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. TIFF2024546107000439.tif4174

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Patent Application No. 63 / 287,866, filed December 9, 2021, and U.S. Provisional Patent Application No. 63 / 393,440, 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 mutant 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 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 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 unusually high 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 those that inhibit both BRAF and CRAF isoforms, and specifically those that inhibit both RAF protomers present in signaling BRAF / BRAF homodimers and 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-mutant cancers. Summary of the Invention

[0011] Described herein, in part, are compounds that are RAF inhibitors, e.g., BRAF or CRAF inhibitors, and methods of use thereof, e.g., treating cancers driven by oncogenic forms of RAS or BRAF. In one embodiment, the compounds of the disclosure inhibit both BRAF and CRAF isoforms. In another embodiment, the compounds of the disclosure inhibit both RAF protomers present in signaling BRAF / BRAF homodimers and BRAF / CRAF heterodimers.

[0012] In one embodiment, the compound represented by formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 4are each independently 5 or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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, and 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 2 and X 4 But both are N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, E 7 is morpholinyl, and X 1 and X 4 But both are N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, E 7 is morpholinyl, and X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 If L 3 -E 3is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5- or 6-membered heteroaryl, or amido; X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, E 7 is morpholinyl, and X 1 is CH and X 2 is N and X 3 But, COL 3 -E 3 and X 4 is CH and X 6 is CH, CD, or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, and E 7 is morpholinyl, and X 1 is CH and X 2 But, COL 2 -E 2 and X 3 is N and X 4 is CH and X 6is CH, CD, or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, E 7 is morpholinyl, and X 1 is CH and X 2 is N and X 3 But, COL 3 -E 3 and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; E 7 is morpholinyl, and X 1 is CH and X 2 But, COL 2 -E 2 and X 3 is N and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1- E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy;3 -E 3 , (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 ,and (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond, and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 is C=O and X 3 But NL 3 -E 3 If L 3 -E 3 is not selected from the group consisting of H, methyl, hydroxyethyl, hydroxypropyl, and 2,3-dihydroxypropyl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 is CH, CD, or CF, and X 2is N and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[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 is a method 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 the subject matter of this specification 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-C, 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 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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), where at least one of the rings is aromatic, and the other cyclic rings may be, for example, 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.

[0036] 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.

[0037] 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 independently 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).

[0038] As used herein, the term "carbamoyl" refers to a group represented by: [ka] 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.

[0039] As used herein, the term "formyl" refers to a -C(=O)H group.

[0040] 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]

[0041] 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.

[0042] 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 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 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.

[0044] 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.

[0045] As used herein, "alkylamino" and "alkylamine" refer to an amino group, as defined above, substituted with at least one alkyl group.

[0046] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

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

[0048] As used herein, the term "cyanoalkyl" refers to an alkyl group substituted with a cyano group.

[0049] 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-.

[0050] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

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

[0052] 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.

[0053] As used herein, the term "cycloalkylalkyl" or "carbocyclylalkyl" refers to an alkyl group substituted with a cycloalkyl group. The alkyl group of the carbocyclyl and / or carbocyclylalkyl may be further substituted as defined above for cycloalkyl and alkyl, respectively.

[0054] 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.

[0055] As used herein, the term "cyano" refers to the group --CN.

[0056] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0057] As used herein, the terms "halo" or "halogen," alone or in combination with other terms, mean chloro, fluoro, bromo, and iodo.

[0058] 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).

[0059] 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 4- to 6-membered ring selected from the group consisting of imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and N-oxides thereof. More preferably, "heterocycloalkyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocycloalkyls are optionally substituted with one or more of the aforementioned groups.

[0060] As used herein, "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkyl of the heterocyclyl and / or heterocyclylalkyl can be further substituted as defined above for heterocyclyl and alkyl, respectively.

[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, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, alpha-carboline, indolizinyl, benzisothiazolyl, These include, but are not limited to, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, 7-azaindolyl, 7-azaindazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, oxazolonepyridinyl, oxazolonepyrimidinyl, imidazolonepyridinyl, imidazolonepyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, tetrahydronaphthyridinyl, tetrahydropyridolpyriminyl, dihydronaphthyridinonyl, naphthyridinonyl, oxazinanonepyridinyl, oxazinanonepyrimidinyl, carbazolyl, dibenzothienyl, acridinyl, and the like.

[0062] E as described herein 1 Regarding E 1 teeth, [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" refers to a group selected from the group consisting of -S(O)2-R 6 refers to a group, wherein R 6 represents an optionally substituted hydrocarbyl.

[0065] As used herein, ZH is an alcohol or amine where the H is directly attached to an oxygen or nitrogen in the Z moiety.

[0066] As used herein, ZB(OR)2 is a boronic acid or boronic ester, where the boronate is attached directly to a carbon within the Z moiety.

[0067] "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.

[0068] "Disease," "disorder," and "condition" are used interchangeably herein.

[0069] 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.).

[0070] As used herein, the MAPK pathway is a signal transduction pathway that includes RAS→RAF→MEK→ERK.

[0071] "MAPK pathway inhibitors" are inhibitors of the MAP kinase signaling pathway. Inhibitors of this pathway include RAS inhibitors (e.g., AMG-510, MRTX849), RAF inhibitors (e.g., dabrafenib, vemurafenib, LY3009120, encorafenib), MEK inhibitors (e.g., trametinib, binimetinib, selumetinib, cobimetinib), and ERK inhibitors (e.g., ulixertinib, SCH772984, LY3214996). The terms "MAPK pathway inhibitor" and "MAPK kinase inhibitor" are used interchangeably herein.

[0072] "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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] "Treating" includes any effect that results in an improvement of a condition, disease, disorder, etc., eg, amelioration, alleviation, modulation, or elimination.

[0079] 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.

[0080] Individual enantiomers and diastereomers of the disclosed compounds may be prepared synthetically 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.

[0081] As used herein, "compounds of the disclosure" include compounds of Formula I, Formula IA, Formula IB, Formula IC, Formula I-CA, Formula ID, Formula I-DA, Formula IE, Formula I-EA, Formula IF, Formula I-FA, Formula I-FB, Formula IG, Formula I-GA, Formula IH, Formula I-HA, Formula IJ, Formula I-JA, Formula I-JB, Formula I-JC, Formula IK, Formula I-KA, Formula IL, Formula I-LA, Formula IM, Formula I-MA, 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, Formula IT, and Formula I-TA.

[0082] compound In one embodiment, the compound represented by formula I: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 1 and X 4 are each independently 5 or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X 3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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, and 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 2 and X 4 But both are N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, E 7is morpholinyl, and X 1 and X 4 But both are N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, E 7 is morpholinyl, and X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 If L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5- or 6-membered heteroaryl, or amido; X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, E 7 is morpholinyl, and X 1 is CH and X 2 is N and X 3 But, COL 3 -E 3and X 4 is CH and X 6 is CH, CD, or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, and E 7 is morpholinyl, and X 1 is CH and X 2 But, COL 2 -E 2 and X 3 is N and X 4 is CH and X 6 is CH, CD, or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, E 7 is morpholinyl, and X 1 is CH and X 2 is N and X 3 But, COL 3 -E 3 and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; E 7 is morpholinyl, and X 1 is CH and X 2 But, COL 2 -E 2and X 3 is N and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4)-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 , (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 ,and (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond, and E 3is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 is C=O and X 3 But NL 3 -E 3 If L 3 -E 3 is not selected from the group consisting of H, methyl, hydroxyethyl, hydroxypropyl, and 2,3-dihydroxypropyl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 is CH, CD, or CF, and X 2 is N and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0083] In some embodiments, the compound is IA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are independently CH, CR 5 , or N, X 3 COL 3 -E 3 , C.L. 3-E 3 , CN(R 4 )-L 3 -E 3 , CH, or N; X 5 and X 6 are each independently CH, CF, or N; However, X 1 , X 3 , and X 4 provided that at most one of L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, haloalkoxy, hydroxy, alkoxy, alkoxylalkyl, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 4 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, E 7 is morpholinyl, and X1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X3 is CL 3 -E 3 If L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5- or 6-membered heteroaryl, or amido; X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, E 7 is morpholinyl, and X 1 is CH and X 3 But, COL 3 -E 3 and X 4 is CH and X 6 is CH or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, E 7 is morpholinyl, and X 1is CH and X 3 But, COL 3 -E 3 and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 , (iii) N(R 4 )-L 3 -E 3is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 ,and (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 is CH, CD, or CF, and X 2 is N and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0084] In some embodiments, the compound is IB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are independently CH, CR 5 , or N, However, X 1 , and X 4 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; X 31 is O or N(R 4 ) and L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 1 is CH and X 31 is O and X 4 is CH and X 6 is CH or CF, and R 3If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; E 7 is morpholinyl, and X 1 is CH and X 31 is O and X 4 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 1 is N or CH, and X 4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and X1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0085] In some embodiments, the compound has an IC: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 )p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently H, alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 3 is haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently H, alkyl, alkoxy, alkoxyalkyl, amido, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are H, 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, alkoxycyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31two 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 4 is CH and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 ,and (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 is not selected from the group consisting of L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X4 is CH and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 is CH, CD, or CF, and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0086] In some embodiments, the compound is I-CA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted aryl, wherein the optionally substituted substituents, at each occurrence, are independently H, alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0087] In some embodiments, the compound has the ID: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 31 is O or N(R 4 ) and X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 4 is CH and X 5is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0088] In some embodiments, the compound is I-DA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 31 is O or N(R 4 ) and X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or X is selected from C1-C6 alkyl optionally substituted with 5 If N, then L 1 is R 3 , and L 1and R 3 may be taken together with the N atom to which it is attached to form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0089] In some embodiments, the compound is IE: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are independently CH, CR 5 , or N, However, X 1 , and X 4 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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 H, alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 H, alkyl, amine, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0090] In some embodiments, the compound is I-EA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, as described herein, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond, E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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 H, alkyl, alkoxy, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 alkyl, Z is L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0091] In some embodiments, the compound is IF: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are independently CH, CR 5 , or N, However, X 1 , and X 4 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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, or cyano, cyanoalkyl, 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 1 is N or CH, and X4 is N or CH, and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; 3 -E 3 is not selected from the group consisting of H, methyl, hydroxyethyl, hydroxypropyl, and 2,3-dihydroxypropyl.

[0092] In some embodiments, the compound has formula I-FA or formula I-FB: [ka] [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond, E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 alkyl, Z is L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; However, E 7 is not oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0093] In some embodiments, the compound is IG: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 or CH, X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 5 is N or CH, and X 6 is CH and E 7is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 When selected from the group consisting of X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 ,and (iii) N(R 4 )-L 3 -E 3is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 is not selected from the group consisting of L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 When selected from the group consisting of E7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl.

[0094] In some embodiments, the compound is I-GA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 is a direct bond, E 7is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0095] In some embodiments, the compound is IH: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 31 is O or N(R 4 ) and X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 H, 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino.

[0096] In some embodiments, the compound is I-HA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 31 is O or N(R 4 ) and X 5 and X6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 H, 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0097] In some embodiments, the compound is IJ: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, or N; X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) pC1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 3 is haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31two 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 L 7 -E 7 and L 7 is selected from the group consisting of a direct bond; E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl and R 5 is H and X 5 and X 6 is CH and R 1 is -CH3 and X3 is CL 3 -E 3 If L 3 -E 3 is not optionally substituted C1-C8 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted 5- or 6-membered heteroaryl, or amido; R 5 is H and X 5 and X 6 is CH and R 1 is -CH3 and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, E 7 is morpholinyl, and X 3 But, COL 3 -E 3 and R 5 is H and X 6 is CH or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, E 7 is morpholinyl, and X 3But, COL 3 -E 3 and R 5 is H and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 , (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L3 -E 3 (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 is CH, CD, or CF, and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0098] In some embodiments, the compound is I-JA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is CL 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond, E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 alkyl 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; Z is L 7 -E 7 and L 7is selected from the group consisting of a direct bond; E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0099] In some embodiments, the compound is I-JB: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) mor R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 teeth, optionally substituted heteroaryl, 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, and heterocyclyl; and optionally substituted aryl, 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, and cyano; 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 3is haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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, cyano, 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 L 7 -E 7 and L 7 is selected from the group consisting of a direct bond; E 7 is an optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0100] In some embodiments, the compound is I-JC: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 L 7 -E 7 and L 7 is selected from the group consisting of a direct bond; E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0101] In some embodiments, the compound has the formula IK: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; X 31 is O or N(R 4 ) and L 1 is a direct bond and (E11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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, or cyano, cyanoalkyl, 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, or cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl and R 5 is H and X 6 is CH, CD, or CF, and X 31 is O and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl; E 7 is morpholinyl and R 5 is H and X 31 is O and X 6 When is CH, CD, or CF, L 1 is R3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0102] In some embodiments, the compound is I-KA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; X 31 is O or N(R 4 ) and L 1 is a direct bond and (E 11 ) m or X is selected from C1-C6 alkyl optionally substituted with 5 If N, then L 1 is R 3 , and L 1 and R 3 may be taken together with the N atom to which it is attached to form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl, and wherein the moiety is covalently bonded to H or the optionally substituted substituent; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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, or cyano, cyanoalkyl, 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, or cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0103] In some embodiments, the compound is an IL: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, an 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, or cyano, cyanoalkyl, 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not a heteroaryl, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 ,and (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 is not selected from the group consisting of L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; E 7is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 is CH, CD, or CF, and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0104] In some embodiments, the compound is I-LA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is CL 3 -E 3 or CH, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 alkyl 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0105] In some embodiments, the compound is IM: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; X 31 is O or N(R 4 ) and L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 31 -L 3 -E 3 is not selected from the group consisting of methoxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, bis(2-hydroxyethyl)amino, and (2-hydroxyethyl)amino; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0106] In some embodiments, the compound is I-MA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; X 31 is O or N(R 4 ) and L 1 is a direct bond and (E 11 ) m or X is selected from C1-C6 alkyl optionally substituted with 5 If N, then L 1 is R 3 , and L 1 and R 3 may be taken together with the N atom to which it is attached to form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0107] In some embodiments, the compound is IN: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 or CH, X 5 and X 6are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 2 teeth, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 ,and (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 provided that the amine is not selected from the group consisting of:

[0108] In some embodiments, the compound is I-NA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0109] In some embodiments, the compound is IO: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , CH, or N; X 3 , CH, COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , or N, However, X 2 , and X 3 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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, or cyano, cyanoalkyl, 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, cyano, 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 L 7 -E 7 and L7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3is not a heteroaryl, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: X 3 teeth, (i)L 3 -E 3is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 , (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 ,and (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond, and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl.

[0110] In some embodiments, the compound is I-OA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , CH, or N; X 3 , CH, COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , or N, However, X 2 , and X 3 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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, or cyano, cyanoalkyl, 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, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0111] In some embodiments, the compound is IP: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , CH, or N; X 3 , CH, COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , or N, However, X 2 , and X 3 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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, or 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, or cyano; E 31 is independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 , (iii) N(R 4 )-L3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 ,and (iv) N, L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond, and E 3 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4)-L 2 -E 2 ,and (iv) N, when selected from the group consisting of: E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 is CH, CD, or CF, and X 2 is N and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0112] In some embodiments, the compound is I-PA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0113] In some embodiments, the compound has an IQ: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 are each independently 5 or N, X 2 COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , CH, or N; However, X 1 , and X 2 provided that at most one of X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 11two 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 L 7 -E 7 and L 7 , direct binding; E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is morpholinyl, and X 1 is CH and X 2 But, COL 2 -E 2 and R 5 is H and X 6 is CH, CD or CF, and R 3 If H, then L 1 -E 1 is not optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl, E 7 is morpholinyl, and X 1 is CH and X 2But, COL 2 -E 2 and R 5 is H and X 6 When is CH, CD, or CF, L 1 is R 3 , and L 1 and R 3 does not, together with the N atom to which it is attached, form an optionally substituted heterocycle having 4 to 8 atoms in the ring structure; L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and X 1 is N or CH, and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, X 2 teeth, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 , (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino;4 )-L 2 -E 2 ,and (iv) N, provided that:

[0114] In some embodiments, the compound is I-QA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 are each independently 5 or N, X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 , direct binding, E 7is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0115] In some embodiments, the compound has an IR: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 , CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 and X 3 , CH, COL 3 -E 3 , C.L. 3 -E 3 , or CN(R 4 )-L 3 -E 3 and X 5 and X 6are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amido, haloalkyl, cyano, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, 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; 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, or 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, cyano, 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 L 7 -E 7 and L 7 , direct binding, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, L 1 -E 1 but, [ka] and R 1 is methyl and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and E 7 is a substituent selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 ,and (iii) N(R 4 )-L 2 -E 2is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 When selected from the group consisting of X 3 teeth, (i)L 3 -E 3 is selected from the group consisting of H, methyl, 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; 3 -E 3 , (ii)OL 3 -E 3 is selected from the group consisting of methoxy, 2-hydroxyethoxy, and 2,3-dihydroxypropoxy; 3 -E 3 ,and (iii) N(R 4 )-L 3 -E 3 is selected from the group consisting of bis(2-hydroxyethyl)amino and (2-hydroxyethyl)amino, CN(R 4 )-L 3 -E 3 is not selected from the group consisting of L 1 -E 1 but, [ka] and R 1 is methyl, and R 2 is H and R 3 is H and R 5 is H and X 5 is N or CH, and X 6 is CH and X 3 But CL 3 -E 3 and L 3 is a direct bond, and E 3is selected from the group consisting of oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; and X 2 but, (i)L 2 -E 2 is selected from H, CL 2 -E 2 , (ii)OL 2 -E 2 is selected from the group consisting of methoxy, ethoxy, isopropoxy, 2-methoxyethoxy, 2-hydroxyethoxy, (tetrahydro-2H-pyran-4-yl)oxy, and (1-ethylpiperidin-4-yl)oxy; 2 -E 2 ,and (iii) N(R 4 )-L 2 -E 2 is selected from the group consisting of (2-methoxyethyl)amino, (2-hydroxyethyl)(methyl)amino, and (1-hydroxypropan-2-yl)amino; 4 )-L 2 -E 2 When selected from the group consisting of E 7 is not selected from the group consisting of 3-hydroxyoxetan-3-yl, 4-hydroxy-piperidin-1-yl, 4-amino-4-methylpiperidin-1-yl, and 2-oxooxazolidin-3-yl; E 7 is a 5- or 6-membered optionally substituted heteroaryl or a 5- or 6-membered optionally substituted heterocyclyl, and R 5 is H or F, and X 5 is CH and X 6 is CH, CD, or CF, and X 2 is N and X 3 But, COL 3 -E 3 or CN(R 4 )-L 3 -E 3 If L 1 is R 3 , and L1 and R 3 together with the N atom to which it is attached do not form an optionally substituted heterocyclic ring having from 4 to 7 atoms in the ring structure.

[0116] In some embodiments, the compound is an I-RA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 and X 6 are each independently CH, CF, or N; L 1 is a direct bond and (E 11 ) m or R 3 , and L 1 and R 3 when taken together with the N atom to which it is attached, forms an optionally substituted heterocycle having 4 to 8 atoms in the ring structure, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 1 is hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; optionally substituted heteroaryl, 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, and heterocyclyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; 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 L 7 -E 7 and L 7 , direct binding, E 7is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen.

[0117] In some embodiments, E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; Optionally substituted heteroaryl, 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, and heterocyclyl, wherein the optionally substituted heteroaryl is [ka] Instead, in the formula, s1 is L 1 and s2 is a moiety covalently bonded to H or an optionally substituted substituent; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[0118] In some embodiments, E 1 is H, hydroxy, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkoxy, amine, alkylamine, 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 aryl, alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, heterocyclyl, and cyano; Optionally substituted heteroaryl, 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, and heterocyclyl, wherein the optionally substituted heteroaryl is [ka] Instead, in the formula, s1 is L 1 and s2 is a moiety covalently bonded to H or an optionally substituted substituent; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, 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, amido, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[0119] In some embodiments, the compound is IS: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are each independently 5 , or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X 3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1a and E 1b each independently represents H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of 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; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; or or E1a and E 1b taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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; or E 1a and E 1b are attached to the same carbon atom, E 1a and E 1b together with the carbon atom to which they are attached to form oxo, E 2 is H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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, and 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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; W is CH2, O, or NR 10 is selected from the group consisting of Z is L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 10 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; each occurrence of q is independently 1, 2, or 3; however, E 7 is not morpholinyl, X 1 , X 4 , X5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, and X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 When E is CH, CD, or CF, 7 is not an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl.

[0120] In some embodiments, the compound is I-SA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are each independently 5 , or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X 3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 )p C1-C6 alkyl optionally substituted with E 1a and E 1b each independently represents H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of 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; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; or or E 1a and E 1b taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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; or E 1a and E 1b are attached to the same carbon atom, E 1a and E 1b together with the carbon atom to which they are attached to form oxo, E 2is H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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, and 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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; W is CH2, O, or NR 10 is selected from the group consisting of Z is L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; R 10 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; each occurrence of q is independently 1, 2, or 3; however, X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 When E is CH, CD, or CF, 7 is not an optionally substituted 5- or 6-membered heteroaryl.

[0121] In some embodiments, the compound is IT: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are each independently 5 , or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X 3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1a and E 1b each independently represents H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of 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; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; or or E 1a and E 1b taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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; or E 1a and E 1bare attached to the same carbon atom, E 1a and E 1b together with the carbon atom to which they are attached to form oxo, E 2 is H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, 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 L 7 -E 7 and L 7 is a direct bond, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, E 7 is not morpholinyl, X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond and E 3 is morpholinyl, E 7 is not an optionally substituted C3-C6 heterocyclyl or an optionally substituted 5- or 6-membered heteroaryl, X 1 and X 4 are each independently N, CH, or CF, and X5 is CH and X 6 When E is CH, CD, or CF, 7 is not an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 5- or 6-membered heterocyclyl.

[0122] In some embodiments, the compound is I-TA: [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 1 and X 4 are each independently 5 , or N, X 5 and X 6 are each independently CH, CF, or N; X 2 are N, CH, C=O, COL 2 -E 2 , C.L. 2 -E 2 , CN(R 4 )-L 2 -E 2 , or NL 2 -E 2 and X 3 COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , CH, C═O, N, or NL 3 -E 3 and However, X 1 , X 2 , X 3 , and X 4 provided that no more than two of However, X 2 If N, then X 3COL 3 -E 3 , C.L. 3 -E 3 , CN(R 4 )-L 3 -E 3 , N, or CH; However, X 3 If N, then X 2 are N, CH, COL 2 -E 2 , C.L. 2 -E 2 , or CN(R 4 )-L 2 -E 2 provided that: However, X 2 If C=O, then X 3 NL 3 -E 3 provided that: However, X 3 If C=O, then X 2 NL 2 -E 2 provided that: L 2 is a direct bond or (E 21 ) p C1-C6 alkyl optionally substituted with L 3 is a direct bond or (E 31 ) p C1-C6 alkyl optionally substituted with E 1a and E 1b each independently represents H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of 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; and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; or or E 1a and E 1b taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl ring or an optionally substituted heterocyclyl ring having 3 to 6 atoms in the ring structure, 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; or E 1a and E 1b are attached to the same carbon atom, E 1a and E 1b together with the carbon atom to which they are attached to form oxo, E 2 is H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, sulfone, hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are 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, 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 independently selected at each occurrence from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or E 31two 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 L 7 -E 7 and L 7 is a direct bond, E 7 is an optionally substituted heteroaryl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, amidine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; each occurrence of m is independently 0, 1, 2, 3, or 4; each occurrence of p is independently 0, 1, or 2; R 1 is selected from the group consisting of H, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 is selected from the group consisting of H, C1-C5 alkyl, and C3-C5 cycloalkyl; R 4 is independently in each occurrence H or alkyl; R 5 is, at each occurrence, independently selected from the group consisting of H, alkyl, and halogen; however, X 1 , X 4 , X 5 , and X 6 is CH and R 1 is -CH3 and X 2 is N and X 3 But CL 3 -E 3 and L 3 is a direct bond, E 3 is not morpholinyl, X 1 and X 4 are each independently N, CH, or CF, and X 5 is CH and X 6 When is CH, CD, or CF, E 7 is not an optionally substituted 5- or 6-membered heteroaryl.

[0123] In some embodiments, E 1a is selected from the group consisting of H and OMe, and in some embodiments, E 1a H,OMe, [ka] In some embodiments, E 1b is selected from the group consisting of H and OMe. In some embodiments, H, OMe, [ka] In some embodiments, W is selected from the group consisting of: In some embodiments, W is CH2 or O. In some embodiments, W is CH2.

[0124] In some embodiments, E 1 are H, Me, CF3, CH2CF3, OMe, OEt, OCF3, F, CN, [ka] is selected from the group consisting of:

[0125] In some embodiments, E 1 is selected from the group consisting of H, Me, CF3, CH2CF3, OMe, OEt, OCF3, F, and CN.

[0126] In some embodiments, E 1 is selected from the group consisting of: [ka]

[0127] In some embodiments, E 1 is selected from the group consisting of: [ka]

[0128] In some embodiments, E 11 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, cyano, C1-C6 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, and halogen; or E 11 The two occurrences of, taken together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring. 11 is, at each occurrence, independently selected from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetanyl, OCF3, F, and CN, or E 11 The two occurrences of together with the carbon atoms to which they are attached form a cyclopropyl ring.

[0129] In some embodiments, L 1 is a direct bond, [ka] is selected from the group consisting of:

[0130] In some embodiments, L 1 is a direct bond. In some embodiments, L 1 is (E 11 )m is C1-C6 alkyl optionally substituted with m. In some embodiments, L 1 is R 3 , and L 1 and R 3 together with the N atom to which it is attached to form a heterocycle having 4 to 8 atoms in the ring structure.

[0131] In some embodiments, [ka] is selected from the group consisting of: [ka]

[0132] In some embodiments, [ka] is selected from the group consisting of: [ka]

[0133] In some embodiments, [ka] is selected from the group consisting of: [ka]

[0134] In some embodiments, L 1 is a direct bond, [ka] is selected from the group consisting of: [ka]

[0135] In some embodiments, L 1 is a direct bond, [ka] is selected from the group consisting of: [ka]

[0136] In some embodiments, L 1 is a direct bond, [ka] is selected from the group consisting of: [ka]

[0137] In some embodiments, L 1 and R 3 together with the N atom to which they are attached form a heterocyclic ring having 4 to 8 atoms in the ring structure, the ring structure being selected from the group consisting of: [ka]

[0138] In some embodiments, the ring structure is selected from the group consisting of: [ka] In the formula, the carbon substituent site is E 1 is bonded to.

[0139] In some embodiments, the ring structure is selected from the group consisting of: [ka]

[0140] In some embodiments, the ring structure is selected from the group consisting of: [ka]

[0141] In some embodiments, E 2is selected from the group consisting of hydroxy, C-C alkoxy, C-C alkoxylalkyl, cyano, sulfonyl, H, C-C alkyl, amine, C-C haloalkoxy, C-C haloalkyl, sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C-C alkyl, C-C alkoxy, amido, amine, C-C acyl, C-C haloalkyl, C-C haloalkoxy, halogen, hydroxy, C-C hydroxyal, oxo, cyano, and C-C cyanoalkyl.

[0142] In some embodiments, E 2 are H, Me, NMe2, OH, OMe, CN, SO2Me, and [ka] is selected from the group consisting of:

[0143] In some embodiments, E 2 is selected from the group consisting of H, Me, NMe2, OH, OMe, CN, and SO2Me.

[0144] In some embodiments, E 2 teeth, [ka] is.

[0145] In some embodiments, L 2 is a direct bond, [ka] and one of the binding sites is selected from the group consisting of E 2 is combined with

[0146] In some embodiments, L 2 -E 2 is selected from the group consisting of: [ka]

[0147] In some embodiments, L 2 -E 2 is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[0148] In some embodiments, L 2 -E 2 is selected from the group consisting of: [ka]

[0149] In some embodiments, L 2 -E 2 teeth, [ka] is.

[0150] In some embodiments, L 2 -E 2 is H, alkyl, or cycloalkyl.

[0151] In some embodiments, E 3is hydroxy, C1-C6 alkoxy, C1-C6 alkoxylalkyl, cyano, sulfonyl, C1-C6 haloalkoxy, H, C1-C6 alkyl, C1-C6 acyl, amine, C1-C6 aminoalkyl, amido, C1-C6 haloalkyl; optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, amido, amine, C1-C6 aminoalkyl, C1-C6 acyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, hydroxy, C1-C6 hydroxyalkyl, oxo, cyano, C1-C6 cyanoalkyl, and sulfone; optionally substituted heteroa optionally substituted heteroaryl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of C-C alkyl, C-C alkoxy, amido, amine, C-C acyl, C-C alkoxyalkyl, C-C haloalkyl, C-C haloalkoxy, halogen, hydroxy, C-C 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 C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, halogen, hydroxy, C-C hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl.

[0152] In some embodiments, E 3 is H, Me, N(R 6 )2, C(=O)Me, SO2Me, OR 6 , C.N., [ka] wherein R 6 is, in each occurrence, independently H, C1-C6 alkyl, C3-C5 cycloalkyl, or C1-C6 acyl, and one of the attachment sites is E3 is bonded to.

[0153] In some embodiments, E 3 are H, Me, NMe2, C(=O)Me, SO2Me, OH, CN, [ka] is selected from the group consisting of:

[0154] In some embodiments, E 3 are H, Me, NMe2, C(=O)Me, SO2Me, OH, CN, [ka] is selected from the group consisting of:

[0155] In some embodiments, E 3 is H, Me, N(R 6 )2, C(=O)Me, SO2Me, OR 6 and CN.

[0156] In some embodiments, E 3 is selected from the group consisting of: [ka]

[0157] In some embodiments, E 3 is selected from the group consisting of: [ka]

[0158] In some embodiments, E 3 is selected from the group consisting of: [ka]

[0159] In some embodiments, E31 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, C1-C6 alkoxy, oxetanyl, C1-C6 alkoxylalkyl, cyano, C1-C6 cyanoalkyl, C1-C6 haloalkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, and halogen; or E 31 The two occurrences of, taken together with the carbon atoms to which they are attached, form a C3-C6 cycloalkyl ring. 31 is, at each occurrence, independently selected from the group consisting of H, Me, CF3, OH, OMe, OEt, oxetanyl, OCF3, CH2OH, F, and CN, or E 31 The two occurrences of together with the carbon atoms to which they are attached form a cyclopropyl ring.

[0160] In some embodiments, L 3 is a direct bond, [ka] is selected from the group consisting of:

[0161] In some embodiments, L 3 is a direct bond, [ka] is selected from the group consisting of:

[0162] In some embodiments, L 3 (E 3 )(E 31 ) p is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[0163] In some embodiments, L 3 (E 3 )(E 31 ) p is selected from the group consisting of: [ka]

[0164] In some embodiments, L 3 (E 3 )(E 31 ) p is selected from the group consisting of: [ka]

[0165] In some embodiments, L 3 (E 3 )(E 31 ) p is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[0166] In some embodiments, L 3 (E 3 )(E 31 ) p is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[0167] In some embodiments, E 7 teeth, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heteroaryl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amido, urea, amine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[0168] In some embodiments, E 7 H, optionally substituted heterocyclyl, wherein the optionally substituted substituents, at each occurrence, are independently selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkoxyalkyl, amine, acyl, carbamoyl, formyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and Optionally substituted heteroaryl, wherein the optionally substituted substituents at each occurrence are independently selected from the group consisting of alkyl, alkoxy, amido, carbamoyl, urea, amine, acyl, carbamoyl, formyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano.

[0169] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl; and s1 is X 1 -X 4 indicates the site of attachment to the ring, and if s1 is present, [ka] indicates the site of an optional substituent, or if s1 is absent, [ka] indicates the site of attachment to the ring.

[0170] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl, and when there is more than one binding site, one of the binding sites is attached to the ring and the other of the binding sites is attached to an optional substituent.

[0171] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C-C alkyl, C-C cycloalkyl, and C-C acyl; R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino; R 9 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[0172] In some embodiments, E 7is selected from the group consisting of: [ka] In the formula, R 6 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, C3-C5 cycloalkyl, and C1-C6 acyl.

[0173] In some embodiments, E 7 is selected from the group consisting of: [ka]

[0174] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino; R 9 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[0175] In some embodiments, E 7 is selected from the group consisting of: [ka]

[0176] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0177] In some embodiments, E 7is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0178] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 9 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[0179] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0180] In some embodiments, E 7 is selected from the group consisting of: [ka]

[0181] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0182] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0183] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 9 is, at each occurrence, independently selected from the group consisting of H, C1-C6 alkyl, and C3-C5 cycloalkyl.

[0184] In some embodiments, E 7 is selected from the group consisting of: [ka]

[0185] In some embodiments, E 7 is selected from the group consisting of: [ka] In the formula, R 8 is selected from the group consisting of H, OH, alkoxy, cyano, F, and amino.

[0186] In some embodiments, E 7 is selected from the group consisting of: [ka]

[0187] In some embodiments, X 5 is N and X 6 is CH or CF. In some embodiments, X 5 is CH or CF, and X 6 is N. In some embodiments, X 5 and X6 is CH. In some embodiments, X 5 is N and X 6 is CH. In some embodiments, X 5 is N and X 6 is CF. In some embodiments, X 5 is CH and X 6 is N. In some embodiments, X 5 is CF and X 6 is N. In some embodiments, X 5 and X 6 is CH or CF. In some embodiments, X 5 is CH and X 6 is CH. In some embodiments, X 5 is CH and X 6 is CF. In some embodiments, X 5 is CF and X 6 is CH. In some embodiments, X 5 is CF and X 6 is CF.

[0188] In some embodiments, R 1 is selected from the group consisting of H, alkyl, haloalkyl, haloalkoxy, cyano, and halogen. 1 is selected from the group consisting of H, C1-C6 alkyl, CN, and halogen. 1 is selected from the group consisting of H, Me, Et, F, Br, and Cl. 1 is selected from the group consisting of Me and F.

[0189] In some embodiments, R 2 is H or F. In some embodiments, R 2 is H. In some embodiments, R 2 is F.

[0190] In some embodiments, R 3 is H or Me. In some embodiments, R 3is H.

[0191] In some embodiments, R 4 is H or C1-C6 alkyl. In some embodiments, R 4 is H or Me.

[0192] In some embodiments, R 5 is selected from the group consisting of H, C1-C6 alkyl, and halogen. 5 is selected from the group consisting of H, Me, Et, F, and Cl. 5 is H.

[0193] In some embodiments, described herein is a compound selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

[0194] Treatment method The compounds described herein can function as RAF inhibitors, e.g., BRAF or CRAF inhibitors, and are therefore useful for treating diseases and disorders such as cancer in patients in need of such treatment. Exemplary cancers include, but are not limited to, melanoma, multiple myeloma, thyroid cancer, ovarian cancer, colorectal cancer, colon cancer, pancreatic cancer, lung cancer, bladder cancer, gastrointestinal stromal tumor, solid tumor, 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 some embodiments, the cancer described herein is a BRAF V600X-driven cancer, an atypical BRAF-mutated cancer, a BRAF fusion cancer, a CRAF fusion cancer, or a RAS mutant cancer. In some embodiments, the cancer has a BRAF oncogenic mutation. In some embodiments, the cancer has a RAS oncogenic mutation. In some embodiments, the RAS oncogenic mutation is a RAS Q61R or Q61K mutation. In some embodiments, the cancer has an NF1 oncogenic mutation. In some embodiments, the lung cancer is non-small cell lung cancer (NSCL). In some embodiments, the colorectal cancer is colon cancer. In some embodiments, the colorectal cancer is rectal cancer.

[0195] The compounds provided herein can be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be understood that the dosage required for any particular application will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the age and condition of the patient, any concomitant medications or special diets the patient may be following, and other factors that will be recognized by those skilled in the art, and that the appropriate dosage will ultimately be at the discretion of the attending physician. To treat the above-mentioned clinical conditions and diseases, the compounds provided herein can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration can include subcutaneous injection, intravenous or intramuscular injection, or infusion techniques.

[0196] Treatment can be continued for as long or as short a period as desired. The composition may be administered, for example, one to four times daily or more. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinitely. The treatment period can be terminated when the desired results are achieved.

[0197] Combination therapy The compounds described herein, e.g., compounds of the present disclosure described herein, can be administered in combination with one or more additional therapeutic agents to treat the disorders described herein, such as the cancers described herein. For example, the present disclosure provides pharmaceutical compositions comprising a compound described herein, e.g., a compound of the present disclosure described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of the present disclosure described herein and one additional therapeutic agent are administered. In some embodiments, a compound of the present disclosure described herein and two additional therapeutic agents are administered. In some embodiments, a compound of the present disclosure described herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of the present disclosure described herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, e.g., a pharmaceutical composition comprising a compound of the present disclosure described herein as one therapeutic agent and one or more additional therapeutic agents, such as a MAPK pathway inhibitor or a chemotherapeutic agent. For example, the compounds of the present disclosure described herein and the additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. Two or more agents in combination therapy can be administered simultaneously, but they do not have to be administered simultaneously. For example, the administration of a first agent (or combination of agents) can precede the administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, two or more agents can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessary, for two or more agents used in combination therapy to be present in the patient's body at the same time.

[0198] Combination therapy can also include more than one administration of one or more of the combined agents, using a different sequence of the component agents. For example, when agent X and agent Y are used in combination, they can be administered one or more times sequentially in any combination, e.g., in the sequence XYX, XXY, YXY, YYX, XXYY, etc.

[0199] In some embodiments, the compounds described herein are combined with other agents, including MAPK pathway inhibitors. In some embodiments, the other agents are RAS inhibitors. In some embodiments, the other agents are KRAS G12C inhibitors. In some embodiments, the other agents are MEK inhibitors. In some embodiments, the other agents are ERK inhibitors.

[0200] In some embodiments, a compound described herein is combined with an immunomodulatory agent. In some embodiments, the immunomodulatory agent enhances adaptive immune responses. In some embodiments, the immunomodulatory agent enhances the activity of antigen-presenting cells. In some embodiments, the immunomodulatory agent enhances the anti-tumor activity of myeloid cells, including macrophages. In some embodiments, the immunomodulatory agent enhances the anti-tumor activity of natural killer cells. In some embodiments, the immunomodulatory agent enhances the activity of effector T cells, including cytotoxic T cells.

[0201] In some embodiments, one or more additional therapeutic agents that may be administered in combination with the compounds provided herein may be MAPK pathway inhibitors, including, for example, MEK inhibitors, ERK inhibitors, and Ras inhibitors.

[0202] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, mirdametinib, and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to, ulixertinib, SCH772984, LY3214996, ravoxertinib, VX-11e, ASN-007, GDC-0994, MK-8353, ASTX-029, LTT462, KO-947, and pharmaceutically acceptable salts thereof. Exemplary Ras inhibitors include, but are not limited to, AMG-510, MRTX849, ARS-1620, ARS-3248, LY3499446, and pharmaceutically acceptable salts thereof.

[0203] In some embodiments, the additional therapeutic agent may be an immunomodulatory agent, including an anti-PD-1 or anti-PDL-1 therapeutic, including, but not limited to, pembrolizumab, nivolumab, pidilizumab, cemiplimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some embodiments, the additional therapeutic agent may be an anti-TIM3 (anti-HAVcr2) therapeutic agent, including but not limited to TSR-022 or MBG453, an anti-LAG3 therapeutic agent, including but not limited to leratolimab, LAG525, or TSR-033, an anti-4-1BB (anti-CD37, anti-TNFRSF9) therapeutic agent, a CD40 agonist therapeutic agent, including but not limited to SGN-40, CP-870,893, or RO7009789, an anti-CD47 therapeutic agent, including but not limited to Hu5F9-G4, an anti-CD20 therapeutic agent, an anti-CD38 therapeutic agent, a STING agonist, including but not limited to ADU-S100, MK-1454, ASA404, or an amidobenzimidazole. In some embodiments, the additional therapeutic agent may be an anti-CTLA4 agent, including ipilimumab or tremelimumab. In some embodiments, the additional therapeutic agent may be a hypomethylating agent, including but not limited to azacitidine or decitabine, epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, other immunomodulatory therapies, including but not limited to thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agent may be an immunotherapeutic agent, including targeted therapeutic agents, cancer vaccines, and CAR-T cell therapies.

[0204] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancer. Such other therapeutic agents include radiation therapy, antitubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intercalators, antiestrogens, antiandrogens, steroids, anti-EGFR drugs, kinase inhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependent kinase inhibitors, CD4 / CD6 kinase inhibitors, topoisomerase inhibitors, histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, antiangiogenic agents, proteasome inhibitors, PARP (poly ADP-ribose polymerase) inhibitors, cell cycle-regulating kinase inhibitors, thalidomide, lenalidomide, and antibody-drug conjugates (ADCs).

[0205] In one embodiment, the additional therapeutic agent is an antitubulin agent (e.g., paclitaxel, paclitaxel protein-bound particles for injectable suspension including but not limited to nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatin, or a maytansinoid), vinorelbine, a DNA alkylating agent (e.g., cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide, The therapeutic agent may be a chemotherapeutic agent, including but not limited to, a DNA intercalating agent or a DNA topoisomerase inhibitor (e.g., an anthracycline such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin; a camptothecin such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine, and methotrexate.

[0206] In some embodiments, the additional therapeutic agent can be a kinase inhibitor, including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, ripretinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, da...

Claims

1. Compounds represented by formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt, or stereoisomer thereof, During the ceremony, X １ and X ４ are each independently CR ５ or N, X ５ is CH or N, X ６ is CH, X ２ is N, CH, or NL ２ -E ２ and X ３ is C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ , CH, C═O, N, or N-L ３ -E ３ and However, X １ , X ２ , X ３ , and X ４ provided that no more than two of However, X ２ If N, then X ３ But, C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ , N, or CH; However, X ３ If N, then X ２ is N or CH; However, X ２ When C=O, X ３ But N-L ３ -E ３ provided that: However, X ３ When C=O, X ２ But N-L ２ -E ２ provided that: -L １ -E １ is selected from the group consisting of: 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 Or, R ３ , and L １ and R ３ together with the N atom to which it is attached to form an optionally substituted heterocycle selected from the group consisting of: 【Transformation 5】 L ２ is a direct bond, 【Transformation 6】 is selected from the group consisting of L ３ is a direct bond, 【Transformation 7】 is selected from the group consisting of E ２ is H, Me, N(CH ３ ) ２ , OH, OCH ３ , C.N., S.O. ２ CH ３ , and 【Transformation 8】 is selected from the group consisting of E ３ は、H、Me、NMe ２ 、C(=O)Me、SO ２ Me, OH, CN, 【Chemistry 9】 is selected from the group consisting of Z is L ７ -E ７ and L ７ is a direct bond, E ７ is selected from the group consisting of: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 R １ is H, C １ -C ６ selected from the group consisting of alkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is H, R ４ is H, R ５ is H, A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1 represented by formula IA: 【Chemistry 13】 or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound of claim 1 represented by formula I-B: 【Chemistry 14】 In the formula, X ３１ is O or N(R ４ ) A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound of claim 1 represented by formula I-CA: 【Chemistry 15】 or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound of claim 1 represented by formula I-DA: 【Chemistry 16】 In the formula, X ３１ is O or N(R ４ ) and E ７ is selected from the group consisting of: 【Chemistry 17】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The compound of claim 1 represented by formula I-EA: [Chemistry 18] In the formula, E ７ is selected from the group consisting of: 【Chemistry 19】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

7. The compound of claim 1 represented by formula I-FA or I-FB: 【Chemistry 20】 【Chemistry 21】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 22】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound of claim 1 represented by formula I-GA: 【Chemistry 23】 or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The compound of claim 1 represented by formula I-HA: 【Chemistry 24】 or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The compound of claim 1 represented by formula I-JA: 【Chemistry 25】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X ３ is C-L ３ -E ３ or CH, L ３ is a direct bond, E ３ is CH ３ and 【Chemistry 26】 is selected from the group consisting of E ７ is selected from the group consisting of: 【Chemistry 27】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

11. The compound of claim 1 represented by formula I-JB: 【Chemistry 28】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X ３ is C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ or CH, -L １ -E １ is selected from the group consisting of: 【Chemistry 29】 E ７ is selected from the group consisting of: 【Transformation 30】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

12. The compound of claim 1 represented by formula I-JC: 【Chemistry 31】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 32】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

13. The compound of claim 1 represented by formula I-KA: 【Transformation 33】 During the ceremony, X ３１ is O or N(R ４ ) and E ７ is selected from the group consisting of: 【Transformation 34】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The compound of claim 1 represented by formula I-LA: 【Chemistry 35】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X ３ is C-L ３ -E ３ or CH, E ３ is CH ３ and selected from the group consisting of: 【Transformation 36】 E ７ is selected from the group consisting of: 【Chemistry 37】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The compound of claim 1 represented by formula I-MA: 【Transformation 38】 During the ceremony, X ３１ is O or N(R ４ ) and E ７ is selected from the group consisting of: 【Chemistry 39】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The compound of claim 1 represented by formula I-NA: 【Chemistry 40】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 41】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The compound of claim 1 represented by formula I-OA: 【Chemistry 42】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X ２ is CH or N, X ３ is CH, C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ , or N, E ７ is selected from the group consisting of: 【Chemistry 43】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound of claim 1 represented by formula I-PA: 【Chemistry 44】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 45】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

19. The compound of claim 1 represented by formula I-QA: 【Chemistry 46】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 47】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

20. The compound of claim 1 represented by formula I-RA: 【Chemistry 48】 In the formula, E ７ is selected from the group consisting of: 【Chemistry 49】 A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

21. The compound of claim 1 represented by formula I-SA: [Transformation 50] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X １ and X ４ are each independently CR ５ or N, X ５ is CH or N, X ６ is CH, X ２ is N, CH, or NL ２ -E ２ and X ３ is C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ , CH, C═O, N, or N-L ３ -E ３ and However, X １ , X ２ , X ３ , and X ４ provided that no more than two of However, X ２ If N, then X ３ But, C-O-L ３ -E ３ , C.-L. ３ -E ３ , C-N(R ４ )-L ３ -E ３ , N, or CH; However, X ３ If N, then X ２ is N or CH; However, X ２ When C=O, X ３ But N-L ３ -E ３ provided that: However, X ３ When C=O, X ２ But N-L ２ -E ２ provided that: L ２ is a bond, 【Chemistry 51】 is selected from the group consisting of L ３ is a bond, 【Chemistry 52】 is selected from the group consisting of E １ａ and E １ａ each independently represents H, OMe, 【Chemistry 53】 is selected from the group consisting of E ２ is H, Me, N(CH ３ ) ２ , OH, OCH ３ , C.N., S.O. ２ CH ３ , and 【Chemistry 54】 is selected from the group consisting of E ３ は、H、Me、NMe ２ 、C(=O)Me、SO ２ Me, OH, CN, 【Transformation 55】 is selected from the group consisting of W is CH ２ , O, or N-R １０ is selected from the group consisting of Z is L ７ -E ７ and L ７ is a direct bond, E ７ is selected from the group consisting of: 【Transformation 56】 R １ is H, C １ -C ６ selected from the group consisting of alkyl, cyano, and halogen; R ２ is selected from the group consisting of H and F; R ３ is H, R ４ is H, R ５ is H, R １０ In each occurrence, H and C １ -C ６ independently selected from the group consisting of alkyl, each occurrence of q is independently 1, 2, or 3; A compound or a pharmaceutically acceptable salt or stereoisomer thereof.

22. The compound of claim 21 represented by formula I-TA: 【Chemistry 57】 or a pharmaceutically acceptable salt or stereoisomer thereof.

23. W is CH ２ or O, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. -L １ -E １ but, a) selected from the group consisting of: 【Chemistry 58】 b) selected from the group consisting of: 【Chemistry 59】 c) selected from the group consisting of: 【Transformation 60】 d) selected from the group consisting of: 【Chemistry 61】 or e) selected from the group consisting of: 【Transformation 62】 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

25. E ７ but, a) selected from the group consisting of: 【Transformation 63】 b) selected from the group consisting of: 【Chemistry 64】 or c) selected from the group consisting of: 【Transformation 65】 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

26. a) X ５ is N; or b) X ５ is CH, 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

27. R １ but, a) selected from the group consisting of H, Me, Et, F, Br, and Cl; or b) selected from the group consisting of Me and F; 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

28. R ２ but, a) H; or b) is F; 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

29. The group consisting of: 【Chemistry 66-1】 【Chemistry 66-2】 【Chemistry 66-3】 【Chemistry 66-4】 【Chemistry 66-5】 【Transformation 66-6】 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof.

30. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt or stereoisomer thereof, or a compound according to claim 29 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

31. 31. The pharmaceutical composition of claim 30 for treating cancer in a patient in need thereof.

32. 32. The pharmaceutical composition of claim 31, 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.

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

34. 31. The pharmaceutical composition of claim 30 for treating a disorder 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 in a patient in need of such treatment.

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