiments, X 1 is CH and X 2 is CH. In some embodiments, X 1 is CH and X 2 is N. In some embodiments, X 3 is CH and X 4 is N.

[0258] In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl.

[0144] In some embodiments,

[0259] [ka]

[0260] teeth,

[0261] [ka]

[0262] is selected from the group consisting of:

[0145] In some embodiments,

[0263] [ka]

[0264] teeth,

[0265] [ka]

[0266] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0267] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro.

[0148] In some embodiments,

[0268] [ka]

[0269] teeth,

[0270] [ka]

[0271] is selected from the group consisting of:

[0149] In some embodiments,

[0272] [ka]

[0273] teeth,

[0274] [ka]

[0275] is selected from the group consisting of: In some embodiments, R 7 is H, alkyl, or haloalkyl. In some embodiments, R 7 is H.

[0276] In some embodiments, E is optionally substituted C. 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are 1 -C 6 Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted, at each occurrence, is selected from the group consisting of C 1 -C 6 Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 3 -C 6 Cycloalkyl, H, C 1 -C 6 It is selected from the group consisting of alkenyl, cyano, haloalkoxy, haloalkyl, and halogen.

[0277] In some embodiments, L is (E 11 ) m When E is alkyl optionally substituted with H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0278] [ka]

[0279] is selected from the group consisting of: In some embodiments, L is (E 11 ) m When E is alkyl optionally substituted with H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl,

[0280] [ka]

[0281] is selected from the group consisting of:

[0155] In some embodiments,

[0282] [ka]

[0283] teeth,

[0284] [ka]

[0285] is selected from the group consisting of:

[0156] In some embodiments,

[0286] [ka]

[0287] teeth,

[0288] [ka]

[0289] is selected from the group consisting of:

[0157] In some embodiments,

[0290] [ka]

[0291] teeth,

[0292] [ka]

[0293] is selected from the group consisting of:

[0158] In some embodiments,

[0294] [ka]

[0295] teeth,

[0296] [ka]

[0297] is selected from the group consisting of:

[0159] In some embodiments,

[0298] [ka]

[0299] teeth,

[0300] [ka]

[0301] is selected from the group consisting of: In some embodiments, when L is a direct bond,

[0302] [ka]

[0303] teeth,

[0304] [ka]

[0305] is selected from the group consisting of: In some embodiments, R 7 is L and R 7 and L, together with the N atom to which they are attached, form an optionally substituted ring, where the substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, and haloalkyl.

[0306] In some embodiments, R 7 is L and R 7 and L together with the N atom to which they are attached form an optionally substituted ring, and in the case of two occurrences of substituents, together with the atoms to which they are attached form a 4- to 6-membered ring.

[0307] In some embodiments, R 7 is L and R 7 and together with the N atom to which L is attached,

[0308] [ka]

[0309] and forming a ring structure selected from the group consisting of: Compounds of formula IN, formula IO, formula IP, and formula IQ In one embodiment, the compound represented by formula IN:

[0310] [ka]

[0311] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. wherein the substituents of the optionally substituted amide are independently, at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4is selected from the group consisting of H, F, alkyl, and alkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; However, the compound is

[0312] [ka]

[0313] Provided that: In one embodiment, the compound represented by formula IO:

[0314] [ka]

[0315] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 is an optionally substituted alkyl group, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; each occurrence of m is independently 0, 1, 2, 3, or 4; However, the compound is

[0316] [ka]

[0317] Provided that: In one embodiment, the compound represented by formula IP:

[0318] [ka]

[0319] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; each occurrence of m is independently 0, 1, 2, 3, or 4; However, the compound is

[0320] [ka]

[0321] Provided that: In one embodiment, the compound represented by formula IQ:

[0322] [ka]

[0323] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, and Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 selected from the group consisting of optionally substituted alkyl, independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; each occurrence of m is independently 0, 1, 2, 3, or 4; However, the compound is

[0324] [ka]

[0325] Provided that: In some embodiments, R 1is H, haloalkyl, optionally substituted C 1 -C 6 Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6alkyl.

[0326] In some embodiments, R 1 H,

[0327] [ka]

[0328] is selected from the group consisting of: In some embodiments, R 1 H,

[0329] [ka]

[0330] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6 Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen.1 -C 6 Heterocyclyl, optionally substituted C 1 -C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0331] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 ,

[0332] [ka]

[0333] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0334] [ka]

[0335] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C 1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 is independently selected from the group consisting of alkyl and halogen.

[0336] In some embodiments, R 2 H,

[0337] [ka]

[0338] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 3 is F or alkoxy.

[0339] In some embodiments, R 3 is F. In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy.

[0340] In some embodiments, R 4 is H. In some embodiments, X 1 , X 2 , X 3 , and X 4 are independently CH or N, with the proviso that X 3 and X 4 The condition is that at most one of is N.

[0341] In some embodiments, X 1 is CH and X 2 is CH. In some embodiments, X 1 is CH and X 2 is N. In some embodiments, X 3 is CH and X 4 is N.

[0342] In some embodiments, X 1 is N and X 2 is CH and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is N and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is N and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is CH and X 4 is either N or X 1 is N and X 2 is N and X 3 is CH and X 4 is CH or X 1 is N and X 2 is N and X 3 is N and X 4 is CH or X 1 is N and X 2 is N and X 3 is CH and X 4 is N.

[0343] In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl.

[0187] In some embodiments,

[0344] [ka]

[0345] teeth,

[0346] [ka]

[0347] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0348] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro. In some embodiments,

[0349] [ka]

[0350] teeth,

[0351] [ka]

[0352] is selected from the group consisting of: In some embodiments,

[0353] [ka]

[0354] teeth,

[0355] [ka]

[0356] It is. In some embodiments,

[0357] [ka]

[0358] teeth,

[0359] [ka]

[0360] It is. In some embodiments, E is an optionally substituted amide, wherein the substituents, at each occurrence, are optionally substituted C 1 -C 6 and optionally substituted amides, each of which is independently selected from the group consisting of alkyl, alkyl, and alkyl groups, each of which is independently selected from the group consisting of alkyl, alkyl, and alkyl groups. 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano), H, cyano, haloalkoxy, haloalkyl, and halogen.

[0361] In some embodiments, E is selected from the group consisting of H, fluoro, methoxy, and cyano.

[0195] In some embodiments,

[0362] [ka]

[0363] teeth,

[0364] [ka]

[0365] is selected from the group consisting of: Compounds of formula IR, formula IS, formula IT, and formula IU

[0196] In one embodiment, the compound represented by formula IR:

[0366] [ka]

[0367] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. wherein the substituents of the optionally substituted amide are independently, at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0368] In one embodiment, the compound represented by formula IS:

[0369] [ka]

[0370] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 is an optionally substituted alkyl group, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0371] In one embodiment, the compound represented by formula IT:

[0372] [ka]

[0373] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, cyano, alkoxy, haloalkoxy, haloalkyl, halogen, Optionally substituted amides, wherein the substituents, at each occurrence, are selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl ( The optionally substituted alkyl substituents at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, independently selected from the group consisting of cycloalkyl and heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 The two occurrences of together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0374] In one embodiment, the compound represented by formula IU:

[0375] [ka]

[0376] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 is selected from the group consisting of alkyl, E is H, cyano, alkoxy, haloalkoxy, haloalkyl, halogen, Optionally substituted amides, wherein the substituents, at each occurrence, are selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl ( The optionally substituted alkyl substituents at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted alkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein each occurrence of the optionally substituted substituent is selected from the group consisting of C 1 -C 6 an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein each occurrence of the optionally substituted substituent is C 1 -C 6 optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of optionally substituted alkoxy, which are independently selected from the group consisting of cycloalkyl, heterocyclyl; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 The two occurrences of together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of F and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; Each occurrence of m is independently 0, 1, 2, 3, or 4.

[0377] In some embodiments, R 1 is H, haloalkyl, optionally substituted C 1 -C 6 Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6 alkyl.

[0378] In some embodiments, R 1 H,

[0379] [ka]

[0380] is selected from the group consisting of: In some embodiments, R 1 H,

[0381] [ka]

[0382] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 Heterocyclyl, optionally substituted C 1 -C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0383] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 ,

[0384] [ka]

[0385] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0386] [ka]

[0387] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C 1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 is independently selected from the group consisting of alkyl and halogen.

[0388] In some embodiments, R 2 H,

[0389] [ka]

[0390] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 3 is F or alkoxy.

[0391] In some embodiments, R 3 is F. In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy.

[0392] In some embodiments, R 4 is H. In some embodiments, X 1 , X 2 , X 3 , and X 4 are independently CH or N, with the proviso that X 3 and X 4 The condition is that at most one of is N.

[0393] In some embodiments, X 1 is CH and X 2 is CH. In some embodiments, X 1 is CH and X 2 is N. In some embodiments, X 3 is CH and X 4 is N.

[0394] In some embodiments, X 1 is N and X 2 is CH and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is N and X 3 is CH and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is N and X 4 is CH or X 1 is CH and X 2 is CH and X 3 is CH and X 4 is either N or X 1 is N and X 2 is N and X 3 is CH and X 4 is CH or X 1is N and X 2 is N and X 3 is N and X 4 is CH or X 1 is N and X 2 is N and X 3 is CH and X 4 is N.

[0395] In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl.

[0219] In some embodiments,

[0396] [ka]

[0397] teeth,

[0398] [ka]

[0399] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0400] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro.

[0222] In some embodiments,

[0401] [ka]

[0402] teeth,

[0403] [ka]

[0404] is selected from the group consisting of:

[0223] In some embodiments,

[0405] [ka]

[0406] is selected from the group consisting of: In some embodiments,

[0407] [ka]

[0408] teeth,

[0409] [ka]

[0410] is selected from the group consisting of: In some embodiments, E is an optionally substituted amide, wherein the substituents, at each occurrence, are optionally substituted C. 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Heterocyclyl and optionally substituted C 3 -C 6 Optionally substituted amides independently selected from the group consisting of cycloalkyl (optionally substituted C 1 -C 6 The alkyl substituents, in each occurrence, are C 1 -C6 C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl, and optionally substituted; 3 -C 6 The heterocyclyl substituents, at each occurrence, are C 1 -C 6 C, optionally substituted, independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; 3 -C 6 The cycloalkyl substituents, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano, optionally substituted C 1 -C 6 The alkyl, optionally substituted substituents at each occurrence are 1 -C 6 Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted, at each occurrence, is selected from the group consisting of C 1 -C 6 Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. 3 -C 6 Cycloalkyl, optionally substituted heterocyclyl, each of which is optionally substituted at each occurrence, 1 -C 6optionally substituted heterocyclyl, optionally substituted alkoxy, independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, where the optionally substituted substituents at each occurrence are selected from the group consisting of optionally substituted alkoxy, cyano, alkoxy, haloalkoxy, haloalkyl, and halogen, independently selected from the group consisting of cycloalkyl, heterocyclyl, and H.

[0411] In some embodiments, E is H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0412] [ka]

[0413] is selected from the group consisting of: In some embodiments, E is H, fluoro, methyl, trifluoromethyl, methoxy, cyano,

[0414] [ka]

[0415] is selected from the group consisting of:

[0228] In some embodiments,

[0416] [ka]

[0417] teeth,

[0418] [ka]

[0419] is selected from the group consisting of: Compounds of Formula IV, Formula IW, Formula IX, and Formula IY

[0229] In one embodiment, the compound represented by formula IV:

[0420] [ka]

[0421] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. wherein the substituents of the optionally substituted amide are independently, at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4.

[0422]

[0230] In one embodiment, the compound represented by formula IW:

[0423] [ka]

[0424] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 is an optionally substituted alkyl group, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4.

[0425] In one embodiment, the compound represented by formula IX:

[0426] [ka]

[0427] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 The two occurrences of together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4.

[0428]

[0232] In one embodiment, the compound represented by formula IY:

[0429] [ka]

[0430] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 The two occurrences of together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 8 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 10 is selected from the group consisting of H and alkyl, or R 8 , and R 8 and R 10 together with the N atom to which it is attached form an optionally substituted heterocyclyl having 4 to 8 atoms in the ring structure, the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4.

[0431] In some embodiments, R 1 is H, haloalkyl, optionally substituted C 1 -C 6Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6 alkyl.

[0432] In some embodiments, R 1 H,

[0433] [ka]

[0434] is selected from the group consisting of: In some embodiments, R 1 H,

[0435] [ka]

[0436] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6 Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 Heterocyclyl, optionally substituted C 1-C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0437] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 ,

[0438] [ka]

[0439] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0440] [ka]

[0441] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C 1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 is independently selected from the group consisting of alkyl and halogen.

[0442] In some embodiments, R 2H,

[0443] [ka]

[0444] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 3 is F, H, or alkoxy.

[0445] In some embodiments, R 3 is F. In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy.

[0446] In some embodiments, R 4 is H. In some embodiments, X 1 and X 2 is independently CH or N. In some embodiments, X 1 is CH and X 2 is CH.

[0447] In some embodiments, X 1 is CH and X 2 is N. In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl.

[0448]

[0250] In some embodiments,

[0449] [ka]

[0450] teeth,

[0451] [ka]

[0452] is selected from the group consisting of:

[0251] In some embodiments,

[0453] [ka]

[0454] teeth,

[0455] [ka]

[0456] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0457] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro.

[0254] In some embodiments,

[0458] [ka]

[0459] teeth,

[0460] [ka]

[0461] is selected from the group consisting of:

[0255] In some embodiments,

[0462] [ka]

[0463] is as follows:

[0464] [ka]

[0465] is selected from the group consisting of: In some embodiments, R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl.

[0466] In some embodiments, R 8 is C 1 -C 6 It is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl. In some embodiments, R 10 is selected from the group consisting of H and alkyl.

[0467] In some embodiments, R 10 H and C 1 -C 6 alkyl. In some embodiments, R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; R 10 is selected from the group consisting of H and alkyl.

[0468] In some embodiments, R8 teeth,

[0469] [ka]

[0470] R 10 is selected from the group consisting of H, methyl, ethyl, and isopropyl. In some embodiments, R 8 is R 10 , and R 8 and R 10 Together with the N atom to which it is attached,

[0471] [ka]

[0472] and forming a ring structure selected from the group consisting of: In some embodiments, L is a direct bond and R 8 teeth,

[0473] [ka]

[0474] R 10 is H. Compounds of formula IZ, formula I-AA, formula I-AB, and formula I-AC

[0264] In one embodiment, the compound represented by formula IZ:

[0475] [ka]

[0476] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 1 is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6haloalkoxy, hydroxy, and oxo; Optionally substituted cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is

[0477] [ka]

[0478] Provided that:

[0265] In one embodiment, the compound represented by formula I-AA:

[0479] [ka]

[0480] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; X 3 and X 4 are each independently CH or N, with the proviso that X 3 and X 4 , provided that at most one of is N, E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 is an optionally substituted alkyl group, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is

[0481] [ka]

[0482] Provided that:

[0266] In one embodiment, the compound represented by formula I-AB:

[0483] [ka]

[0484] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 2 are each independently selected from the group consisting of N, CH, and CF; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is

[0485] [ka]

[0486] Provided that:

[0267] In one embodiment, the compound represented by formula I-AC:

[0487] [ka]

[0488] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: E 11 is independently selected at each occurrence from the group consisting of H, alkyl, and halogen, or E 11 when taken together with the C atom to which they are attached, form an optionally substituted cycloalkyl having 3-4 atoms in the ring structure, the optional substituents being C 1 -C 6 Alkyl, halogen, C 1-C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 selected from the group consisting of haloalkoxy, hydroxy, and oxo; R 2 is selected from the group consisting of H and optionally substituted alkoxy, where the optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R 5 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl and halogen; R 3 is selected from the group consisting of H, F, and alkoxy; R 4 is selected from the group consisting of H, F, alkyl, and alkoxy; R 5 teeth, Optionally substituted alkyl, where the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide are, independently at each occurrence, C 1 -C 6 is alkyl, The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of an optionally substituted alkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of an optionally substituted heterocyclyl at each occurrence are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of an optionally substituted cycloalkyl, at each occurrence, are C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R 11 is selected from the group consisting of H and alkyl, or R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having 4 to 7 atoms in the ring structure, wherein the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is

[0489] [ka]

[0490] Provided that: In some embodiments, R 1 is H, haloalkyl, optionally substituted C 1 -C 6 Alkoxy, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkoxy (optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1 -C 6 The substituents of the alkyl, optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, cyano, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 haloalkoxy, hydroxy, and oxo), optionally substituted C 4 -C 6 Cycloalkyloxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C 1 -C 6 Alkyl, amine, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. 4 -C 6 Cycloalkyloxy and optionally substituted C 1 -C 6 Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. 1 -C 6 alkyl.

[0491] In some embodiments, R 1 H,

[0492] [ka]

[0493] is selected from the group consisting of: In some embodiments, R 1 H,

[0494] [ka]

[0495] is selected from the group consisting of: In some embodiments, R 5 is an optionally substituted C 1 -C 6 Optionally substituted C alkyl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. 1 -C 6 The substituents of the alkyl(optionally substituted amide, at each occurrence, are independently selected from the group consisting of C 1-C 6 The substituents of the optionally substituted heterocyclyl are each independently selected from the group consisting of C 1 -C 6 independently selected from the group consisting of alkyl, alkoxy, and halogen, optionally substituted C 1 -C 6 Heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 Heterocyclyl, optionally substituted C 1 -C 6 Optionally substituted cycloalkyl, wherein the optionally substituted substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen. 1 -C 6 cycloalkyl.

[0496] In some embodiments, R 5 is methyl, ethyl, CF 3 , CHF 2 , C.H. 2 CF 3 ,

[0497] [ka]

[0498] is selected from the group consisting of: In some embodiments, R 5 is methyl,

[0499] [ka]

[0500] is selected from the group consisting of: In some embodiments, R 2 is H and optionally substituted C1 -C 6 An optionally substituted substituent selected from the group consisting of alkoxy, at each occurrence, is independently alkoxy, amine, heterocyclyl, or R 1 When taken together with, form an optionally substituted heterocyclyl having 5 to 6 atoms in the ring structure, the optionally substituted substituents, at each occurrence, are each independently selected from the group consisting of C 1 -C 6 is independently selected from the group consisting of alkyl and halogen.

[0501] In some embodiments, R 2 H,

[0502] [ka]

[0503] is selected from the group consisting of: In some embodiments, R 2 is H. In some embodiments, R 1 and R 2 Together,

[0504] [ka]

[0505] and forming a ring structure selected from the group consisting of: In some embodiments, R 2 and R 5 Together,

[0506] [ka]

[0507] wherein s3 is a site covalently bonded to the bicyclic ring structure and s4 is a site covalently bonded to the oxygen atom. In some embodiments, R 3 is H, F, or alkoxy.

[0508] In some embodiments, R 3 is F. In some embodiments, R 4 is H, F, C 1 -C 6 It is selected from the group consisting of alkyl, and alkoxy.

[0509] In some embodiments, R 4 is H. In some embodiments, X 1 and X 2 is independently CH or N. In some embodiments, X 1 is CH and X 2 is CH.

[0510] In some embodiments, X 1 is CH and X 2 is N. In some embodiments, L is a direct bond and (E 11 ) m C optionally substituted with 1 -C 6 alkyl.

[0511]

[0287] In some embodiments,

[0512] [ka]

[0513] teeth,

[0514] [ka]

[0515] is selected from the group consisting of: In some embodiments, E 11 In each occurrence, H, C 1 -C 6 Alkyl, C 3 -C 5 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halogen.

[0516] In some embodiments, E 11 is independently selected at each occurrence from the group consisting of H, methyl, and fluoro.

[0290] In some embodiments,

[0517] [ka]

[0518] teeth,

[0519] [ka]

[0520] is selected from the group consisting of: In some embodiments, R 9 is C 1 -C 6 It is an alkyl. In some embodiments, R 9 is alkyl.

[0521] In some embodiments, R 9 teeth,

[0522] [ka]

[0523] is selected from the group consisting of: In some embodiments, R 11is selected from the group consisting of H and alkyl.

[0524] In some embodiments, R 11 H and C 1 -C 6 alkyl. In some embodiments, R 9 is C 1 -C 6 is alkyl, R 11 H and C 1 -C 6 alkyl.

[0525] In some embodiments, R 9 teeth,

[0526] [ka]

[0527] R 11 is selected from the group consisting of H and methyl. In some embodiments, R 11 is R 9 , and R 9 and R 11 are each taken together with the atom to which they are attached to form an optionally substituted ring structure having from 4 to 7 atoms in the ring structure, and the optional substituents, at each occurrence, are independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy.

[0528] In some embodiments, R 11 is R 9 , and R 9 and R 11 Together with the atoms attached to each other,

[0529] [ka]

[0530] and forming an optionally substituted ring structure selected from the group consisting of:

[0300] In one embodiment, a compound selected from:

[0531] [ka]

[0532] [ka]

[0533] [ka]

[0534] [ka]

[0535] [ka]

[0536] [ka]

[0537] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein. Combination therapy In one embodiment, described herein relates to combination therapy involving a compound of the present disclosure and one or more therapeutic agents. The combination therapy described herein can be used by itself or in further combination with one or more additional therapeutic agents (e.g., one or more additional therapeutic agents described below). For example, the compound of the present disclosure can be administered together with a cancer targeting therapeutic agent, a cancer targeting biologic, an immune checkpoint inhibitor, or a chemotherapeutic agent. The therapeutic agent can be administered together with another therapeutic agent described herein or sequentially in combination therapy.

[0538] Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. Alternatively, combination therapy can be achieved by administering two or more therapeutic agents in a single formulation.

[0539] Other combinations are also included in combination therapy. Two or more drugs in combination therapy can be administered at the same time, but they do not have to be administered at the same time. For example, administration of a first drug (or combination of drugs) can precede administration of a second drug (or combination of drugs) by minutes, hours, days, or weeks. Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessary, that two or more drugs used in combination therapy are present in the patient's body at the same time.

[0540] Combination therapy can also include more than one administration of one or more of the combined drugs, using a different sequence of the component drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times sequentially in any combination, such as in the sequence XYX, XXY, YXY, YYX, XXYY, etc.

[0541] In some embodiments, the additional therapeutic agent includes a cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile hydrochloride, (R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-trifluoroethylene, 1,2-difluoropropanediol ...5-Tetrahydro-1H-benzodiazepine-7-carbonitrile, cetuximab, imatinib, interferon alpha-2b, pegylated interferon alpha-2b, aromatase combination, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-methyl- Leucaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone Propionate, testolactone, medroxyprogesterone acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17α-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, ana These may include, but are not limited to, anastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thiotepa, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, and valrubicin.

[0542] In some embodiments, the additional therapeutic agent includes an AKT inhibitor, an alkylating agent, an all-trans retinoic acid, an antiandrogen, an azacytidine, a BCL2 inhibitor, a BCL-XL inhibitor, a BCR-ABL inhibitor, a BTK inhibitor, a BTK / LCK / LYN inhibitor, a CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, a CDK4 / 6 inhibitor, a CDK9 inhibitor, a CBP / p300 inhibitor, an EGFR inhibitor, an endothelin receptor antagonist, a RAF inhibitor, a MEK (mitogen-activated protein kinase kinase) inhibitor, an ERK inhibitor, a farnesyltransferase inhibitor, an FLT 3 inhibitors, glucocorticoid receptor agonists, HDM2 inhibitors, histone deacetylase inhibitors, IKKβ inhibitors, immunomodulatory drugs (IMiDs), ingenol, ITK inhibitors, JAK1 / JAK2 / JAK3 / TYK2 inhibitors, MTOR inhibitors, PI3 kinase inhibitors, dual PI3 kinase / MTOR inhibitors, proteasome inhibitors, protein kinase C agonists, SUV39H1 inhibitors, TRAIL, VEGFR2 inhibitors, Wnt / β-catenin signaling inhibitors, decitabine, and anti-CD20 monoclonal antibodies.

[0543] In some embodiments, the additional therapeutic agent is a CTLA4 inhibitor, such as, but not limited to, ipilimumab and tremelimumab; a PD1 inhibitor, such as, but not limited to, pembrolizumab and nivolumab; a PDL1 inhibitor, such as, but not limited to, atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, PDR001; a 4-1BB or 4-2BB inhibitor, such as, but not limited to, urelumab and PF-05082566. 1BB ligand inhibitors; OX40 ligand agonists such as but not limited to MEDI6469; GITR agents such as but not limited to TRX518; CD27 inhibitors such as but not limited to varlilumab; TNFRSF25 or TL1A inhibitors; CD40 agonists such as but not limited to CP-870893; HVEM or LIGHT or LTA or BTLA or CD160 inhibitors; LAG3 inhibitors such as but not limited to BMS-986016; TIM3 inhibitors; Siglec inhibitors; ICOS or ICOS ligand agonists; B7 H3 inhibitors such as but not limited to MGA271; B7 H4 inhibitors; VISTA inhibitors; HHLA2 or TMIGD2 inhibitors; inhibitors of butyrophilins, including BTNL2 inhibitors; CD244 or CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIR inhibitors such as but not limited to lirilumab; inhibitors of ILT and LIR; NKG2D and NKG2A inhibitors such as but not limited to IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors such as but not limited to emactuzumab, caviralizumab, pexidartinib, ARRY382, BLZ945; IDO inhibitors such as but not limited to INCB024360; TGFβ inhibitors such as but not limited to thalidomide, lenalidomide, galunisertib; adenosine or CD39 or CD73 inhibitors;Ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-1-amino-5-guanidino-1-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-1,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl) an immunomodulatory agent selected from the group consisting of a CXCR4 or CXCL12 inhibitor, such as but not limited to, riacontahydro-1H,16H-pyrrolo[2,1-p][1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontin-12-carboxamide BKT140; a phosphatidylserine inhibitor, such as but not limited to, bavituximab; a SIRPA or CD47 inhibitor, such as but not limited to, CC-90002; a VEGF inhibitor, such as but not limited to, bevacizumab; and a neuropilin inhibitor, such as but not limited to, MNRP1685A;

[0544]

[0308] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent selected from the group consisting of chemotherapeutic agents including, but not limited to, antitubulin agents (paclitaxel, paclitaxel protein-bound particles for injectable suspension, e.g., nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine), vinorelbine, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate.

[0545] In some embodiments, the additional therapeutic agent is paclitaxel, paclitaxel protein-bound particles for injectable suspension paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacitadine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelasib, quizartinib, tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, prednisone, dexamethasone, irinotecan, camptothecin, topotecan, etoposide, etoposide phosphate, mitoxantrone, vorinostat, romidepsin, panobinostat, valproic acid, belinostat, DZNep Selected from the group consisting of 5-aza-2'-deoxycytidine, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, labrolizumab, nivolumab, MPDL3280A, bevacizumab, aflibercept, brentuximab vedotin, ado-trastuzumab emtansine, radiation therapy, and sipuleucel-T.

[0546]

[0310] In some embodiments, the additional therapeutic agent is a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, and quizartinib.

[0547]

[0311] In some embodiments, one or more additional therapeutic agents that may be administered in combination with the compounds provided herein may be MAPK pathway inhibitors, such as MEK inhibitors, ERK inhibitors, and Ras inhibitors.

[0548] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof.Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and pharmaceutically acceptable salts thereof.Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and pharmaceutically acceptable salts thereof.

[0549] In some embodiments, the additional therapeutic agent is an anti-PD1 therapeutic agent. Examples of anti-PD1 therapeutic agents that can be administered in combination with the compounds of the present disclosure or their pharma- ceutical acceptable salts, or compositions comprising the compounds of the present disclosure or their pharma-ceutical acceptable salts, as described herein, include, but are not limited to, nivolumab, pidilizumab, tislelizumab, AMP-224, AMP-514, and pembrolizumab.

[0550] In some embodiments, the additional therapeutic agent is selected from the group consisting of immunomodulatory agents, including but not limited to anti-PD-L1 therapeutic agents, including atezolizumab, durvalumab, BMS-936559, and avelumab, anti-TIM3 therapeutic agents, including TSR-022 and MBG453, anti-LAG3 therapeutic agents, including leratolimab, LAG525, and TSR-033, CD40 agonist therapeutic agents, including SGN-40, CP-870,893, and RO7009789, anti-CD47 therapeutic agents, including Hu5F9-G4, anti-CD20 therapeutic agents, anti-CD38 therapeutic agents, and other immunomodulatory therapeutic agents, including thalidomide, lenalidomide, pomalidomide, prednisone, and dexamethasone. In some embodiments, the additional therapeutic agent is avelumab.

[0551] In some embodiments, the additional therapeutic agent is an antitubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, abraxane, docetaxel, ixabepilone, taxiterem, vincristine, or vinorelbine), an LHRH antagonist, including but not limited to leuprorelin, goserelin, triptorelin, or histrelin, an antiandrogen, including but not limited to abiraterone, flutamide, bicalutamide, nilutamide, cyproterone acetate, enzalutamide, and apalutamide, tamoxifen, flutamide, fluoxetine ... The chemotherapeutic agent is selected from the group consisting of antiestrogen, including but not limited to, bestrant, anastrozole, letrozole, and exemestane, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, and temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine methotrexate, bortezomib, and carfilzomib.

[0552] In some embodiments, the additional therapeutic agent is the kinase inhibitor erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, idelalisib, quizartinib, avapritinib, BLU-667, BLU-263, Loxo 292, targeted therapy including larotrectinib, and quizartinib; antiestrogens including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane; antiandrogens including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate; steroids including but not limited to prednisone and dexamethasone; PARP inhibitors including but not limited to neraparib, olaparib, and rucaparib; topoisomerase I inhibitors including but not limited to irinotecan, camptothecin, and topotecan; etoposide, etoposide phosphate, and mitoxantrone. and / or topoisomerase II inhibitors, histone deacetylase (HDAC) inhibitors, including but not limited to, vorinostat, romidepsin, panobinostat, valproic acid, and belinostat, DNA methylation inhibitors, including but not limited to, DZNep and 5-aza-2'-deoxycytidine, proteasome inhibitors, including but not limited to, bortezomib and carfilzomib, thalidomide, lenalidomide, pomalidomide; biologics, including but not limited to, trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab, vaccines, including but not limited to, sipuleucel-T, and radiation therapy.

[0553]

[0317] In some embodiments, the additional therapeutic agent is selected from the group consisting of inhibitors of TIE2 immune kinase, including revastinib or ARRY-614.

[0318] In some embodiments, the additional therapeutic agent is selected from the group consisting of inhibitors of TIE2 immune kinase, including revastinib or ARRY-614, and anti-PD1 therapeutic agents.

[0554]

[0319] In some embodiments, the additional therapeutic agent is selected from the group consisting of antiangiogenic agents, including AMG386, bevacizumab, and aflibercept, and antibody-drug conjugates (ADCs), including ADCs containing payloads such as brentuximab vedotin, trastuzumab emtansine, and derivatives of camptothecin, pyrrolobenzodiazepine dimers (PBDs), indolinobenzodiazepine dimers (IGNs), DM1, DM4, MMAE, or MMAF.

[0555]

[0320] In some embodiments, the additional therapeutic agent is selected from luteinizing hormone releasing hormone (LHRH) analogs, including goserelin and leuprolide. In some embodiments, the additional therapeutic agent is everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, of atumtunab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, jamatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY 317615, neuradiab, vitespam, rta 744, sdx 102, talampanel, atrasentan, xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pi rimidin-5-yl)-ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib,AG-013736, AVE-0005, acetate of [D-Ser(Bu t)6, Azgly 10] (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH2 acetate C59H84N18Oi4-(C2H4O2)x (wherein x=1-2.4)], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, furutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF Antibodies, Erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, Carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, Gleevec, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna , methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine,5-Deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin Niftitox, Gefitinib, Bortezimib, Irinotecan, Topotecan, Doxorubicin, Docetaxel, Vinorelbine, Bevacizumab (monoclonal antibody) and Erbitux, Cremophor-free Paclitaxel, Epithilon B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony stimulating factor, hepatitis C Strelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwiener-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor blockers, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixtures thereof.

[0556] In some embodiments, the additional therapeutic agent is an HSP90 inhibitor (e.g., AT13387). In some embodiments, the additional therapeutic agent is cyclophosphamide. In some embodiments, the additional therapeutic agent is an AKT inhibitor (e.g., perifosine). In some embodiments, the additional therapeutic agent is a BCR-ABL inhibitor (e.g., nilotinib). In some embodiments, the additional therapeutic agent is an mTOR inhibitor (e.g., RAD001). In some embodiments, the additional therapeutic agent is an FGFR inhibitor (e.g., erdafitinib, KO947, or BGJ398). In some embodiments, the additional therapeutic agent is an anti-PDL1 therapeutic agent. In some embodiments, the additional therapeutic agent is a Bcl2 inhibitor (e.g., venetoclax). In some embodiments, the additional therapeutic agent is an autophagy inhibitor (e.g., hydroxychloroquine). In some embodiments, the additional therapeutic agent is a MET inhibitor.

[0557] Pharmaceutical Compositions and Kits In one embodiment, pharmaceutical compositions comprising the compounds of the present disclosure formulated together with a pharma- ceutically acceptable carrier are described herein. In particular, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure formulated together with one or more pharma- ceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable administration form in any given case depends on the extent and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions may be formulated as a unit dose and / or may be formulated for oral or subcutaneous administration.

[0558]

[0324] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, containing one or more of the compounds of the present disclosure as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. The active ingredients may be compounded with conventional non-toxic pharma- ceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other forms suitable for use. The subject active compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0559]

[0325] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture of the compound of the present disclosure, or a non-toxic pharma-ceutically acceptable salt thereof. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0560]

[0326] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as glycerol; Disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarders such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, (7) wetting agents such as acetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, the composition may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0561]

[0327] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. Molded tablets can be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets, as well as other solid dosage forms such as dragees, capsules, pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0562]

[0328] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0563]

[0329] Suspending agents may include, in addition to the subject compositions, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0564]

[0330] Formulations for rectal or vaginal administration may be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and may be presented as a suppository which is solid at room temperature but becomes liquid at body temperature and thus melts within the body cavity releasing the active agent(s).

[0565]

[0331] The dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

[0566]

[0332] Ointments, pastes, creams, and gels may contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0567]

[0333] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0568] Alternatively, the pharmaceutical compositions and compounds of the present disclosure may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation, or solid particles containing the compounds. A non-aqueous (e.g., fluorocarbon propellant) suspension may be used. An ultrasonic nebulizer may be used because it minimizes exposure of the drug to shear, which may result in degradation of the compounds contained in the subject compositions. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of the subject compositions with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular subject compositions, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0569]

[0335] Pharmaceutical compositions of the present disclosure may be suitable for parenteral administration and include the subject compositions in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, and may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0570]

[0336] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0571] In one embodiment, an enteral pharmaceutical formulation is provided, comprising the compound of the present disclosure, an enteric material, and their pharma- ceutically acceptable carriers or excipients.The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and is predominantly soluble in intestinal fluids at a particular pH.The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum.The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5.

[0572]

[0338] Thus, the enteric material does not dissolve until the pH is, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymers, natural resins such as zein, shellac, and copalcohol, as well as several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit Examples of suitable enteric materials include enteric esters such as enteric esters L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is either known or readily determinable in vitro. While the foregoing is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that will meet the objectives described herein.

[0573] Advantageously, kits are provided herein for use by a purchaser in need of, for example, a cancer treatment. Such kits include suitable dosage forms, such as those described above, and instructions describing how to use such dosage forms to mediate, reduce, or prevent inflammation. The instructions direct the consumer or medical practitioner to administer the dosage forms according to an administration mode known to those skilled in the art. Such kits may advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. These recesses have the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil with the face of the foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses, through which the tablets or capsules can then be removed.

[0574]

[0340] It may be desirable to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, which correspond to the days of the regimen on which the tablets or capsules so designated should be taken. Another example of such a memory aid is a calendar printed on a card, for example: "Week 1, Monday, Tuesday, ... etc., Week 2, Monday, Tuesday, ...", etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or multiple tablets or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule and a daily dose of a second compound can consist of multiple tablets or capsules, and vice versa. The memory aid should reflect this.

[0575] Methods and Uses The compounds described herein can act as KIT inhibitors and are therefore useful for treating patients in need of such disease and disorders, such as cancer.Exemplary diseases include, but are not limited to, gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, seminoma or dysgerminoma germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is gastrointestinal stromal tumor (GIST). In some embodiments, the disease is KIT-activated gastrointestinal stromal tumor (GIST). In some embodiments, the KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the disease is melanoma. In some embodiments, the melanoma is a KIT-activated melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma. In some embodiments, the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic melanoma, and desmoplastic melanoma, hi some embodiments, the non-cutaneous melanoma is selected from ocular melanoma and mucosal melanoma.

[0576] In some embodiments, the pharmaceutical composition may be used to prepare a medicament for the treatment of a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, seminoma or dysgerminoma germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer. In some embodiments, the disease is gastrointestinal stromal tumor (GIST). In some embodiments, the disease is a KIT-activated gastrointestinal stromal tumor (GIST). In some embodiments, the KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the disease is a melanoma. In some embodiments, the melanoma is a KIT-activated melanoma. In some embodiments, the KIT-activated melanoma has a baseline mutation selected from the group consisting of KIT exon 9 mutation, KIT exon 11 mutation, KIT exon 13 mutation, KIT exon 17 mutation, and KIT exon 18 mutation. In some embodiments, the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma. In some embodiments, the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic melanoma, and desmoplastic melanoma. In some embodiments, the non-cutaneous melanoma is selected from ocular melanoma and mucosal melanoma.

[0577] The compounds of the present disclosure may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be understood that the dosage required for use in any particular application will vary from patient to patient, depending not only on the particular compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concomitant medications or special diets the patient is subsequently following, and other factors that one skilled in the art would recognize, and that the appropriate dosage will ultimately be left to the discretion of the attending physician. To treat the above-mentioned clinical conditions and diseases, the compounds provided herein may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmacologic acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections, or infusion techniques.

[0578] Treatment can continue for as long or as short as desired. The composition may be administered, for example, in a regimen of 1 to 4 times a day or more. A suitable treatment period can be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinitely. The treatment period can be terminated when the desired results are achieved. EXAMPLES

[0579]

[0345] The compounds described herein can be prepared in several ways based on the teachings contained herein and the disclosure of synthetic procedures in the art. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the selection of solvents, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected to be the standard conditions for the reaction, unless otherwise indicated. It is understood by those skilled in the art of organic synthesis that the functionality present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are not compatible with the reaction conditions will be clear to those skilled in the art, and therefore alternative methods are shown. The starting materials of the examples are commercially available or easily prepared by standard methods from known materials.

[0580]

[0346] ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, Mass.) was used to name structures of intermediates and exemplified compounds.

[0581] The following abbreviations are used in this disclosure and have the following definitions: "ADP" is adenosine diphosphate, "Aq" is aqueous, "ATP" is adenosine triphosphate, "Ar" is argon gas, "Boc" is t-butyl carbonate, "BSA" is bovine serum albumin, "BTFFH" is 1-(fluoro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V), "conc." is concentrated, and "Cs 2 CO 3" is cesium carbonate, "CuCN" is copper(I) cyanide, "CuI" is copper(I) iodide, "DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" is dichloromethane, "DIAD" is diisopropyl azodicarboxylate, "DIEA" is N,N-diisopropylethylamine, "DMA" is N,N-dimethylacetamide, "DMAP" is 4-(dimethylamino)pyridine, "DMF" is N,N-dimethylformamide, "DMEM" is Dulbecco's modified Eagle's medium, "DMSO" is dimethylsulfoxide, "DPPA" is diphenylphosphoryl azide, "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "ESI" is electrospray ionization, and "Et 3 N" is triethylamine, and "Et 2 "O" is diethyl ether, "EtOAc" is ethyl acetate, "EtOH" is ethanol, "GST" is glutathione S-transferase, "h" is time, "HATU" is azabenzotriazole tetramethyluronium hexafluorophosphate, and "H 2 " is hydrogen gas, "HCl" is hydrochloric acid, "Hex" is hexane, and "H 2 SO 4 " is sulfuric acid, "HOBt" is hydroxybenzotriazole, and "IC 50 " is the half-maximal inhibitory concentration, and "K 2 CO 3 " is potassium carbonate, "KI" is potassium iodide, and "K 3 PO 4 " is potassium phosphate, "LAH" is lithium aluminum hydride, "LiOH" is lithium hydroxide, "mCPBA" is meta-chloroperoxybenzoic acid, and "CH 3 "CN" is acetonitrile, "MeOH" is methanol, and "MgSO 4" is magnesium sulfate, "MHz" is megahertz, "min" is minute, "MS" is mass spectrometry, "MTBE" is methyl tert-butyl ether, "NADH" is nicotinamide adenine dinucleotide, "NaH" is sodium hydride, and "NaHCO 3 " is sodium bicarbonate, "NaOH" is sodium hydroxide, "NaOMe" is sodium methoxide, and "Na 2 SO 4 " is sodium sulfate, and "NH 4 "Cl" is ammonium chloride, and "NH 4 "OH" is ammonium hydroxide, "NMR" is nuclear magnetic resonance, "OTs" is O-tosylate, "PBS" is phosphate buffered saline, "Pd" is palladium, "Pd-C" is palladium on carbon, and "Ph 3 "P" is triphenylphosphine, "Prep HPLC" is preparative high performance liquid chromatography, "PyAOP" is ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), "rt" is room temperature, also known as "ambient temperature" (which will be understood to comprise the range of normal laboratory temperatures ranging from 15 to 25°C), "SFC" is supercritical fluid chromatography, "SM" is starting material, "T3P" is n-propanephosphonic anhydride, "TBAF" is tetrabutylammonium fluoride, "TCFH" is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, and "Tf 2 "O" is trifluoromethanesulfonic anhydride, "THF" is tetrahydrofuran, "TrocCl" is 2,2,2-trichloroethyl chloroformate, and "XtalFluor-E" is diethylaminodifluorosulfinium tetrafluoroborate.

[0582] general chemistry

[0348] Exemplary compounds described herein are accessible by the general synthetic methods illustrated in the following schemes, intermediate preparations, and accompanying examples.

[0583] Synthesis scheme

[0584] [ka]

[0585] Scheme 1 shows an exemplary preparation of quinazoline intermediates 1-8a and 1-8b. 2 CO 3 , Cs 2 CO 3 , or NaH) and polar aprotic solvents (DMSO, DMF, THF, etc.) 5 -Br and R 5 Alkylation of 1-1 (2,6-difluoro-4-hydroxybenzonitrile) with -OTs (commercially available or synthesized by one skilled in the art) gives the ether 1-2. Alternatively, compound 1-1 can be prepared by condensation (e.g., with Ph 3 The alcohol (R) was reacted with 1,2-dichlorophenyl phosphate (P) and DIAD under standard Mitsunobu conditions. 5 —OH) to give the ether 1-2. The ether 1-2 can be reacted with aqueous NH 3 to give aniline 1-3 by aromatic substitution. Aniline 1-3 reacts with DMF-DMA at elevated temperature to give formamidine 1-4. Cyclization between 1-4 and aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) gives quinazoline 1-6. Intermediate 1-6 is reacted with NaOMe in a dry aprotic solvent such as THF at elevated temperature to give 1-7. Finally, boc deprotection of 1-6 and 1-7 under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM gives 1-8a (R 3 =F) and 1-8b (R 3 =OMe).

[0586] [ka]

[0587] Scheme 2 shows an exemplary preparation of quinazoline intermediate 2-5. 2 SO 4 Cyclization of compound 1-3 (see Scheme 1) with formic acid under acidic conditions such as 1H, 2H, 3H, 4H, 5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 14H, 15H, 16H, 17H, 18H, 19H, 20H, 21H, 22H, 23H, 24H, 25H, 26H, 27H, 28H, 29H, 30H, 31H, 32H, 33H, 34H, 35H, 36H, 37H, 38H, 39H, 40H, 41H, 42H, 43H, 44H, 45H, 46H, 47H, 48 3 N, Cs 2 CO 3 Aromatic nucleophilic substitution reaction of chloride 2-2 with nucleophile 2-3 in the presence of a base such as 2-4 gives 2-5. In the presence of a hydrogenation catalyst such as palladium or nickel, or zinc or iron and NH 4 Nitro reduction of 2-4 under mild reducing conditions such as Cl affords the corresponding aniline 2-5.

[0588] [ka]

[0589] Scheme 3 illustrates an exemplary preparation of quinazoline intermediates 3-6. R 6 Base-promoted nucleophilic displacement of 3-1 (2-bromo-3,4-difluoro-1-nitrobenzene) with -OH (commercially available or synthesized by one skilled in the art) affords the ether 3-2, which can be purified by SFC purification, crystallization, or chromatography. Cyanation of the aryl bromide 3-2 with CuCN at elevated temperature in a polar solvent such as DMA, DMF, or DMSO gives 3-3. In the presence of a hydrogenation catalyst such as Pd or Ni, or with SnCl 2, zinc or iron, and NH 4 Nitro reduction of 3-3 under mild reducing conditions such as Cl affords the corresponding aniline 3-4. In a similar manner to Scheme 1, aniline 3-4 is reacted with DMF-DMA at elevated temperature to form formamidine 3-5. Cyclization between 3-5 and aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) in acetic acid at elevated temperature affords the boc-quinazoline, which is deprotected under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM to afford 3-6 (R 2 =OR 6 ) can be obtained.

[0590] [ka]

[0591]

[0352] Scheme 4 shows an exemplary preparation of quinazoline intermediate 4-3. In a similar manner to Scheme 1, aniline 4-1 (commercially available or synthesized by one skilled in the art) is reacted with DMF-DMA at elevated temperature to form formamidine 4-2. Cyclization between 4-2 and aniline / aminopyridine 1-5 (commercially available or synthesized by one skilled in the art) in acetic acid at elevated temperature gives boc-quinazoline, which can be deprotected under acidic conditions such as HCl and TFA in an aprotic solvent such as DCM to give 4-3.

[0592] [ka]

[0593] Scheme 5 shows an exemplary preparation of intermediate 5-3. Under Schotten-Baumann conditions (e.g., saturated aqueous NaHCO 3 Activation of 1-8a, 1-8b, and 2-5 with 2,2,2-trichloroethyl chloroformate (or isopropenyl chloroformate) in a mixture of 1,2,2-tetrachloroethyl chloroformate (NaOH) and EtOAc) afforded 5-1, which can be further converted to the amine NHR 7The urea 5-2 can be reacted with -LE (commercially available or synthesized by one skilled in the art) to give the urea 5-2. Alternatively, the urea 5-2 can be reacted with DPPA and a base [Et 3 N]) with the carboxylic acid EL-COOH (commercially available or synthesized by one skilled in the art). Finally, Pd-C catalyzed deprotection of 5-2 under hydrogen affords intermediate 5-3.

[0594] [ka]

[0595]

[0354] Scheme 6 shows an exemplary preparation of intermediate 6-2. Amide 6-1 can be prepared by amide coupling reaction of 1-8a, 1-8b, and 2-5 with acid EL-COOH (commercially available or synthesized by one skilled in the art) in the presence of coupling reagents such as T3P, TCFH, HATU, EDC, and XtalFluor-E. In a similar manner to Scheme 4, Pd-C catalyzed deprotection of 6-1 under hydrogen gives intermediate 6-2.

[0596] [ka]

[0597] Scheme 7 shows an exemplary preparation of intermediate 7-2. Intermediate 6-1a can be prepared by reacting the amine NHR in a suitable solvent such as 1,4-dioxane or THF at elevated temperature. 8 R 10 (commercially available or synthesized by one skilled in the art) to give 7-1. Alternatively, the amine NR 8 R 10Amide coupling reaction of 6-1b with H (commercially available or synthesized by one skilled in the art) gives 7-1. In a similar manner to Scheme 4, Pd-C catalyzed deprotection of 7-1 under hydrogen gives intermediate 7-2.

[0598] [ka]

[0599] Schematic 8 shows an exemplary preparation of compounds of formula I. Under Schotten-Baumann conditions (e.g., saturated aqueous NaHCO 3 Activation of 1-8a, 1-8b, 2-5, 3-6, and 4-3 with 2,2,2-trichloroethyl chloroformate (or isopropenyl chloroformate) in a mixture of 1H,2,3-tetrachloroethane and 1H,2,3-tetrachloroethane afforded 8-1, which can be further converted to the amine HNR 7 -LE or alcohol HO-LE (commercially available or synthesized by one skilled in the art) to give Formula I as a urea. Alternatively, Formula I as a urea can be reacted with DPPA and base [Et 3 Formula I as amides can be prepared by reaction of 1-8a, 1-8b, 2-5, 3-6, and 4-3 with carboxylic acid EL-COOH (commercially available or synthesized by one skilled in the art) in the presence of coupling reagents such as T3P, TCFH, HATU, EDC, and XtalFluor-E, or with Et 3 The amide coupling reactions of 1-8a, 1-8b, 2-5, 3-6, and 4-3 with acyl chlorides EL-COCl (commercially available or synthesized by one skilled in the art) in the presence of a base such as N and DIEA. 3 Et as a base in organic solvents such as CN, DCM, or EtOAc 3 In the presence of a base such as N, DIEA, pyridine, or DBU, Tf 2Activation of 5-3, 6-2, and 7-2 with O gives intermediate 8-2. Sonogashira or Heck coupling reaction of 8-2 to give CC-linked Formula I, followed by appropriate reduction. Alternatively, CC-linked Formula I can be prepared from 8-2 using a boronate or boronic acid under Suzuki conditions, followed by appropriate reduction as needed. In another embodiment, the reaction can be carried out using a base (e.g., K) at temperatures between ambient and 150° C. 2 CO 3 , Cs 2 CO 3 , or NaH) and polar aprotic solvents (DMSO, DMF, THF, etc.) 5 -Br and R 5 Alkylation of 5-3, 6-2, and 7-2 with -OTs (commercially available or synthesized by one skilled in the art) affords compounds of formula I (R 1 =OR 5 , R 2 =H). Finally, compounds of formula I containing an ester functionality can be hydrolyzed under basic conditions such as LiOH or NaOH in a mixture of water / THF or 1,4-dioxane to give the corresponding acid. In a similar manner to Scheme 6, compounds of formula I as esters can be hydrolyzed to give the corresponding acids by hydrolysis under basic conditions such as LiOH or NaOH in a mixture of water / THF or 1,4-dioxane to give the corresponding acids. In a similar manner to Scheme 6, compounds of formula I as esters can be hydrolyzed to give the corresponding amines NR 8 R 10 H (commercially available or synthesized by one skilled in the art) to give a compound of formula I(E=C(O)NR 8 R 10 Alternatively, the amine NR in the presence of coupling reagents such as T3P, TCFH, HATU, EDC, and XtalFluor-E can be coupled to 8 R 10 The amide coupling reaction of the corresponding acid with H (commercially available or synthesized by one skilled in the art) gives the compound of formula I (E=C(O)NR 8 R 10 ) is obtained.

[0600] Preparation of intermediates Using the synthetic procedures and methods described herein, as well as methods known to those skilled in the art, the following compounds were made: General Method A: Alkylation with Alkyl Halides Intermediate A1: 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile

[0601] [ka]

[0602] A suspension of 2,6-difluoro-4-hydroxybenzonitrile (50 g, 322 mmol) and 1-bromo-2-methoxyethane (50 g, 360 mmol) in DMF (300 mL) was added to K 2 CO 3 (100 g, 724 mmol). The resulting reaction mixture was heated at 80° C. for 5 h. The reaction mixture was diluted with water (700 mL) and extracted with dichloromethane (3 times). The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4 The crude product was recrystallized from hexane and MTBE to give 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (50 g, 73%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 ):δ 6.38(s,1H),6.15(m,1H),4.06(m,2H),3.63(m,2H),3.29(s,3H);MS(ESI)m / z:214.0(M+H + ). Using General Method A above, the intermediates in Table A below were prepared.

[0603] [Table A]

[0604] General method B: NH 4 Substitution with OH Intermediate B1: 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile

[0605] [ka]

[0606] A suspension of 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (50 g, 235 mmol) in isopropanol (25 mL) was treated with ammonium hydroxide (100 mL, 856 mmol). The resulting reaction mixture was heated at 70° C. for 10 days. The reaction mixture was cooled to room temperature and stirred. The crystallized solid was filtered, washed with cold water, and dried under high vacuum to give 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (45 g, 91%) as a white solid. MS (ESI) m / z: 211.0 (M+H + ). Using general method B above, the intermediates in Table B below were prepared.

[0607] [Table B]

[0608] Intermediate B5: 6-amino-2-fluoro-3-(2-methoxyethoxy)benzonitrile

[0609] [ka]

[0610] A stirred solution of 2-bromo-3,4-difluoro-1-nitrobenzene (5.0 g, 22.5 mmol) in DCM (100 mL) was treated with tetrabutylammonium hydrogen sulfate (0.07 g, 0.22 mmol). 2-Methoxyethan-1-ol (1.75 g, 22.5 mmol) was added at room temperature, followed by dropwise addition of 1.0 M NaOH solution (30 mL) at the same temperature. The reaction mixture was further stirred at room temperature for 3 h. After complete consumption of starting material, the reaction mass was diluted with water (100 mL) and the aqueous layer was extracted with DCM (2 times). The combined organic extracts were washed with anhydrous Na 2 SO 4The crude material was purified by silica gel column chromatography (15-20% EtOAc / Hexanes) to give 2-bromo-3-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene (3.4 g, 55%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.01(dd,J=9.2,1.6 Hz,1H),7.43(d,J=8.8 Hz,1H),4.35(m,2H),3.71(m,2H),3.31(s,3H). A stirred solution of 2-bromo-3-fluoro-4-(2-methoxyethoxy)-1-nitrobenzene (3.4 g, 11.5 mmol) in DMF (75 mL) was treated with copper(I) cyanide (2.1 g, 23.5 mmol) at room temperature. The suspension was further heated at 130° C. for 2 h. After complete consumption of the starting material, the reaction mass was cooled to room temperature and then slowly poured into ice water (about 75 mL) (solid precipitated during this addition process). The solid was filtered, washed with water, and dried under high vacuum to give 2-fluoro-3-(2-methoxyethoxy)-6-nitrobenzonitrile (2.2 g, 80%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.29(d,J=9.2 Hz,1H),7.73(d,J=8.4 Hz,1H),4.42(m,2H),3.72(m,2H),3.31(s,3H). A stirred solution of 2-fluoro-3-(2-methoxyethoxy)-6-nitrobenzonitrile (2.2 g, 8.9 mmol) in water (30 mL) was treated with sodium dithionite (3.2 g, 18.5 mmol) at room temperature. The suspension was further heated at 100° C. for 16 h. After consumption of the starting material, the reaction was diluted with water (10 mL) and the aqueous layer was extracted with 10% MeOH / DCM (2×). The organic extracts were washed with anhydrous Na 2 SO 4The crude material was purified by silica gel column chromatography to give 6-amino-2-fluoro-3-(2-methoxyethoxy)benzonitrile (0.5 g, 25%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.25(t,J=9.6 Hz,1H),6.52(dd,J=9.2,1.6 Hz,1H),5.98(br s,2H),4.03(m,2H),3.58(m,2H),3.29(s,3H); MS(ESI)m / z: 211.1(M+H + ). Intermediate B6: 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine

[0611] [ka]

[0612] 7-Methoxy-6-(3-morpholinopropoxy)quinazolin-4-ol (1.0 g, 3.1 mmol) CHCl 3 A solution of (25 mL) was treated with DMF (1-2 drops). Oxalyl chloride (excess) was added dropwise to the solution. The mixture was refluxed overnight. The mixture was concentrated to dryness under reduced pressure. The residue was extracted with CHCl 3 (10 mL) and evaporated to dryness. The residue was triturated with DCM (25 mL) and filtered to give 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (1.0 g, 57%) as an off-white solid. MS (ESI) m / z: 320.2 (M+H + ). General Method C: Formamidine Formation and Cyclization

[0367] Intermediate C1: tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate

[0613] [ka]

[0614] A suspension of 2-amino-6-fluoro-4-(2-methoxyethoxy)benzonitrile (13 g, 62 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (30 g, 250 mmol) was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and then the solution was concentrated to give a colorless viscous intermediate. The residue was treated with tert-butyl(4-aminophenyl)carbamate (13 g, 62 mmol) and acetic acid (100 mL). The resulting reaction mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was treated with water (100 mL) and stirred at room temperature. The solid was filtered, washed with water and dried under high vacuum to give tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (18.6 g, 70%) as a brown solid. MS (ESI) m / z: 429.2 (M+H + ).

[0369] Using General Method C above, the intermediates in Table C below were prepared.

[0615] [Table C-1]

[0616] [Table C-2]

[0617] [Table C-3]

[0618] General Method D: Substitution with NaOMe Intermediate D1: tert-butyl (4-((5-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate

[0619] [ka]

[0620] A stirred solution of tert-butyl (4-((5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (5.0 g, 11.7 mmol) in dry THF (100 mL) was treated with NaOMe (25% in MeOH, 5.0 mL, 23.4 mmol) at room temperature. The reaction mixture was heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and then slowly poured into ice water (500 mL). The precipitated solid was filtered, washed thoroughly with water, and dried under high vacuum. The solid was further purified on silica gel column chromatography (6-8% MeOH / DCM) to give tert-butyl (4-((5-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)amino)phenyl)carbamate (3.0 g, 58%) as an off-white solid.

[0621] 1 H NMR (500 MHz, DMSO-d 6 ): δ 9.67(s,1H),9.29(br s,1H),8.36(s,1H),7.64(d,J=8.8 Hz,2H),7.44(d,J=8.4 Hz,2H),6.76(d,J=2.0 Hz,1H),6.69(d,J=2.4 Hz,1H),4.23(m,2H),4.07(s,3H),3.71(m,2H),3.30(s,3H),1.48(s,9H); MS(ESI)m / z: 441.1(M+H + ). General method E: Deprotection Int...

Claims

1. Compounds represented by formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ２ are each independently selected from the group consisting of N, CH, and CF; X ３ and X ４ are each independently CH or N, with the proviso that X ３ and X ４ is N, Q is, 【Chemistry 2】 wherein s1 is a moiety covalently bonded to the ring and s2 is a moiety covalently bonded to L; L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ alkyl, or Q is selected from the group consisting of: 【Transformation 3】 When L is R ７ , and L and R ７ together with the N atom to which it is attached to form an optionally substituted heterocyclyl having 4 to 10 atoms in the ring structure, the optional substituents being selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; E is H, alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted alkyl, wherein the optionally substituted substituent, at each occurrence, is C １ -C ６ optionally substituted alkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of: C １ -C ６ an optionally substituted cycloalkyl independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; Optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl; or Q-L-E together, 【Chemistry 4】 is selected from the group consisting of E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in said ring structure, said optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R １ is H, haloalkyl, Optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of: C １ -C ６ Alkyl, amine, cyano, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, hydroxy, and oxo); Optionally substituted cycloalkyloxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C １ -C ６ Alkyl, amine, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: C １ -C ６ Alkyl, amine, cyano, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R １ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of F and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ７ is independently selected from the group consisting of H, alkyl, haloalkyl, or cycloalkyl; R ８ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １０ is selected from the group consisting of H and alkyl, or R ８ , and R ８ and R １０ together with the N atom to which is attached to form an optionally substituted heterocyclyl having from 4 to 8 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; R ９ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １１ is selected from the group consisting of H and alkyl, or R ９ , and R ９ and R １１ are taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having from 4 to 7 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; each occurrence of m is independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 1, 2, or 3; each heterocyclyl is independently a non-aromatic ring system which may be a monocyclic, polycyclic, bridged, or fused ring system which includes at least one heteroatom; However, the compound is 【Transformation 5】 A compound represented by Formula I, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided that:

2. The compound of claim 1, which is any one of the following (i) to (xvii): (i) A compound represented by formula IA: 【Transformation 6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (ii) A compound represented by formula IG: 【Chemistry 11】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (iii) A compound represented by formula I-H: 【Chemistry 12】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: R ５ is an optionally substituted alkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula I-H, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (iv) A compound represented by formula II: 【Chemistry 13】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (v) Compounds represented by formula IJ: 【Chemistry 14】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (vi) A compound represented by formula I-K: 【Chemistry 15】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula IK, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (vii) Compounds represented by formula IL: 【Chemistry 16】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula IL, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (viii) A compound represented by formula I-O: 【Chemistry 17】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ is selected from the group consisting of alkyl, R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula I-O, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (ix) A compound represented by formula IQ: 【Chemistry 19】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ is selected from the group consisting of alkyl, R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula IQ, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (x) A compound represented by formula I-T: 【Chemistry 21】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ is selected from the group consisting of alkyl, R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula I-T, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xi) A compound represented by formula IU: 【Chemistry 22】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ is selected from the group consisting of alkyl, R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; A compound represented by formula IU, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xii) Compounds represented by formula IV: 【Chemistry 23】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ２ are each independently selected from the group consisting of N, CH, and CF; X ３ and X ４ are each independently CH or N, with the proviso that X ３ and X ４ is N, E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R １ is H, haloalkyl, Optionally substituted alkoxy, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of: C １ -C ６ Alkyl, amine, cyano, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, hydroxy, and oxo); Optionally substituted cycloalkyloxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C １ -C ６ Alkyl, amine, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ optionally substituted cycloalkyloxy independently selected from the group consisting of haloalkoxy, hydroxy, and oxo; Optionally substituted heterocyclyloxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of: C １ -C ６ Alkyl, amine, cyano, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ optionally substituted heterocyclyloxy, which are haloalkoxy, hydroxy, and oxo; optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R １ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ８ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １０ is selected from the group consisting of H and alkyl, or R ８ , and R ８ and R １０ together with the N atom to which is attached to form an optionally substituted heterocyclyl having from 4 to 8 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4; A compound represented by Formulas IV, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xiii) A compound represented by formula I-W: 【Chemistry 24】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ２ are each independently selected from the group consisting of N, CH, and CF; X ３ and X ４ are each independently CH or N, with the proviso that X ３ and X ４ is N, E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R ５ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ５ is an optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R ８ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １０ is selected from the group consisting of H and alkyl, or R ８ , and R ８ and R １０ together with the N atom to which is attached to form an optionally substituted heterocyclyl having from 4 to 8 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4; A compound represented by formula I-W, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xiv) Compounds represented by formula IX: 【Chemistry 25】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ２ are each independently selected from the group consisting of N, CH, and CF; E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R ５ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R ８ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １０ is selected from the group consisting of H and alkyl, or R ８ , and R ８ and R １０ together with the N atom to which is attached to form an optionally substituted heterocyclyl having from 4 to 8 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4; A compound represented by formula I-X, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xv) A compound represented by formula I-Y: 【Chemistry 26】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R ５ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R ８ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １０ is selected from the group consisting of H and alkyl, or R ８ , and R ８ and R １０ together with the N atom to which is attached to form an optionally substituted heterocyclyl having from 4 to 8 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, haloalkoxy, and oxo; n is 0, 1, 2, 3, or 4; A compound represented by formula I-Y, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xvi) Compounds represented by formula I-AB: 【Chemistry 27】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ２ are each independently selected from the group consisting of N, CH, and CF; E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R ５ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R ９ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １１ is selected from the group consisting of H and alkyl, or R ９ , and R ９ and R １１ are taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having from 4 to 7 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is 【Chemistry 28】 provided that it is not A compound represented by formula I-AB, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof; or (xvii) Compounds represented by formula I-AC: 【Chemistry 29】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: E １１ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen, or E １１ when taken together with the C atoms to which they are attached form an optionally substituted cycloalkyl having 3 to 4 atoms in the ring structure, the optional substituents being C １ -C ６ Alkyl, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ selected from the group consisting of haloalkoxy, hydroxy, and oxo; R ２ is selected from the group consisting of H and optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently alkoxy, amine, heterocyclyl, or R ５ when taken together with - form an optionally substituted heterocyclyl having 5 to 6 atoms in said ring structure, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl and halogen; R ３ is selected from the group consisting of H, F, and alkoxy; R ４ is selected from the group consisting of H, F, alkyl, and alkoxy; R ５ teeth, Optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, cycloalkyl, optionally substituted amido, and optionally substituted heterocyclyl; The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl are, at each occurrence, C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen); optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, oxo, and halogen; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, and halogen; R ９ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, and optionally substituted cycloalkyl; The substituents of the optionally substituted alkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, cycloalkyl, and heterocyclyl; The substituents of the optionally substituted heterocyclyl, at each occurrence, are selected from the group consisting of C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, oxo, and cyano; The substituents of the optionally substituted cycloalkyl, at each occurrence, are C １ -C ６ independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano; R １１ is selected from the group consisting of H and alkyl, or R ９ , and R ９ and R １１ are taken together with the atom to which they are attached to form an optionally substituted heterocyclyl having from 4 to 7 atoms in said ring structure, said optional substituents, at each occurrence, being independently selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, and haloalkoxy; p is 1, 2, or 3; However, the compound is 【Transformation 30】 provided that it is not A compound represented by formula I-AC, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

3. R １ is H, haloalkyl, Optionally substituted C １ -C ６ Optionally substituted C alkyl groups, wherein the optionally substituted substituents are independently selected at each occurrence from the group consisting of alkoxy, acetamido, amine, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, carboxylic acid, optionally substituted amide, and optionally substituted heterocyclyl. １ -C ６ Alkoxy ( The substituents of the optionally substituted amide, in each occurrence, are independently selected from the group consisting of C １ -C ６ is alkyl, The substituents of the optionally substituted heterocyclyl, at each occurrence, are independently selected from the group consisting of: C １ -C ６ Alkyl, amine, cyano, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, hydroxy, and oxo); Optionally substituted C ４ -C ６ cycloalkyloxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from C １ -C ６ Alkyl, amine, halogen, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Optionally substituted C independently selected from the group consisting of haloalkoxy, hydroxy, and oxo. ４ -C ６ cycloalkyloxy, and Optionally substituted C １ -C ６ Optionally substituted C alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, haloalkoxy, and hydroxy. １ -C ６ 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of alkyl.

4. (i) (a) R １ But, H, 【Chemistry 31】 or the group consisting of H. 【Chemistry 32】 or (b) R ５ However, methyl, ethyl, CF ３ , CHF ２ , C.H. ２ CF ３ , 【Transformation 33】 or the group consisting of Methyl, 【Transformation 34】 and / or (ii) R ２ But, H, 【Chemistry 35】 or H is 3. The compound according to claim 1 or 2.

5. R ３ is F; and / or R ４ But H, F, C １ -C ６ selected from the group consisting of alkyl, and alkoxy; and / or R ４ is H; and / or X １ , X ２ , X ３ , and X ４ are independently CH or N, with the proviso that X ３ and X ４ is N; and / or X １ is CH, and X ２ is CH; and / or X １ is CH, and X ２ is N; and / or X ３ is CH, and X ４ is N, 3. The compound according to claim 1 or 2.

6. L is a direct bond and (E １１ ) ｍ C optionally substituted with １ -C ６ 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of alkyl.

7. (i) (a) 【Transformation 38】 but, 【Chemistry 39】 and / or (b) E １１ But in each occurrence, H, C １ -C ６ Alkyl, C ３ -C ５ independently selected from the group consisting of cycloalkyl, and halogen; or E １１ is, at each occurrence, independently selected from the group consisting of H, methyl, and fluoro; or (ii) 【Chemistry 40】 but, 【Chemistry 41】 selected from the group consisting of 3. The compound according to claim 1 or 2.

8. E, (i) H, C １ -C ６ alkenyl, cyano, haloalkoxy, haloalkyl, halogen, Optionally substituted C １ -C ６ alkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. １ -C ６ Alkyl, Optionally substituted C ３ -C ６ cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ Optionally substituted C independently selected from the group consisting of alkyl, alkoxy, amine, halogen, haloalkyl, haloalkoxy, hydroxy, and cyano. ３ -C ６ cycloalkyl, Optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of C １ -C ６ optionally substituted heterocyclyl independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted alkoxy, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of cycloalkyl and heterocyclyl. or the group consisting of (ii) H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 【Chemistry 42】 A group consisting of 3. The compound according to claim 1 or 2, selected from:

9. (i) 【Chemistry 43】 but, (a) 【Chemistry 44】 The group consisting of: or 【Chemistry 46】 and / or (b) L is (E １１ ) ｍ and E is H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 【Chemistry 47】 or E is selected from the group consisting of H, fluoro, methyl, trifluoromethyl, methoxy, tert-butoxy, trifluoromethoxy, cyano, alkenyl, 【Chemistry 48】 or (ii) 【Chemistry 49】 but, [Transformation 50] selected from the group consisting of: or (iii) When L is a direct bond, 【Chemistry 51】 but, 【Chemistry 52】 selected from the group consisting of 3. The compound according to claim 1 or 2.

10. R ７ but, (i) H, alkyl, or haloalkyl; or (ii) H 3. The compound according to claim 1 or 2, wherein

11. (i) E is (a) the group consisting of H, fluoro, methoxy, and cyano; or (b) H, fluoro, methyl, trifluoromethyl, methoxy, cyano, 【Chemistry 59】 or the group consisting of (c) H, fluoro, methyl, trifluoromethyl, methoxy, cyano, 【Transformation 60】 or selected from the group consisting of (ii) 【Chemistry 61-1】 but, (a) 【Chemistry 61-2】 is, or (b) 【Chemistry 61-3】 is, or (c) 【Chemistry 61-4】 selected from the group consisting of 3. The compound according to claim 1 or 2. 【Request Item 12】 【Chemistry 61-5】 but, 【Transformation 62】 3. The compound of claim 1 or 2, selected from the group consisting of: 【Request Item 13】 【Chemistry 63】 but, 【Chemistry 64】 The compound according to claim 1 or 2, selected from the group consisting of

14. E １１ But in each occurrence, (i) H, C １ -C ６ Alkyl, C ３ -C ５ the group consisting of cycloalkyl and halogen; or (ii) the group consisting of H, methyl, and fluoro 14. The compound of claim 13, independently selected from:

15. (i) R ８ is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; R １０ is selected from the group consisting of H and alkyl; or (ii) R ８ but, 【Transformation 65】 and R １０ is selected from the group consisting of H, methyl, ethyl, and isopropyl; or (iii) R ８ But, R １０ , and R ８ and R １０ together with the N atom to which it is attached, 【Chemical Formula 66】 or forming a ring structure selected from the group consisting of (iv) L is a direct bond and R ８ but, 【Transformation 67】 and R １０ The compound of claim 1 or 2, wherein is H.

16. A compound selected from: 【Chemistry 68-1】 【Chemistry 68-2】 【Chemistry 68-3】 【Chemistry 68-4】 【Chemistry 68-5】 【Chemistry 68-6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

17. 17. A pharmaceutical composition comprising a compound of any one of claims 1, 2 and 16, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

18. The pharmaceutical composition of claim 17 for use in the treatment of a disorder.

19. 18. The pharmaceutical composition of claim 17, for use in treating a disease selected from the group consisting of gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-activated gastrointestinal stromal tumor, PDGFRa-activated gastrointestinal stromal tumor (GIST), melanoma, acute myeloid leukemia, germ cell tumors such as seminoma or dysgerminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, squamous cell lung cancer, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, and non-small cell lung cancer in a patient in need of such treatment. (i) the disease is gastrointestinal stromal tumor (GIST), or (ii) the disease is a KIT-activated gastrointestinal stromal tumor (GIST), or (iii) the disease is a KIT-activated gastrointestinal stromal tumor (GIST), and the KIT-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation; or (iv) the disease is a PDGFRa-activated gastrointestinal stromal tumor (GIST), or (v) the disease is a PDGFRa-activated gastrointestinal stromal tumor (GIST), and the PDGFRa-activated gastrointestinal stromal tumor (GIST) has a baseline mutation selected from PDGFRA D842V; or (vi) the disease is melanoma, or (vii) the disease is melanoma, and the melanoma is KIT-activated melanoma; or (viii) the melanoma is a KIT-activated melanoma, and the KIT-activated melanoma has a baseline mutation selected from the group consisting of a KIT exon 9 mutation, a KIT exon 11 mutation, a KIT exon 13 mutation, a KIT exon 17 mutation, and a KIT exon 18 mutation; or (ix) the disease is melanoma, and the melanoma is selected from the group consisting of cutaneous melanoma and non-cutaneous melanoma; or (x) the disease is cutaneous melanoma, and the cutaneous melanoma is selected from the group consisting of superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, amelanotic melanoma, and desmoplastic melanoma; or (xi) the disease is non-cutaneous melanoma, and the non-cutaneous melanoma is selected from ocular melanoma and mucosal melanoma.

20. The pharmaceutical composition of claim 19.

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