RAF kinase inhibitors and methods of use thereof

Abstract

Described herein is Compound I, a RAF inhibitor, and its use in the treatment of disorders such as cancer. TIFF2024546478000465.tif4093

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 287,873, filed December 9, 2021, and U.S. Provisional Patent Application No. 63 / 393,445, filed July 29, 2022, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] The BRAF V600X (i.e., V600E) mutant form of BRAF is known to be oncogenic, and several BRAF inhibitors are currently available on the market to inhibit the signaling of oncogenic BRAF V600E in melanoma and other cancers. BRAF V600E signals as a monomer and is constitutively active, independent of upstream regulation by RAS. Commercially available BRAF V600E inhibitors include vemurafenib, dabrafenib, and encorafenib.

[0003] With the exception of BRAF V600X mutants, almost all other oncogenic forms of BRAF signaling transduce signals through the formation of homodimers (BRAF-BRAF dimers) or heterodimers (e.g., BRAF-CRAF dimers) that are refractory to BRAF inhibitors such as vemurafenib, dabrafenib, and encorafenib. These dimers form in cancers driven by BRAF fusions, atypical BRAF mutations, or RAS-mutated cancers.

[0004] Oncogenic BRAF fusions arise from genomic rearrangements that place the 3-prime portion of the BRAF gene, encoding the kinase domain, after another gene at the 5-prime position. The rearrangement results in the expression of tumor proteins that exhibit constitutive kinase activity due to the loss of the BRAF N-terminal autoinhibitory domain. These BRAF fusions exhibit constitutive kinase activity through spontaneous dimerization, thus enabling aberrant signaling in cancer cells independent of upstream effectors or regulatory mechanisms. In addition, some 5-prime translocation rearranged genes contribute an N-terminal domain that can further induce dimerization, thereby enhancing the activation of the BRAF fusion protein kinase domain dimerization. Because the expression of these genomic rearrangements is controlled by the promoter of the 5-prime partner, overexpression of BRAF fusion transcripts often occurs due to inefficient or excessive promoter activity. BRAF fusions are one of the most common kinase translocations in solid tumors. Since its initial description as an oncogene in papillary thyroid cancer in 2005, hundreds of tumors harboring BRAF kinase domain fusions to one of over 110 distinct five-prime partner genes have been identified across at least 15 different tumor types. BRAF fusions have been found in papillary thyroid cancer, astrocytoma, and melanoma, and have also been identified in drug-resistant EGFR-mutant lung cancer. BRAF fusion proteins signal through dimerization in a RAS-independent manner and are resistant to many BRAF inhibitors, such as vemurafenib and dabrafenib, which are unable to inhibit both protomers of the signaling homodimeric BRAF fusion. Rare CRAF fusion proteins have also been demonstrated to be tumor drivers. These CRAF fusion proteins signal as CRAF-CRAF homodimers.

[0005] Other so-called atypical BRAF mutations also result in spontaneous dimerization and signaling independent of RAS control. Like BRAF fusions, these atypical BRAF mutants signal as abnormal homodimers.

[0006] RAS-mutant cancers account for approximately 26-30% of all human cancers. RAS-mutant cancers signal through the RAS→RAF→MEK→ERK MAPK signaling pathway. In this signaling cascade, kinase-inactive RAF monomers (including ARAF, BRAF, and CRAF isoforms) are recruited to oncogenic RAS, which then induces the formation of kinase-active, signaling RAF dimers. The predominant RAF heterodimer recruited to mutant RAS is the BRAF / CRAF heterodimer.

[0007] A combinatorial siRNA screening approach identified RAF as a dominant node in RAS-mutant cancers, and its co-depletion of both BRAF and CRAF, together with depletion of the autophagy gene ATG7, resulted in the best synthetic lethal inhibition of RAS-mutant signaling and provided the best therapeutic window for signaling inhibition in RAS-mutant cells compared with normal RAS wild-type cells. Furthermore, inhibition of the RAF→MEK→ERK pathway in combination with an autophagy inhibitor has been reported to effectively block RAS-mutant cancer growth in vitro and in vivo.

[0008] Vertical inhibition of the RAF→MEK→ERK pathway through pan-inhibition of RAF (specifically, BRAF+CRAF) and ERK kinase activity has been shown to elicit highly synergistic effects in blocking MAPK pathway signaling in KRAS-mutant pancreatic cancer cells, organoid studies, and mouse models of KRAS-mutant pancreatic cancer. Vertical inhibition of RAF (BRAF+CRAF) and MEK kinase activity has also been shown to be synergistic in KRAS-mutant tumors.

[0009] The importance of inhibiting both BRAF and CRAF isoforms, as well as the need for inhibitors that successfully bind to and inhibit both protomers of the signaling RAF dimer, has been well documented. The failure of RAF inhibitors, particularly BRAF inhibitors, to successfully bind to and inhibit both protomers of the signaling RAF dimer in RAS-mutant cancers results in paradoxical pathway stimulation rather than the desired pathway inhibition. Such BRAF inhibitors are contraindicated for the treatment of RAS-mutant cancers.

[0010] There is a need to identify RAF inhibitors that can inhibit multiple RAF isoforms. Specifically, there is a need to identify RAF inhibitors that can inhibit both BRAF and CRAF isoforms. In particular, there is a need to identify RAF inhibitors that can inhibit both RAF protomers present in signaling BRAF / BRAF homodimers and both protomers in BRAF / CRAF heterodimers. Such pan-RAF inhibitors would find utility in treating BRAF V600X-driven cancers, atypical BRAF-mutated cancers, BRAF fusion cancers, CRAF fusion cancers, and RAS-mutated cancers. Summary of the Invention

[0011] Described herein are compounds that are RAF inhibitors and methods of use thereof. In some embodiments, the compounds are BRAF or CRAF inhibitors. In some embodiments, the compounds are useful for treating cancers driven by oncogenic forms of RAS or BRAF. In some embodiments, the compounds inhibit both BRAF and CRAF isoforms. In some other embodiments, the compounds inhibit both RAF protomers present in signaling BRAF / BRAF homodimers and both protomers present in signaling BRAF / CRAF heterodimers. In some other embodiments, the compounds inhibit ARAF, BRAF, and CRAF present in signaling homodimers or heterodimers.

[0012] In one embodiment, the present disclosure provides a compound represented by formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 Each of the 3 and N are independently selected from X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , and NL 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3、 C=O, N, and NL 3 -E 3 is selected from the group consisting of However, X 1 , X 2 , X 3 , and X 4 At most two of are N, X 2 If N, then X 3 But CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 3 If N, then X 2 But N, CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R4 )-L 2 -E 2 is selected from the group consisting of X 2 If C=O, then X 3 But NL 3 -E 3 and X 3 If C=O, then X 2 But NL 2 -E 2 provided that: X 5 are independently selected from the group consisting of CH, CF, and N; X 6 are independently selected from the group consisting of CH and CF; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH). m an optionally substituted heterocyclyl or heterocyclyl(CH) independently selected from the group consisting of NH—; m NH-, in each occurrence, independently represents R 9 optionally substituted with one or more occurrences of R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each occurrence of p is independently 0, 1, or 2; each occurrence of m is independently 0, 1, 2, 3, or 4; however, X 1 and X 2 is N and X 5 and X 6are each independently selected from CH and CF; 4 But, CR 3 and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 1 and X 4 is N and X 5 and X 6 are each independently selected from CH and CF; 2 But CL 2 -E 2 and L 2 is a direct bond, and E 2 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 But not N-linked heterocyclyl, X 6 is CH and X 5 is CH or CF, and X 4 But, CR 3 and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and X 1 is CH or N, and X 4 is CH and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH—, L 1 -E 1 is not an alkyl substituted with an amine.

[0013] In another embodiment, described herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of the present disclosure described herein) and a pharmaceutically acceptable carrier or excipient.

[0014] In another embodiment, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of the present disclosure described herein).

[0015] In another embodiment, described herein are methods of treating a disorder selected from the group consisting of histiocytosis, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, blood-borne cancer, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of the present disclosure described herein). DETAILED DESCRIPTION OF THE INVENTION

[0016] The features and other details of the present disclosure will now be more particularly described. Certain terms employed in the specification, examples, and appended claims are summarized here. These definitions should be read in light of the remainder of the 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.

[0017] definition The definitions set forth in this application are intended to clarify terms used throughout this application.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. As 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.

[0019] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When substituents are listed without indicating the atom through which such substituent is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such substituent. Combinations of substituents, positions of substituents, and / or variables are permissible only if such combinations result in stable compounds.

[0020] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0021] As used herein, the term "herein" means the entire application.

[0022] As used herein, "deuterated" means that at least one hydrogen atom is replaced by deuterium. In any sample of a deuterated compound, it is likely that some individual molecules of the compound will have hydrogen rather than deuterium at the specified position. However, the percentage of molecules of the deuterated compound that have deuterium at the specified position will be much greater than that which occurs naturally. Deuterium at the deuterated position is enriched.

[0023] 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 to cases where the alkyl is unsubstituted.

[0024] It will be appreciated that the substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skill in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as the methods described below. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or different carbons, so long as a stable structure results.

[0025] As used herein, the term "optionally substituted" refers to the replacement of 1 to 6 hydrogen atoms in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OC(=O)-CH2-Oalkyl. Preferably, "optionally substituted" refers to the replacement of 1 to 4 hydrogen atoms in a given structure with the aforementioned substituents. More preferably, 1 to 3 hydrogen atoms are replaced by the aforementioned substituents. It is understood that the substituents may be further substituted.

[0026] As used herein, the term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. 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, and that the substitution results in a stable compound that does not undergo spontaneous 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, for appropriate organic compounds. For purposes of this application, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms.

[0027] 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, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, heteroaralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that, where appropriate, the substituents can themselves be substituted. For example, substituents of substituted alkyls can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. 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.

[0028] As used herein, the term "alkyl" refers to a fully saturated, straight-chain or branched, non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has from 1 to about 20, preferably from 1 to about 10, carbon atoms, e.g., C1 to C6, unless otherwise defined. 10It may be alkyl or, for example, C1-C6 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 substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. An "alkyl" group may be optionally substituted.

[0029] When used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, 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 " refers to a substituted or unsubstituted saturated hydrocarbon group, 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. C0 alkyl represents a hydrogen when the group is in a terminal position and a bond when it is internal.

[0030] As used herein, the term "hydrocarbyl" refers to a group that does not have =0 or =S substituents and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally contain heteroatoms, bonded through a carbon atom. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (having an =0 substituent on the bonded carbon) and ethoxy (bonded through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. "Hydrocarbyl" groups may be optionally substituted.

[0031] As described herein, Q can be either an amide linkage -NH-C(O)- or a reverse amide linkage -C(O)-NH-. The amide linkage -NH-C(O)- is defined as a bond between the -NH of the amide linkage and R 1 and R 2 This occurs when the -NH of the reverse amide linkage is directly attached to the containing ring (e.g., in compounds of formula I, IA, I-AA, I-AB, I-AC, IB, IB, IC, I-CA, ID, I-DA, I-DB, IE, I-EA, I-EB, IF, I-FA, IG, I-GA, IH, I-HA, IJ, I-JA, IK, I-KA, IL, I-LA, IM, IN, I-NA, IO, IO, IP, I-PA, IQ, I-QA, IR, I-RA, IS, I-SA-i, I-SA-ii, or IT). The reverse amide linkage, -C(O)-NH-, occurs when the -NH of the reverse amide linkage is directly attached to the containing ring (e.g., in compounds of formula I, IA, I-AA, I-AB, I-AC, IB, IB, IC, I-CA, ID, I-DA, I-DB, IE, I-EA, I-EB, IF, I-FA, IG, I-GA, IH, I-HA, IJ, I-JA, IK, I-KA, IL, I-LA, IM, IN, I-NA, IO, IO, IP, I-PA, IQ, I-QA, IR, I-RA, IS, I-SA-i, I-SA-ii, or IT). 1(e.g., in a compound of formula I, IA, I-AA, I-AB, I-AC, IB, IB, IC, I-CA, ID, I-DA, I-DB, IE, I-EA, I-EB, IF, I-FA, IG, I-GA, IH, I-HA, IJ, I-JA, IK, I-KA, IL, I-LA, IM, IN, I-NA, IO, IO, IP, I-PA, IQ, I-QA, IR, I-RA, IS, I-SA-i, I-SA-ii, or IT).

[0032] 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., may be a C1-C6 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and the like. An "alkoxy" group may be optionally substituted.

[0033] As used herein, the term "alkoxyalkyl" refers to an alkyl group (as defined above) substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl. Examples of alkoxyalkyl groups include, but are not limited to, methyl-O-ethylene-, ethyl-O-ethylene-. An "alkoxyalkyl" group may be optionally substituted.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group (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. A "haloalkyl" group may be optionally substituted.

[0035] 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, but are not limited to, difluoromethoxy (-OCHF), trifluoromethoxy (-OCF), or trifluoroethoxy (-OCHCF). A "haloalkyl" group may be optionally substituted.

[0036] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. The ring is preferably 5- to 7-membered, and more preferably 6-membered. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings (fused rings), and at least one of the rings is aromatic. For example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The term "fused" means that a second ring is attached to or formed by having two adjacent atoms common to the first ring. The term "fused" is equivalent to the term "fused." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, phenol, aniline, or indanyl. Unless otherwise specified, all aryl groups described herein may be optionally substituted.

[0037] As used herein, the terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which one or more atoms are common to two or more adjacent rings. For example, the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms in the ring, preferably 5 to 7 atoms.

[0038] As used herein, the term "acyl" refers to a group selected from the group consisting of -C(=O)-R w where R w is optionally substituted alkyl. Examples of "acyl" include, but are not limited to, R w But C1-C 10 Alkyl (C1-C 10 acyl) or C1-C 6-Examples include alkyl(C1-C6 acyl). In some embodiments, each occurrence of an optionally substituted substituent is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino. Additional examples of "acyl" include -C(=O)-CH3, -C(=O)-CH2-CH3, -C(=O)-CH2-CH2-CH3, or -C(=O)-CH(CH3).

[0039] As used herein, the term "carbamoyl" refers to a group represented by: [ka]

[0040] In the formula, R z independently represent hydrogen or an optionally substituted hydrocarbyl group, or R z The groups, taken together with the -NC(=O)-O- moiety to which they are attached, complete a heterocycle having from 5 to 8 atoms in the ring structure which can be optionally substituted.

[0041] As used herein, the term "formyl" refers to a -C(=O)H group.

[0042] As used herein, the terms "amine" and "amino" refer to both unsubstituted and substituted amines and their salts, for example, moieties represented by the formula: [ka] In the formula, R z independently represent hydrogen or an optionally substituted hydrocarbyl group, or R z The groups, together with the N atom to which they are attached, complete a heterocycle having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0043] As used herein, the terms "amide" and "amido" each refer to a group represented by the formula: [ka] In the formula, R x , R y , and R z each independently represents hydrogen or an optionally substituted hydrocarbyl group, or R y and R z taken together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure which may be optionally substituted.

[0044] As used herein, the term "amidine" refers to a group represented by the formula: [ka] In the formula, R x , R y , and R z each independently represents hydrogen or an optionally substituted hydrocarbyl group, or R y and R z The groups, together with the N atom to which they are attached, complete a heterocycle having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0045] As used herein, the term "urea" refers to a group represented by the formula: [ka] In the formula, R x , R y , and R z each independently represents hydrogen or an optionally substituted hydrocarbyl group, or R y and R z taken together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure which may be optionally substituted.

[0046] As used herein, "alkylamino" and "alkylamine" refer to an amino group, as defined above, substituted with at least one alkyl group.

[0047] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0048] As used herein, the term "amidoalkyl" refers to an alkyl group substituted with an amide group.

[0049] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0050] As used herein, the term "alkoxythio" refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-S-.

[0051] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0052] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0053] 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., C3-C4). 10Cycloalkyl, or, for example, C3-C6 cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The second ring of a bicyclic cycloalkyl, or the second or third ring of a tricyclic cycloalkyl, can 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 ring 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, can be selected from saturated, unsaturated, and aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, etc. Cycloalkyls can alternatively be polycyclic, having more than two rings. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.

[0054] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with a cycloalkyl group.

[0055] As used herein, the term "carbocycle" or "carbocyclic" includes bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as long as valences permit. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, 4,5-naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions that can have a hydrogen atom.

[0056] As used herein, the term "cyano" refers to the group --CN.

[0057] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0058] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean chloro, fluoro, bromo, and iodo.

[0059] 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).

[0060] As used herein, the terms "heterocyclyl," "heterocycloalkyl," "heterocycle," and "heterocyclic" refer to a 3- to 15-membered, monocyclic, polycyclic (e.g., bicyclic, tricyclic), bridged or fused, non-aromatic, saturated, or partially saturated ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O), NH, or C(O), with the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. 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, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups may be optionally substituted with one or more suitable groups, such as one or more of the aforementioned groups. Preferably, "heterocyclyl" refers to a 5- or 6-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. More preferably, "heterocyclyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocyclyls are optionally substituted with one or more of the aforementioned groups.

[0061] As used herein, the term "heteroaryl" refers to a substituted or unsubstituted aromatic single ring structure, preferably a 5- to 7-membered ring, more preferably a 5- to 6-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The term "heteroaryl" also refers to a substituted or unsubstituted aromatic or partially aromatic ring system containing at least one heteroatom, having two or more cyclic rings (bicyclic, tricyclic, or polycyclic), containing 8 to 20 ring atoms, preferably 5 to 10 ring atoms, which are covalently bonded or fused, in which two or more atoms are common to two adjacent rings, and in which at least one of the rings is heteroaromatic, e.g., the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. The ring may contain N or S atoms, which are optionally oxidized, or in which the N atoms are optionally quaternized. All heteroaryls are optionally substituted. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.Examples of heteroaryl include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, alpha-carbocyclic alkyl aryl ... Examples of such alkyl aryl groups include, but are not limited to, benzothiadiazolyl, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, 7-azaindolyl, 7-azaindazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, oxazolonepyrimidinyl, imidazolonepyridinyl, imidazolonepyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, tetrahydronaphthyridinyl, tetrahydropyridolpyriminyl, dihydronaphthyridinonyl, naphthyridinonyl, oxazinanonepyridinyl, oxazinanonepyrimidinyl, carbazolyl, dibenzothienyl, acridinyl, and the like.

[0062] E as described herein 1 Regarding [ka] wherein s1 is not a ring selected from the group consisting of L 1 and s2 is a moiety covalently bonded to H or an optionally substituted substituent.

[0063] As used herein, the term "sulfonamide" is represented as follows: [ka] In the formula, R x , R y , and R z represents, independently in each occurrence, hydrogen, an optionally substituted hydrocarbyl group, or R z The groups, together with the N atom to which they are attached, complete a heterocycle having from 4 to 8 atoms in the ring structure, which may be optionally substituted.

[0064] As used herein, the term "sulfone" or "sulfonyl" refers to a group selected from the group consisting of -S(O)-R 6d refers to a group, wherein R 6d represents an optionally substituted hydrocarbyl.

[0065] "Combination therapy" is treatment that involves the administration of two or more therapeutic agents, for example, a compound of the present disclosure and a MAPK pathway inhibitor, to a patient in need thereof.

[0066] "Disease," "disorder," and "condition" are used interchangeably herein.

[0067] The terms "individual," "patient," or "subject" are used interchangeably herein and include any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human. The compounds described herein can be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, 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.).

[0068] As used herein, the MAPK pathway is a signal transduction pathway that includes RAS→RAF→MEK→ERK.

[0069] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX 849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, encorafenib), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996, ERAS-007). The terms "MAPK pathway inhibitor" and "MAPK kinase inhibitor" are used interchangeably herein.

[0070] "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.

[0071] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also include other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0072] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group that may be present in a compound used in the present composition. Compounds included in the present composition that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically 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 pharmaceutically 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 compound may exist as an acid addition salt, zwitterion, or base salt.

[0074] 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 substituents around the stereogenic carbon atom, although those of skill in the art will recognize that the structure may implicitly indicate chiral centers. These compounds may also be designated by "(+)" and "(-)" based on their optical rotatory properties. The compounds described herein encompass various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated by the symbol "(±)" in nomenclature, although those of skill in the art will recognize that the structure may implicitly indicate chiral centers.

[0075] As used herein, the term "therapeutically effective amount" refers to an amount of a subject compound that elicits the biological or medical response of a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds described herein are administered in a therapeutically effective amount to treat a disorder.

[0076] "Treating" includes any effect that results in an improvement of a condition, disease, disorder, etc., eg, amelioration, alleviation, modulation, or elimination.

[0077] 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 may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35S, 18 F, and 36 For example, compounds of the present disclosure may have one or more H atoms replaced with deuterium.

[0078] Individual enantiomers and diastereomers of the disclosed compounds may be synthetically prepared from commercially available starting materials containing an asymmetric or stereogenic center, or by the preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of a 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 a mixture of optical enantiomers on 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, 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.

[0079] As used herein, "compounds of the disclosure" include compounds of Formula I, Formula IA, Formula I-AA, Formula I-AB, Formula I-AC, Formula IB, Formula I-BA, Formula IC, Formula I-CA, Formula ID, Formula I-DA, Formula I-DB, Formula IE, Formula I-EA, Formula I-EB, Formula IF, Formula I-FA, Formula IG, Formula I-GA, Formula IH, Formula I-HA, Formula IJ, Formula I-JA, Formula IK, Formula I-KA, Formula IL, Formula I-LA, Formula IM, Formula IN, Formula I-NA, Formula IO, Formula I-OA, Formula IP, Formula I-PA, Formula IQ, Formula I-QA, Formula IR, Formula I-RA, Formula IS, Formula I-SA-i, Formula I-SA-ii, and Formula IT, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0080] compound In one embodiment, the compound represented by formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, provided herein, wherein: X 1 and X 4 Each of the 3 and N are independently selected from X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , and NL 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3、 C=O, N, and NL 3 -E 3 is selected from the group consisting of However, X1 , X 2 , X 3 , and X 4 At most two of are N, X 2 If N, then X 3 But CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 3 If N, then X 2 But N, CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R 4 )-L 2 -E 2 is selected from the group consisting of X 2 If C=O, then X 3 But NL 3 -E 3 and X 3 If C=O, then X 2 But NL 2 -E 2 provided that: X 5 are independently selected from the group consisting of CH, CF, and N; X 6 are independently selected from the group consisting of CH and CF; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH). m an optionally substituted heterocyclyl or heterocyclyl(CH) independently selected from the group consisting of NH—; m NH-, in each occurrence, independently represents R 9 optionally substituted with one or more occurrences of R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each occurrence of p is independently 0, 1, or 2; each occurrence of m is independently 0, 1, 2, 3, or 4; however, X 1 and X 2 is N and X 5 and X 6 are each independently selected from CH and CF; 4 But, CR 3 and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 1 and X 4 is N and X 5 and X 6 are each independently selected from CH and CF; 2 But CL 2 -E 2 and L 2 is a direct bond, and E 2 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 But not N-linked heterocyclyl, X 6 is CH and X 5 is CH or CF, and X 4 But, CR 3 and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and X 1 is CH or N, and X 4 is CH and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH—, L 1 -E 1 is not an alkyl substituted with an amine.

[0081] In some embodiments, U is an optionally substituted heteroaryl, and the optionally substituted substituents, at each occurrence, are selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH). m an optionally substituted heterocyclyl or heterocyclyl(CH) independently selected from the group consisting of NH—; m NH-, in each occurrence, independently represents R 9 is optionally substituted with one or more occurrences of

[0082] In some embodiments, U is [ka] wherein X 7 , X 8 , and X 9 is CR 3 and N, where X 7 , X 8 , and X 9 is N, and Z is -NHC(O)R 6 , -NHC(O)OR 6, or -C(O)NHR 7 and R 6 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R 8 and optionally substituted with one or more independent occurrences of the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0083] In some embodiments, U is [ka] wherein X 7 , X 8 , and X 9 is CR 3 and N, where X 7 , X 8 , and X 9 is N, and Z is -NHC(O)R 6 and R 6 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R 8 and optionally substituted with one or more independent occurrences of the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0084] In some embodiments, U is [ka] wherein X 7 , X 8 , and X 9 is CR 3 and N, where X 7 , X 8 , and X 9 is N, and Z is -NHC(O)R 6 and R 6 is methyl, ethyl, or iso-propyl. In some embodiments, Z is —NHC(O)R 6 and R 6 In some embodiments, Z is —NHC(O)R 6 and R 6 is cyclopropyl or cyclobutyl. In some embodiments, Z is —NHC(O)R 6 and R 6 In some embodiments, Z is —NHC(O)R 6 and R 6 is H. In some embodiments, Z is —NHC(O)R 6 and R 6 is CH2N(R 4 In some embodiments, Z is —NHC(O)R 6 and R 6 is CH2-CN. In some embodiments, Z is -NHC(O)R 6 and R 6 is CH2-OH. In some embodiments, Z is -NHC(O)R 6and R 6 is CH2-OMe.

[0085] In some embodiments, U is [ka] wherein X 7 , X 8 , and X 9 is CR 3 and N, where X 7 , X 8 , and X 9 and Z is -C(O)NHR, provided that not more than one of 7 and R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0086] In some embodiments, Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, at each occurrence, are independently selected from R 9 is.

[0087] In some embodiments, Z is —C(O)NHR 7 In some embodiments, Z is —C(O)NHR 7 and R 7 is H. In some embodiments, Z is —C(O)NHR 7 and R 7 is alkyl. In some embodiments, Z is —C(O)NHR 7 and R 7 is methyl. In some embodiments, Z is —C(O)NHR 7 and R 7 In some embodiments, Z is —C(O)NHR 7 and R 7is isopropyl. In some embodiments, Z is -NH2. In some embodiments, Z is carbamoyl. In some embodiments, Z is formyl. In some embodiments, Z is methylamino. In some embodiments, Z is ethylamino. In some embodiments, Z is beta-hydroxyethylamino. In some embodiments, Z is beta-methoxyethylamino. In some embodiments, Z is heterocyclyl. In some embodiments, Z is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, Z is morpholinyl. In some embodiments, Z is heterocyclylalkylamino. In some embodiments, Z is oxetanylalkylamino. In some embodiments, Z is azetidinylalkylamino. In some embodiments, Z is tetrahydropyranylalkylamino. In some embodiments, Z is heteroaryl. In some embodiments, Z is pyrazolyl. In some embodiments, Z is oxazolyl. In some embodiments, Z is oxadiazolyl. In some embodiments, Z is thiazolyl. In some embodiments, Z is selected from the group consisting of H, alkyl, and cycloalkyl. In some embodiments, Z is H. In some embodiments, Z is methyl. In some embodiments, Z is ethyl. In some embodiments, Z is iso-propyl. In some embodiments, Z is cyclopropyl.

[0088] In some embodiments, U is [ka] wherein X 7 , X 8 , and X 9 is CR 3 and N, where X 7 , X 8 , and X 9 is N, and Z is -NHC(O)OR 6 and R 6 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R 8 and optionally substituted with one or more independent occurrences of the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; The heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

[0089] In some embodiments, U is [ka] wherein X 8 , X 10 , and X 11 is independently selected from CH and N.

[0090] In some embodiments, U is [ka] wherein X 8is independently selected from CH and N; X 12 is CH2, CHF, CF2, CH(CH3), C(CH3)2, NR 6 , or O.

[0091] In some embodiments, the compound is IA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0092] In some embodiments, the compound is I-AA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0093] In some embodiments, the compound is I-AB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is CL 3 -E 3 , COL 3 -E 3 , and CN(R4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; Each m is independently 0, 1, 2, 3, or 4.

[0094] In some embodiments, the compound is I-AC: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, sulfone, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0095] In some embodiments, the compound is IB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 , CH, CL 3 -E 3 , COL 3 -E 3, CN(R 4 )-L 3 -E 3 and N, X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and R 3 is H and X 5 and X 6 When is CH and Q is -C(O)-NH-, L 1 -E 1 is not an alkyl substituted with an amine.

[0096] In some embodiments, the compound is I-BA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0097] In some embodiments, the compound has an IC: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R4 )-L 2 -E 2 , and NL 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is, at each occurrence, independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or X 6 is CH and X 5 is CH or CF, and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and R 3 is H and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH, L 1 -E1 is not an alkyl substituted with an amine.

[0098] In some embodiments, the compound is I-CA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is, at each occurrence, independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0099] In some embodiments, the compound has the ID: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0100] In some embodiments, the compound is I-DA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0101] In some embodiments, the compound is I-DB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is CL 3 -E 3 , COL 3 -E 3 , and CN(R4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; Each m is independently 0, 1, 2, 3, or 4.

[0102] In some embodiments, the compound is IE: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 NL 3 -E 3 and X 4 is CR 3and N, X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; However, L 1 is a direct bond, E 1 is not an N-linked heterocyclyl.

[0103] In some embodiments, the compound is I-EA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0104] In some embodiments, the compound is I-EB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 NL 3 -E 3 and X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; Each m is independently 0, 1, 2, 3, or 4.

[0105] In some embodiments, the compound is IF: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 NL 2 -E 2 and X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl; the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; However, L 1 is a direct bond, E 1 is not an N-linked heterocyclyl.

[0106] In some embodiments, the compound is I-FA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0107] In some embodiments, the compound is IG: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L3 -E 3 and N, X 3 , CH, CL 2 -E 2 , COL 2 -E 2 , CN(R 4 )-L 2 -E 2 and N, X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 and X 3 But both are not N, X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 6 is CH and X 5 is CH or CF, and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and R 3 is H and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH, L 1 -E1 is not an alkyl substituted with an amine.

[0108] In some embodiments, the compound is I-GA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0109] In some embodiments, the compound is IH: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0110] In some embodiments, the compound is I-HA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0111] In some embodiments, the compound is IJ: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R 4 )-L 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 But CL 2 -E 2 and L 2 is a direct bond, and E 2 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L1 -E 1 is not unsubstituted methyl.

[0112] In some embodiments, the compound is I-JA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0113] In some embodiments, the compound has the formula IK: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R 4 )-L 2 -E 2 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or X 6 is CH and X 5 is CH or CF, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or R 3 is H and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH—, L 1 -E 1 is not an alkyl substituted with an amine.

[0114] In some embodiments, the compound is I-KA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; and the heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0115] In some embodiments, the compound is an IL: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , CN(R4 )-L 2 -E 2 and N, X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 is N and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0116] In some embodiments, the compound is I-LA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0117] In some embodiments, the compound is IM: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , CN(R4 )-L 2 -E 2 and N, X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; X 8 is selected from the group consisting of N and CH; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 is N and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 But not N-linked heterocyclyl, Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0118] In some embodiments, the compound is IN: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R4 )-L 2 -E 2 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0119] In some embodiments, the compound is I-NA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0120] In some embodiments, the compound is IO: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 and N, X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , and CN(R 4 )-L 3 -E 3 is selected from the group consisting of X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 )p and L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R4 is, at each occurrence, independently selected from H and alkyl; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 2 is N and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl.

[0121] In some embodiments, the compound is I-OA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0122] In some embodiments, the compound is IP: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each m is independently 0, 1, 2, 3, or 4; however, L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or R 3 is H and X 5 and X 6 When is CH and Q is -C(O)-NH-, L 1 -E 1 is not an alkyl substituted with an amine.

[0123] In some embodiments, the compound is I-PA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0124] In some embodiments, the compound has an IQ: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH)NH—, wherein the optionally substituted substituents on the heterocyclyl ring, in each occurrence, are independently selected from R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each m is independently 0, 1, 2, 3, or 4; however, L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or R 3 is H and X 5 and X 6 When is CH and Q is -C(O)-NH-, L 1 -E 1 is not an alkyl substituted with an amine.

[0125] In some embodiments, the compound is I-QA [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2). m and optionally substituted substituents on the heterocyclyl ring are selected, at each occurrence, independently from the group consisting of NH—, R 9 and R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 9 is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; Each m is independently 0, 1, 2, 3, or 4.

[0126] In some embodiments, the compound has an IR: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 Each of the 3 and N are independently selected from X 2are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , and NL 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3、 C=O, N, and NL 3 -E 3 is selected from the group consisting of However, X 1 , X 2 , X 3 , and X 4 At most two of are N, X 2 If N, then X 3 But CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 3 If N, then X 2 But N, CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R 4 )-L 2 -E 2 is selected from the group consisting of X 2 If C=O, then X 3 But NL 3 -E 3 and X 3 If C=O, then X 2 But NL 2 -E2 provided that: X 5 is selected from the group consisting of N, CH, and CF; X 8 , X 9 , and X 10 Each of the 3 and N are independently selected from L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 1 and X 2 is N and X 5 and X 6 are each independently selected from CH and CF; 4 But, CR 3 and R 3 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 But it is not morpholinyl or X 1 and X 4 is N and X 5 and X 6 are each independently selected from CH and CF; 2 But CL 2 -E 2 and L 2 is a direct bond, and E 2 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or X 6 is CH and X 5 is CH or CF, and X 4 But, CR 3 and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and X 1 is CH or N, and X4 is CH and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH—, L 1 -E 1 is not an alkyl substituted with an amine.

[0127] In some embodiments, the compound is an I-RA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 Each of the 3 and N are independently selected from X 2 and X 3 each is independently selected from the group consisting of N and CH; However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of X 8 , X 9 , and X 10 Each of the 3 and N are independently selected from X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L 1 is a direct bond, and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, wherein the heterocyclyl or heteroaryl is C-linked; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; Each m is independently 0, 1, 2, 3, or 4.

[0128] In some embodiments, the compound is IS: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 Each of the 3 and N are independently selected from X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , and NL 2 -E 2 is selected from the group consisting of X 3 , CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3、 C=O, N, and NL 3 -E 3 is selected from the group consisting of However, X 1 , X 2 , X 3 , and X 4 At most two of are N, X 2 If N, then X 3 But CH, CL 3 -E 3 , COL 3 -E 3 , CN(R 4 )-L 3 -E 3 and N, X 3 If N, then X2 But N, CH, COL 2 -E 2 , C.L. 2 -E 2 , and CN(R 4 )-L 2 -E 2 is selected from the group consisting of X 2 If C=O, then X 3 But NL 3 -E 3 and X 3 If C=O, then X 2 But NL 2 -E 2 provided that: X 5 is selected from the group consisting of N, CH, and CF; X 8 is CR 3 and N, X 11 is O, C(R 10 )2, and NR 11 is selected from the group consisting of L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 21 ) p and L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 31 ) p and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 11 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 21 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31 two occurrences of together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 4 is, at each occurrence, independently selected from H and alkyl; R 10 is, at each occurrence, independently selected from the group consisting of H, alkyl, cycloalkyl, and F; R 11 is, at each occurrence, independently selected from the group consisting of H, alkyl, and cycloalkyl; each p is independently 0, 1, or 2; each m is independently 0, 1, 2, 3, or 4; however, X 1 and X 2 is N and X 5 and X 6 are each independently selected from CH and CF; 4 But, CR 3 and R 3 is selected from H and alkyl, and X3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 1 and X 4 is N and X 5 and X 6 are each independently selected from CH and CF; 2 But CL 2 -E 2 and L 2 is a direct bond, and E 2 is selected from H and alkyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, or X 2 But, COL 2 -E 2 and CN(R 4 )-L 2 -E 2 Selected from R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X 3 But, COL 3 -E 3 and CN(R 4 )-L 3 -E 3 Selected from R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L 1 is a direct bond, E 1 is not an N-linked heterocyclyl, or X 6 is CH and X 5 is CH or CF, and X 4 But, CR 3 and X 3 is N, Q is —C(O)NH—, and L 1 is a direct bond, and E 1 C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C 14 aryl, and C1-C9 heteroaryl, X 2 However, CN(R 4 )-L 2 -E 2 Isn't it, or Q is —C(O)—NH—, and L 1 is a direct bond, E 1 is not H, or When Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl, or X 3 is N and X 1 is CH or N, and X 4 is CH and X 5 and X 6 is CH and X 2 When is CH or C—NH2 and Q is —C(O)—NH—, L 1 -E 1 is not an alkyl substituted with an amine.

[0129] In some embodiments, the compound has formula I-SA-i or I-SA-ii: [ka] [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4Each of the 3 and N are independently selected from X 2 and X 3 are each independently selected from the group consisting of N and CH; However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6 alkyl, and the optionally substituted substituent, at each occurrence, is selected from the group consisting of (E 11 ) m and E 1 teeth, optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein the...

Claims

1. Compounds represented by formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ４ Each of the ３ and N are independently selected; X ２ is N, CH, C=O, C-O-L ２ -E ２ , C.-L. ２ -E ２ , C-N(R ４ )-L ２ -E ２ , and N-L ２ -E ２ is selected from the group consisting of X ３ is CH, C-L ３ -E ３ , C-O-L ３ -E ３ , C-N(R ４ )-L ３ -E ３、 C=O, N, and N-L ３ -E ３ is selected from the group consisting of However, X １ , X ２ , X ３ , and X ４ at most two of are N, X ２ If N, then X ３ But CH, C-L ３ -E ３ , C-O-L ３ -E ３ , C-N(R ４ )-L ３ -E ３ and N; X ３ If N, then X ２ But N, CH, C-O-L ２ -E ２ , C.-L. ２ -E ２ , and C-N(R ４ )-L ２ -E ２ is selected from the group consisting of X ２ When C=O, X ３ But N-L ３ -E ３ and X ３ When C=O, X ２ But N-L ２ -E ２ provided that: X ５ are independently selected from the group consisting of CH, CF, and N; X ６ are independently selected from the group consisting of CH and CF; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and L ２ represents a direct bond and an optionally substituted C １ -C ６ alkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of: ２１ ) ｐ and L ３ represents a direct bond and an optionally substituted C １ -C ６ alkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of: ３１ ) ｐ and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; E １ is H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; optionally substituted aryl, wherein the heterocyclyl substituent is independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted aryl, wherein, at each occurrence, the heterocyclyl substituent is independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E ２ is hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amido, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E ２１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E ２１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E ３ is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E ３１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E ３１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; U is optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl (CH ２ ) ｍ NH—, and the optionally substituted heterocyclyl or heterocyclyl(CH ２ ) ｍ NH—, in each occurrence, independently represents R ９ and optionally substituted with one or more occurrences of R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ４ is, at each occurrence, independently selected from H and alkyl; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each occurrence of p is independently 0, 1, or 2; each occurrence of m is independently 0, 1, 2, 3, or 4; however, X １ and X ２ is N and X ５ and X ６ are each independently selected from CH and CF; ４ But, CR ３ and R ３ is selected from H and alkyl; X ３ But C-L ３ -E ３ and L ３ is a direct bond, E ３ is not morpholinyl, or X １ and X ４ is N and X ５ and X ６ are each independently selected from CH and CF; ２ But C-L ２ -E ２ and L ２ is a direct bond, and E ２ is selected from H and alkyl; X ３ But C-L ３ -E ３ and L ３ is a direct bond, E ３ is not morpholinyl, or X ２ But, C-O-L ２ -E ２ and C-N(R ４ )-L ２ -E ２ and R ４ is H, and each L ２ is a direct bond, each E ２ is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or X ３ But, C-O-L ３ -E ３ and C-N(R ４ )-L ３ -E ３ and R ４ is H, and each L ３ is a direct bond, each E ３ is not a 6-, 7-, 8-, 9-, 10-, or 11-membered bicyclic ring containing 0, 1, 2, 3, or 4 atoms selected from N, O, and S; or L １ is a direct bond, E １ but not N-linked heterocyclyl, X ６ is CH, and X ５ is CH or CF, and X ４ But, CR ３ and X ３ is N, Q is —C(O)NH—, and L １ is a direct bond, and E １ But C ３ -C ８ Cycloalkyl, C ２ -C ８ Heterocyclyl, C ６ -C １４ Aryl, and C １ -C ９ When selected from the group consisting of heteroaryl, X ２ But C-N(R ４ )-L ２ -E ２ Isn't it, or Q is —C(O)—NH—, and L １ is a direct bond, E １ is not H, or When Q is —NH—C(O)—, L １ -E １ is not unsubstituted methyl, or X ３ is N and X １ is CH or N, and X ４ is CH, and X ５ and X ６ is CH, and X ２ is CH or C—NH ２ and when Q is —C(O)—NH—, L １ -E １ A compound represented by Formula I, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, with the proviso that is not an alkyl substituted with an amine.

2. The compound of claim 1 represented by formula I-AA: 【Chemistry 2】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-AA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

3. The compound of claim 1 represented by formula I-AB: 【Transformation 3】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ３ is C-L ３ -E ３ , C-O-L ３ -E ３ , and C-N(R ４ )-L ３ -E ３ is selected from the group consisting of X ５ is selected from the group consisting of N, CH, and CF; L ３ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E ３１ ) ｐ and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ alkyl, wherein said optionally substituted substituents, at each occurrence, are selected from the group consisting of: １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E ３ is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E ３１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E ３１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ４ is, at each occurrence, independently selected from H and alkyl; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; A compound represented by formula I-AB, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

4. The compound of claim 1 represented by formula I-AC: 【Chemistry 4】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, sulfone, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-AC, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

5. The compound of claim 1 represented by formula I-BA: 【Transformation 5】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-BA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

6. The compound of claim 1 represented by formula I-CA: 【Transformation 6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is, at each occurrence, independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-CA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

7. The compound of claim 1 represented by formula I-DA: 【Transformation 7】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-DA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

8. The compound of claim 1 represented by formula I-DB: 【Transformation 8】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ３ is C-L ３ -E ３ , C-O-L ３ -E ３ , and C-N(R ４ )-L ３ -E ３ is selected from the group consisting of X ５ is selected from the group consisting of N, CH, and CF; L ３ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E ３１ ) ｐ and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E ３ is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E ３１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E ３１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ４ is, at each occurrence, independently selected from H and alkyl; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; A compound represented by formula I-DB, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

9. The compound of claim 1 represented by formula I-EA: 【Chemistry 9】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-EA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

10. The compound of claim 1 represented by formula I-EB: 【Chemistry 10】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ３ is N-L ３ -E ３ and X ５ is selected from the group consisting of N, CH, and CF; L ３ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E ３１ ) ｐ and Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; E ３ is hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone; and optionally substituted cycloalkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E ３１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E ３１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; A compound represented by formula I-EB, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

11. The compound of claim 1 represented by formula I-FA: 【Chemistry 11】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-FA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

12. The compound of claim 1 represented by formula I-GA: 【Chemistry 12】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-GA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

13. The compound of claim 1 represented by formula I-HA: 【Chemistry 13】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-HA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

14. The compound of claim 1 represented by formula I-JA: 【Chemistry 14】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-JA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

15. The compound of claim 1 represented by formula I-KA: 【Chemistry 15】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; wherein the cycloalkyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; and said heterocyclyl substituent is optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-KA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

16. The compound of claim 1 represented by formula I-LA: 【Chemistry 16】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-LA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

17. The compound of claim 1 represented by formula I-NA: 【Chemistry 17】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-NA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

18. The compound of claim 1 represented by formula I-OA: [Chemistry 18] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-OA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

19. The compound of claim 1 represented by formula I-PA: 【Chemistry 19】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-PA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

20. The compound of claim 1 represented by formula I-QA: 【Chemistry 20】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is acyl, carbamoyl, formyl, amido, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamido, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl (CH ２ ) ｍ NH—, wherein said optionally substituted substituents on the heterocyclyl ring are, at each occurrence, independently selected from the group consisting of R ９ and R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R ９ is independently selected at each occurrence from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; A compound represented by formula I-QA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

21. The compound of claim 1 represented by formula I-RA: 【Chemistry 21】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ４ Each of the ３ and N are independently selected; X ２ and X ３ are each independently selected from the group consisting of N and CH; However, X １ , X ２ , X ３ , and X ４ provided that no more than two of X ８ , X ９ , and X １０ Each of the ３ and N are independently selected; X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; A compound represented by formula I-RA, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

22. The compound of claim 1 represented by formula I-SA-i or I-SA-ii: 【Chemistry 22】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X １ and X ４ Each of the ３ and N are independently selected; X ２ and X ３ are each independently selected from the group consisting of N and CH; However, X １ , X ２ , X ３ , and X ４ provided that no more than two of X ５ is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of —NH—C(O)— and —C(O)—NH—; L １ represents a direct bond and an optionally substituted C １ -C ６ and optionally substituted substituents selected from the group consisting of alkyl, at each occurrence: (E １１ ) ｍ and E １ teeth, optionally substituted cycloalkyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; Optionally substituted heteroaryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; the alkyl substituents are, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the cycloalkyl substituent is, independently at each occurrence, optionally substituted with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; the heterocyclyl substituents are independently, at each occurrence, optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; Optionally substituted aryl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amine, amido, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl; said alkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said cycloalkyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl; said heterocyclyl substituents are optionally substituted, independently at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and an optionally substituted heterocyclyl, wherein said optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; (L １ is a direct bond, and E １ is an optionally substituted heterocyclyl or optionally substituted heteroaryl, said heterocyclyl or heteroaryl is C-linked; E １１ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E １１ taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring having from 3 to 6 atoms in the ring structure; R １ is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; A compound represented by formula I-SA-i or I-SA-ii, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each m is independently 0, 1, 2, 3, or 4.

23. Z is -NHC(O)R ６、 -NHC(O)OR ６ , or —C(O)NHR ７ and R ６ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R ８ and optionally substituted with one or more independent occurrences of said heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R ７ is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; said heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R ８ is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; 21. The compound of any one of claims 2 to 20, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein said heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

24. Z is -NHC(O)R ６ and R ６ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R ８ and optionally substituted with one or more independent occurrences of said heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R ８ is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; 24. The compound of claim 23, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

25. Z is -C(O)NHR ７ and R ７ is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; 24. The compound of claim 23, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

26. Z is -NHC(O)OR ６ and R ６ is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; Each of alkyl and cycloalkyl is R ８ and optionally substituted with one or more independent occurrences of said heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R ８ is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl; each of the alkyl and cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl; 24. The compound of claim 23, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone.

27. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein Q is -NH-C(O)-.

28. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein Q is -C(O)-NH-.

29. i) X 1 , X 4 , X 5 , and X 6 are each CH, X 2 is N, and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; ii) X 1 , X 4 , X 5 , and X 6 are each CH, X 2 is CH, and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; iii) X 1 is CR 3 , X 2 and X 4 are each N, X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 , X 5 is CH or N, and X 6 is CH; iv) X 1 and X 4 are each CR 3 , X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N, X 5 is N, and X 2 and X 6 are CH; v) X 1 is CR 3 , X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 , X 2 and X 4 are N, and X 5 and X 6 are CH; vi) X 1 is CR 3 , X 4 is CR 3 or N, X 3 is NL 3 -E 3 , X 2 is C═O, and X 5 and X 6 are CH; vii) X 1 and X 4 are CR 3 , X 3 is C═O, X 2 is NL 2 -E 2 , and X 5 and X 6 are CH; viii) X 1 and X 4 are CR 3 , X 2 is N, X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N, and X 5 and X 6 are CH; ix) X 1 and X 2 are N, X 4 is CR 3 , X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 , and X 5 and X 6 are CH; x) X 1 and X 4 are N, X 5 and X 6 are each CH, X 2 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; xi) X 1 and X 3 are N, X 4 is CR 3 , X 5 and X 6 are each CH, and X 2 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; xii) X 1 is N, X 4 is CR 3 , X 5 and X 6 are each CH, X 2 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 , and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; xiii) X 1 is CR 3 , X 2 and X 6 are CH, and X 3 , X 4 and X 5 are N; or xiv) X 1 is CR 3 , X 2 , X 5 and X 6 are CH, and X 3 and X 4 are N; 10. The compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

30. i) X 1 , X 4 , and X 5 are each CH, X 2 is CH, X 8 is N, and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; ii) X 1 and X 4 are each CR 3 , X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N, X 8 is N, and X 2 , X 5 , and X 6 are CH; iii) X 1 and X 4 are each CR 3 , X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N, X 5 and X 8 are N, and X 2 and X 6 are CH; or iv) X 1 is CR 3 , X 2 , X 5 and X 6 are CH, and X 3 , X 4 and X 8 are N; 22. The compound of claim 21, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

31. E 3 is i) selected from the group consisting of H, alkyl, and cycloalkyl, wherein cycloalkyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, haloalkoxy, hydroxy, and cyano; ii) selected from the group consisting of hydroxy, alkoxy, and cyano; or iii) The compound of any one of claims 1, 3, 8, 29, and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

32. E ２ is selected from the group consisting of H, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of substituents independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl, alkyl, amine, haloalkoxy, haloalkyl, and sulfonyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

33. R 1 is i) selected from the group consisting of H, alkyl, haloalkyl, and halogen, or ii) The compound of any one of claims 1 to 22, 29, and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein the aryl group is selected from the group consisting of methyl and fluorine.

34. R ２ is selected from H and F, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

35. The Z-substituted ring is i) selected from the group consisting of: 【Chemistry 23】 ii) selected from the group consisting of: 【Chemistry 24】 iii) selected from the group consisting of: 【Chemistry 25】 iv) selected from the group consisting of: 【Chemistry 26】 wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; v) selected from the group consisting of: 【Chemistry 27】 vi) selected from the group consisting of: 【Chemistry 28】 vii) selected from the group consisting of: 【Chemistry 29】 wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; viii) selected from the group consisting of: 【Transformation 30】 ix) selected from the group consisting of: 【Chemistry 31】 x) selected from the group consisting of: 【Chemistry 32】 wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; xi) selected from the group consisting of: 【Transformation 33】 or xii) selected from the group consisting of: 【Transformation 34】 31. The compound of any one of claims 2 to 20, 29, and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl.

36. E 1 is i) selected from the group consisting of: 【Chemistry 35】 ii) selected from the group consisting of: 【Transformation 36】 iii) selected from the group consisting of: 【Chemistry 37】 iv) selected from the group consisting of: 【Transformation 38】 31. A compound according to any one of claims 1 to 22, 29 and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof. 【Request Item 37】 【Chemistry 39】 but, i) selected from the group consisting of: 【Chemistry 40】 ii) selected from the group consisting of: 【Chemistry 41】 iii) selected from the group consisting of: 【Chemistry 42】 31. A compound according to any one of claims 1 to 22, 29 and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof.

38. i) When L 1 is a direct bond, 【Chemistry 43】 is selected from the group consisting of: 【Chemistry 44】 ii) when L 1 is a direct bond, 【Chemistry 45】 is selected from the group consisting of: 【Chemistry 46】 iii) when L 1 is a direct bond, 【Chemistry 47】 is selected from the group consisting of: 【Chemistry 48】 31. A compound according to any one of claims 1 to 22, 29 and 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof. 【Request Item 39】 【Chemistry 49】 but, i） [Transformation 50] and X 3 is selected from the group consisting of CH, CL 3 -E 3 , C-OL 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; ii) 【Chemistry 51】 That is, iii) 【Chemistry 52】 and X 3 is selected from the group consisting of CH, CL 3 -E 3 , C-OL 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; iv) 【Chemistry 53】 That is, v） 【Chemistry 54】 That is, vi) 【Transformation 55】 and X 3 is selected from the group consisting of CH, CL 3 -E 3 , C-OL 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; vii) 【Transformation 56】 and X 3 is NL 3 -E 3 ; viii) 【Chemistry 57】 and X 3 is NL 3 -E 3 ; ix) 【Chemistry 58】 and X 2 is NL 2 -E 2 ; x） 【Chemistry 59】 wherein X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 , and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; xi) 【Transformation 60】 and X 3 is selected from the group consisting of CH, CL 3 -E 3 , C-OL 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; xii) 【Chemistry 61】 is, or xiii) 【Transformation 62】 and X 3 is selected from the group consisting of CH, CL 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

40. A compound selected from the group consisting of: 【Chemistry 63-1】 【Chemistry 63-2】 【Chemistry 63-3】 【Chemistry 63-4】 【Chemistry 63-5】 【Transformation 63-6】 【Chemistry 63-7】 【Transformation 63-8】 【Chemistry 63-9】 【Chemistry 63-10】 【Chemistry 63-11】 and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, 29, 30, 39 and 40, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

42. The pharmaceutical composition of claim 41 for treating cancer in a patient in need of such treatment.

43. 43. The pharmaceutical composition of claim 42, wherein the cancer is selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, blood-borne cancer, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

44. The cancer is a) harboring a BRAF oncogenic mutation; b) has a RAS oncogenic mutation, optionally the RAS oncogenic mutation is a RAS Q61R or Q61K mutation; and / or c) NF1 oncogenic mutation.

45. 42. The pharmaceutical composition of claim 41 for treating a disorder in a patient in need thereof selected from the group consisting of melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, brain cancer, glioma, glioblastoma, astrocytoma, blood-borne cancer, hairy cell leukemia, acute myeloid leukemia (AML), or other cancers caused by activation of the RAS→RAF→MEK→ERK signaling pathway.

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